Pathogenesis and treatment options of cancer related anemia: Perspective for a targeted mechanism-based approach

Frontiers in Physiology

Volumn 9, Issue SEP, 2018, Pages

  Madeddu, Clelia ^a   Gramignano, Giulia ^b   Astara, Giorgio ^c   Demontis, Roberto ^a   Sanna, Elisabetta ^d   Atzeni, Vinicio ^d   Macciò, Antonio ^d  

^a UNIVERSITY OF CAGLIARI   (Italy)

^b NS Bonaria Hospital   (Italy)

^c DEPARTMENT OF RADIOLOGY   (Italy)

^d BROTZU HOSPITAL   (Italy)

Author keywords

Cancer related anemia; Erythropoiesis; Erythropoiesis stimulating agents; Hepcidin; Inflammation; Interleukin 6; Iron; Leptin

Indexed keywords

ERYTHROPOIETIN; INTERLEUKIN 1; INTERLEUKIN 6; REACTIVE OXYGEN METABOLITE; RECOMBINANT ERYTHROPOIETIN; RECOMBINANT HUMAN ERYTHROPOIETIN BETA; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG;

ANEMIA; CANCER GROWTH; CANCER RELATED ANEMIA; CELL PROLIFERATION; CELL SURVIVAL; CYTOKINE RELEASE; DRUG HALF LIFE; ENERGY METABOLISM; ENZYME INHIBITION; ENZYME SYNTHESIS; ERYTHROCYTE; ERYTHROID PRECURSOR CELL; ERYTHROPOIESIS; HUMAN; IN VITRO STUDY; IN VIVO STUDY; IRON BALANCE; IRON HOMEOSTASIS; MALIGNANT NEOPLASM; NONHUMAN; NUTRITIONAL STATUS; OXIDATION REDUCTION STATE; PATHOGENESIS; QUALITY OF LIFE; REVIEW;

EID: 85055256069     PISSN: None     EISSN: 1664042X     Source Type: Journal    
DOI: 10.3389/fphys.2018.01294     Document Type: Review

References (209)

1. Aapro, M., Osterwalder, B., Scherhag, A., and Burger, H. U. (2009). Epoetin-beta treatment in patients with cancer chemotherapy-induced anaemia: the impact of initial haemoglobin and target haemoglobin levels on survival, tumour progression and thromboembolic events. Br. J. Cancer. 101, 1961-1971. Doi: 10.1038/sj.bjc.6605255
2. Abella, V., Scotece, M., Conde, J., Pino, J., Gonzalez-Gay, M. A., Gómez-Reino, J. J., et al. (2017). Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat. Rev. Rheumatol. 13, 100-109. Doi: 10.1038/nrrheum.2016.209
3. Adamson, J. W. (2008). The anemia of inflammation/malignancy: mechanisms and management. Hematol. Am. Soc. Hematol. Educ. Program 2008, 159-165. Doi: 10.1182/asheducation-2008.1.159
4. Alvarez-Hernandez, X., Licéaga, J., McKay, I. C., and Brock, J. H. (1989). Induction of hypoferremia and modulation of macrophage iron metabolism by tumor necrosis factor. Lab. Invest. 61, 319-322.
5. An, M. S., Yoo, J. H., Kim, K. H., Bae, K. B., Choi, C. S., Hwang, J. W., et al. (2015). T4 stage and preoperative anemia as prognostic factors for the patients with colon cancer treated with adjuvant FOLFOX chemotherapy. World J. Surg. Oncol. 13: 64. Doi: 10.1186/s12957-015-0488-7
6. Argilés, J. M., Busquets, S., Stemmler, B., and López-Soriano, F. J. (2014). Cancer cachexia: understanding the molecular basis. Nat. Rev. Cancer 14, 754-762. Doi: 10.1038/nrc3829
7. Auerbach, M., Ballard, H., Trout, R. J., McIlwain, M., Ackerman, A., Bahrain, H., et al. (2004). Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J. Clin. Oncol. 22, 1301-1307. Doi: 10.1200/JCO.2004.08.119
8. Axelsson, J., Qureshi, A. R., Heimburger, O., Lindholm, B., Stenvinkel, P., and Barany, P. (2005). Body fat mass and serum leptin levels influence epoetin sensitivity in patients with ESRD. Am. J. Kidney Dis. 46, 628-634. Doi: 10.1053/j.ajkd.2005.06.004
9. Baribeault, D., and Auerbach, M. (2011). Iron replacement therapy in cancer-related anemia. Am. J. Health Syst. Pharm. 68(10 Suppl. 1), S4-S14. Doi: 10.2146/ajhp110039
10. Basseri, R. J., Nemeth, E., Vassilaki, M. E., Basseri, B., Enayati, P., Shaye, O., et al. (2012). Hepcidin is a key mediator of anemia of inflammation in Crohn's disease. J. Crohns Colitis 7, e286-e291. Doi: 10.1016/j.crohns.2012.10.013
11. Bastit, L., Vandebroek, A., Altintas, S., Gaede, B., Pintér, T., Suto, T. S., et al. (2008). Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J. Clin. Oncol. 26, 1611-1618. Doi: 10.1200/JCO.2006.10.4620
12. Bayliss, T. J., Smith, J. T., Schuster, M., Dragnev, K. H., and Rigas, J. R. (2011). A humanized anti-IL-6 antibody (ALD518) in non-small cell lung cancer. Expert. Opin. Biol. Ther. 11, 1663-1668. Doi: 10.1517/14712598.2011.627850
13. Beguin, Y. (1998). Prediction of response to optimize outcome of treatment with erythropoietin. Semin. Oncol. 25(3 Suppl. 7), 27-34.
14. Benedik, P. S., and Hamlin, S. K. (2014). The physiologic role of erythrocytes in oxygen delivery and implications for blood storage. Crit. Care Nurs. Clin. North Am. 26, 325-335. Doi: 10.1016/j.ccell.2014.04.002
15. Bennett, C. L., Silver, S. M., Djulbegovic, B., Samaras, A. T., Blau, C. A., Gleason, K. J., et al. (2008). Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299, 914-924. Doi: 10.1001/jama.299.8.914
16. Bennett, G. D., and Kay, M. M. (1981). Homeostatic removal of senescent murine erythrocytes by splenic macrophages. Exp. Hematol. 9, 297-307.
17. Bertero, M. T., and Caligaris-Cappio, F. (1997). Anemia of chronic disorders in systemic autoimmune diseases. Haematologica 82, 375-381.
18. Bing, C., Russell, S., Becket, E., Pope, M., Tisdale, M. J., Trayhurn, P., et al. (2006). Adipose atrophy in cancer cachexia: morphologic and molecular analysis of adipose tissue in tumour-bearing mice. Br. J. Cancer 95, 1028-1037. Doi: 10.1038/sj.bjc.6603360
19. Birgegård, G., Aapro, M. S., Bokemeyer, C., Dicato, M., Drings, P., Hornedo, J., et al. (2005). Cancer-related anemia: pathogenesis, prevalence and treatment. Oncology 68(Suppl. 1), 3-11. Doi: 10.1159/000083128
20. Bistrian, B. R., and Carey, L. A. (2000). Impact of inflammation on nutrition, iron status, and erythropoietin responsiveness in ESRD patients. Nephrol. Nurs. J. 27, 616-622.
21. Blackwell, K., Gascón, P., Sigounas, G., and Jolliffe, L. (2004). RHuEPO and improved treatment outcomes: potential modes of action. Oncologist 9(Suppl. 5), 41-47. Doi: 10.1634/theoncologist.9-90005-41
22. Bogdanos, J., Karamanolakis, D., Milathianakis, K., Repousis, P., Chloraki-Bobota, A., Majed, H., et al. (2004). Epoetin beta (NeoRecormon) corrects anaemia in patients with hormone-refractory prostate cancer and bone metastases. Anticancer Res. 24, 1957-1961.
23. Bohlius, J., Schmidlin, K., Brillant, C., Schwarzer, G., Trelle, S., Seidenfeld, J., et al. (2009). Erythropoietin or Darbepoetin for patients with cancer-meta-analysis based on individual patient data. Cochrane Database Syst. Rev. 3: CD007303. Doi: 10.1002/14651858.CD007303.pub2
24. Bohlius, J., Tonia, T., Nüesch, E., Jüni, P., Fey, M. F., Egger, M., et al. (2014). Effects of erythropoiesis-stimulating agents on fatigue-and anaemia-related symptoms in cancer patients: systematic review and meta-analyses of published and unpublished data. Br. J. Cancer 111, 33-45. Doi: 10.1038/bjc.2014.171
25. Bohlius, J., Weingart, O., Trelle, S., and Engert, A. (2006). Cancer-related anemia and recombinant human erythropoietin-an updated overview. Nat. Clin. Pract. Oncol. 3, 152-164. Doi: 10.1038/ncponc0451
26. Boushel, R. (2017). Linking skeletal muscle blood flow and metabolism to the limits of human performance. Appl. Physiol. Nutr. Metab. 42, 111-115. Doi: 10.1139/apnm-2016-0393
27. Bron, D., Meuleman, N., and Mascaux, C. (2001). Biological basis of anemia. Semin. Oncol. 28(2 Suppl. 8), 1-6.
28. Brown, E., Hurlow, A., Rahamn, A., Coss, S. J., and Bennet, M. I. (2010). Assessment of fatigue after blood transfusion in palliative care patients: a feasibility study. J. Palliat. Med. 13, 1327-1330. Doi: 10.1089/jpm.2010.0143
29. Brown, W. M., Maxwell, P., Graham, A. N., Yakkundi, A., Dunlop, E. A., Shi, Z., et al. (2007). Erythropoietin receptor expression in non-small cell lung carcinoma: a question of antibody specificity. Stem Cells 25, 718-722. Doi: 10.1634/stemcells.2006-0687
30. Buck, I., Morceau, F., Grigorakaki, C., Dicato, M., and Diederich, M. (2009). Linking anemia to inflammation and cancer: the crucial role of TNFalpha. Biochem. Pharmacol. 77, 1572-1579. Doi: 10.1016/j.bcp.2008.12.018
31. Buemi, M., Cavallaro, E., Floccari, F., Sturiale, A., Aloisi, C., Trimarchi, M., et al. (2003). The pleiotropic effects of erythropoietin in the central nervous system. J. Neuropathol. Exp. Neurol. 62, 228-236. Doi: 10.1093/jnen/62.3.228
32. Bukowska, B., Sicinska, P., Paja?k, A., Koceva-Chyla, A., Pietras, T., Pszczólkowska, A., et al. (2015). Oxidative stress and damage to erythrocytes in patients with chronic obstructive pulmonary disease-changes in ATPase and acetylcholinesterase activity. Biochem. Cell. Biol. 93, 574-580. Doi: 10.1139/bcb-2015-0066
33. Burke, S. J., Stadler, K., Lu, D., Gleason, E., Han, A., Donohoe, D. R., et al. (2015). IL-1β reciprocally regulates chemokine and insulin secretion in pancreatic β-cells via NF-?B. Am. J. Physiol. Endocrinol. Metab. 309, E715-E726. Doi: 10.1152/ajpendo.00153.2015
34. Camaschella, C. (2008). Recent advances in the understanding of inherited sideroblastic anaemia. Br. J. Haematol. 143, 27-38. Doi: 10.1111/j.1365-2141.2008.07290.x
35. Camaschella, C., Pagani, A., Nai, A., and Silvestri, L. (2016). The mutual control of iron and erythropoiesis. Int. J. Lab. Hematol. 38, 20-26. Doi: 10.1111/ijlh.12505
36. Carbó, N., Costelli, P., Tessitore, L., Bagby, G. J., López-Soriano, F. J., Baccino, F. M., et al. (1994). Anti-tumour necrosis factor-alpha treatment interferes with changes in lipid metabolism in a tumour cachexia model. Clin. Sci. 87, 349-355.
37. Caro, J. J., Salas, M., Ward, A., and Goss, G. (2001). Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer 91, 2214-2221. Doi: 10.1002/1097-0142(20010615)91: 123.0.CO; 2-P
38. Carson, J. L., Guyatt, G., Heddle, N. M., Grossman, B. J., Cohn, C. S., Fung, M. K., et al. (2016). Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage. JAMA 316, 2025-2035. Doi: 10.1001/jama.2016.9185
39. Cawthorn, W. P., and Sethi, J. K. (2008). TNF-α and adipocyte biology. FEBS Lett. 582, 117-131. Doi: 10.1016/j.febslet.2007.11.051
40. Cella, D. (1998). Factors influencing quality of life in cancer patients: anemia and fatigue. Semin. Oncol. 25(3 Suppl. 7), 43-46.
41. Chamogeorgakis, T., Anagnostopoulos, C., Kostopanagiotou, G., Bhora, F., Toumpoulis, I., Georgiannakis, E., et al. (2008). Does anemia affect outcome after lobectomy or pneumonectomy in early stage lung cancer patients who have not received neo-adjuvant treatment? Thorac. Cardiovasc. Surg. 56, 148-153. Doi: 10.1055/s-2007-989455
42. Chiabrando, D., Mercurio, S., and Tolosano, E. (2014). Heme and erythropoieis: more than a structural role. Haematologica 99, 973-983. Doi: 10.3324/haematol.2013.091991
43. Christ, E. R., Cummings, M. H., Westwood, N. B., Sawyer, B. M., Pearson, T. C., Sönksen, P. H., et al. (1997). The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency. J. Clin. Endocrinol. Metab. 82, 2985-2990.
44. Chung, J., Bauer, D. E., Ghamari, A., Nizzi, C. P., Deck, K. M., Kingsley, P. D., et al. (2015). The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability. Sci. Signal. 8: ra34. Doi: 10.1126/scisignal.aaa5903
45. Cosse, J. P., and Michiels, C. (2008). Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anticancer Agents Med. Chem. 8, 790-797. Doi: 10.2174/187152008785914798
46. Coward, J., Kulbe, H., Chakravarty, P., Leader, D., Vassileva, V., Leinster, D. A., et al. (2011). Interleukin-6 as a therapeutic target in human ovarian cancer. Clin. Cancer Res. 17, 6083-6096. Doi: 10.1158/1078-0432.CCR-11-0945
47. Crawford, J., Cella, D., Cleeland, C. S., Cremieux, P. Y., Demetri, G. D., Sarokhan, B. J., et al. (2002). Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 95, 888-895. Doi: 10.1002/cncr.10763
48. Cybulska, P., Goss, C., Tew, W. P., Parameswaran, R., and Sonoda, Y. (2017). Indications for and complications of transfusion and the management of gynecologic malignancies. Gynecol. Oncol. 146, 416-426. Doi: 10.1016/j.ygyno.2017.05.010
49. Daneryd, P., Svanberg, E., Körner, U., Lindholm, E., Sandström, R., Brevinge, H., et al. (1998). Protection of metabolic and exercise capacity in unselected weight-losing cancer patients following treatment with recombinant erythropoietin: a randomized prospective study. Cancer Res. 58, 5374-5379.
50. Delano, M. J., and Moldawer, L. L. (2006). The origins of cachexia in acute and chronic inflammatory diseases. Nutr. Clin. Pract. 21, 68-81. Doi: 10.1177/011542650602100168
51. Doty, R. T., Phelps, S. R., Shadle, C., Sanchez-Bonilla, M., Keel, S. B., and Abkowitz, J. L. (2015). Coordinate expression of heme and globin is essential for effective erythropoiesis. J. Clin. Invest. 125, 4681-4691. Doi: 10.1172/JCI83054
52. Doulatov, S., Notta, F., Laurenti, E., and Dick, J. E. (2012). Hematopoiesis: a human perspective. Cell Stem Cell 10, 120-136. Doi: 10.1016/j.stem.2012.01.006
53. Dunn, A., Carter, J., and Carter, H. (2003). Anemia at the end of life: prevalence, significance and causes in patients receiving palliative care. J. Pain Symptom Manage. 26, 1132-1139. Doi: 10.1016/j.jpainsymman.2003.04.001
54. Faquin, W. C., Schneider, T. J., and Goldberg, M. A. (1992). Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood 79, 1987-1994.
55. Fearon, K., Strasser, F., Anker, S. D., Bosaeus, I., Bruera, E., Fainsinger, R. L., et al. (2011). Definition and classification of cancer cachexia: an international consensus. Lancet. Oncol. 12, 489-495. Doi: 10.1016/S1470-2045(10)70218-7
56. Finch, C. A. (1982). Erythropoiesis, erythropoietin, and iron. Blood 60, 1241-1246.
57. Fishbane, S., and Kowalski, E. A. (2000). The comparative safety of intravenous iron dextran, iron saccharate, and sodium ferric gluconate. Semin. Dial. 13, 381-384. Doi: 10.1046/j.1525-139x.2000.00104.x
58. Friesen, D. E., Baracos, V. E., and Tuszynski, J. A. (2015). Modeling the energetic cost of cancer as a result of altered energy metabolism: implications for cachexia. Theor. Biol. Med. Model. 12: 17. Doi: 10.1186/s12976-015-0015-0
59. Fuso, L., Mazzola, S., Marocco, F., Ferrero, A., Dompè, D., Carus, A. P., et al. (2005). Pretreatment serum hemoglobin level as a predictive factor of response to neoadjuvant chemotherapy in patients with locally advanced squamous cervical carcinoma: a preliminary report. Gynecol. Oncol. 99(3 Suppl. 1), S187-S191. Doi: 10.1016/j.ygyno.2005.07.079
60. Ganz, T., and Nemeth, E. (2011). Hepcidin and disorders of iron metabolism. Annu. Rev. Med. 62, 347-360. Doi: 10.1146/annurev-med-050109-142444
61. Ganz, T., and Nemeth, E. (2015). Iron homeostasis in host defence and inflammation. Nat. Rev. Immunol. 15, 500-510. Doi: 10.1038/nri3863
62. Gaspar, B. L., Sharma, P., and Das, R. (2015). Anemia in malignancies: pathogenetic and diagnostic considerations. Hematology 20, 18-25. Doi: 10.1179/1607845414Y.0000000161
63. Gautron, L., and Layé, S. (2010). Neurobiology of inflammation-associated anorexia. Front. Neurosci. 3: 59. Doi: 10.3389/neuro.23.003.2009
64. Ghezzi, P., and Mengozzi, M. (2007). Activities of erythropoietin on tumors: an immunological perspective. Eur. J. Immunol. 37, 1427-1430. Doi: 10.1002/eji.200737401
65. Gleason, C., and Spencer, D. (1995). Blood transfusion and its benefits in palliative care. Palliat. Med. 9, 307-313. Doi: 10.1177/026921639500900405
66. Goldberg, K. B., and Goldberg, P. (2008). FDA orders more changes in ESA label, agents not indicated in curative setting. Cancer Lett. 34, 1-2.
67. Goodnough, L. T. (2005). Risks of blood transfusion. Anesthesiol. Clin. North Am. 23, 241-252. Doi: 10.1016/j.atc.2004.07.004
68. Gordon, D., Nichols, G., Ben-Jacob, A., Tomita, D., Lillie, T., and Miller, C. (2008). Treating anemia of cancer with every-4-week darbepoetin alfa: final efficacy and safety results from a phase II, randomized, double-blind, placebo-controlled study. Oncologist 13, 715-724. Doi: 10.1634/theoncologist.2007-0241
69. Grant, M. D., Piper, M., Bohlius, J., Tonia, T., Robert, N., Vats, V., et al. (2013). Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment: Comparative Effectiveness Update. US Report No. 13-EHC077-EF. Rockville MD: Agency for Healthcare Research and Quality.
70. Grogan, M., Thomas, G. M., Melamed, I., Wong, F. L., Pearcey, R. G., Joseph, P. K., et al. (1999). The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 86, 1528-1536. Doi: 10.1002/(SICI)1097-0142(19991015)86: 83.0.CO; 2-E
71. Haag-Weber, M., Eckardt, K. U., Horl, W. H., Roger, S. D., Vetter, A., and Roth, K. (2012). Safety, immunogenicity and efficacy of subcutaneous biosimilar epoetin-α (HX575) in non-dialysis patients with renal anemia: a multi-center, randomized, double-blind study. Clin. Nephrol. 77, 8-17. Doi: 10.5414/CN107304
72. Hagerty, K. (2008). Continued regulatory actions affecting the use of erythropoiesis-stimulating agents. J. Oncol. Pract. 4, 267-270. Doi: 10.1200/JOP.0863501
73. Halstenson, C. E., Macres, M., Katz, S. A., Schnieders, J. R., Watanabe, M., Sobota, J. T., et al. (1991). Abraham PA. Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta. Clin. Pharmacol. Ther. 50, 702-712. Doi: 10.1038/clpt.1991.210
74. Hare, G. M. (2014). Tolerance of anemia: understanding the adaptive physiological mechanisms which promote survival. Transfus. Apher. Sci. 50, 10-12. Doi: 10.1016/j.transci.2013.12.005
75. Hare, G. M., Tsui, A. K., McLaren, A. T., Ragoonanan, T. E., Yu, J., and Mazer, C. D. (2008). Anemia and cerebral outcomes: many questions, fewer answers. Anesth. Analg. 107, 1356-1370. Doi: 10.1213/ane.0b013e318184cfe9
76. Harrison, L., and Blackwell, K. (2004). Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy? Oncologist 9(Suppl. 5), 31-40.
77. Henke, M., Laszig, R., Rübe, C., Schäfer, U., Haase, K. D., Schilcher, B., et al. (2003). Erythropoietin to treat head and neck cancer patients with anaemia undergoing radio-therapy: randomised, double-blind, placebo-controlled trial. Lancet 362, 1255-1260. Doi: 10.1016/S0140-6736(03)14567-9
78. Henke, M., Mattern, D., Pepe, M., Bézay, C., Weissenberger, C., Werner, M., et al. (2006). Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J. Clin. Oncol. 24, 4708-4713. Doi: 10.1200/JCO.2006.06.2737
79. Henry, D. H. (2010). Parenteral iron therapy in cancer-associated anemia. Hematol. Am. Soc. Hematol. Educ. Program 2010, 351-356. Doi: 10.1182/asheducation-2010.1.351
80. Henry, D. H., Dahl, N. V., Auerbach, M., Tchekmedyian, S., and Laufman, L. R. (2007). Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist 12, 231-242. Doi: 10.1634/theoncologist.12-2-231
81. Höckel, M., and Vaupel, P. (2001). Biological consequences of tumor hypoxia. Semin. Oncol. 28(2 Suppl. 8), 36-41. Doi: 10.1016/S0093-7754(01)90211-8
82. Hung, S. C., Tung, T. Y., Yang, C. S., and Tarng, D. C. (2005). High-calorie supplementation increases serum leptin levels and improves response to rHuEPO in long-term hemodialysis patients. Am. J. Kidney Dis. 45, 1073-1083. Doi: 10.1053/j.ajkd.2005.02.020
83. Iglesias, P., Díez, J. J., Fernández-Reyes, M. J., Aguilera, A., Burgués, S., Martínez-Ara, J., et al. (1998). Recombinant human growth hormone therapy in malnourished dialysis patients: a randomized controlled study. Am. J. Kidney Dis. 32, 454-463. Doi: 10.1053/ajkd.1998.v32.pm9740162
84. Jelkmann, W., Pagel, H., Wolff, M., and Fandrey, J. (1992). Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys. Life Sci. 50, 301-308. Doi: 10.1016/0024-3205(92)90338-P
85. Jelkmann, W. (1998). Proinflammatory cytokines lowering erythropoietin production. J. Interferon Cytokine Res. 18, 555-559. Doi: 10.1089/jir.1998.18.555
86. Jelkmann, W. (2010). Biosimilar epoetins and other " follow-on" biologics: update on the European experiences. Am. J. Hematol. 85, 771-780. Doi: 10.1002/ajh.21805
87. Jewell, U. R., Kvietikova, I., Scheid, A., Bauer, C., Wenger, R. H., and Gassmann, M. (2001). Induction of HIF-1 alpha in response to hypoxia is instantaneous. FASEB J. 15, 1312-1314.
88. Juneja, V., Keegan, P., Gootenberg, J. E., Rothmann, M. D., Shen, Y. L., Lee, K. Y., et al. (2008). Continuing reassessment of the risks of erythropoiesis-stimulating agents in patients with cancer. Clin. Cancer Res. 14, 3242-3247. Doi: 10.1158/1078-0432.CCR-07-1872
89. Kader, A. S., Lim, J. T., Berthelet, E., Petersen, R., Ludgate, D., and Truong, P. T. (2007). Prognostic significance of blood transfusions in patients with esophageal cancer treated with combined chemoradiotherapy. Am. J. Clin. Oncol. 30, 492-497. Doi: 10.1097/01.coc.0000264177.66369.18
90. Kalantar-Zadeh, K., Kopple, J. D., Block, G., and Humphreys, M. H. (2001). A malnutrition-inflammation score is correlated with morbidity and mortality in maintenance hemodialysis patients. Am. J. Kidney Dis. 38, 1251-1263. Doi: 10.1053/ajkd.2001.29222
91. Katz, O., Gil, L., Liftshitz, L., Prutchi-Sagiv, S., Gassmann, M., Mittelman, M., et al. (2007). Neumann D. Erythropoietin enhances immune responses in mice. Eur. J. Immunol. 37, 1584-1593. Doi: 10.1002/eji.200637025
92. Kautz, L., Jung, G., Valore, E. V., Rivella, S., Nemeth, E., and Ganz, T. (2014). Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat. Genet. 46, 678-684. Doi: 10.1038/ng.2996
93. Khorana, A. A., Francis, C. W., Blumberg, N., Culakova, E., Refaai, M. A., and Lyman, G. H. (2008). Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer. Arch. Intern. Med. 168, 2377-2381. Doi: 10.1001/archinte.168.21.2377
94. Kling, P. J., Dragsten, P. R., Roberts, R. A., Dos Santos, B., Brooks, D. J., Hedlund, B. E., et al. (1996). Iron deprivation increases erythropoietin production in vitro, in normal subjects and patients with malignancy. Br. J. Haematol. 95, 241-248. Doi: 10.1046/j.1365-2141.1996.d01-1919.x
95. Knight, K., Wade, S., and Balducci, L. (2004). Prevalence and outcomes of anemia in cancer: a systematic review of the literature. Am. J. Med. 116(Suppl. 7A), 11S-26S. Doi: 10.1016/j.amjmed.2003.12.008
96. Ladányi, A., Somlai, B., Gilde, K., Fejös, Z., Gaudi, I., and Tímár, J. (2004). T-cell activation marker expression on tumor-infiltrating lymphocytes as prognostic factor in cutaneous malignant melanoma. Clin. Cancer Res. 10, 521-530. Doi: 10.1158/1078-0432.CCR-1161-03
97. Laftah, A. H., Ramesh, B., Simpson, R. J., Solanky, N., Bahram, S., Schümann, K., et al. (2004). Effect of hepcidin on intestinal iron absorption in mice. Blood 103, 3940-3944. Doi: 10.1182/blood-2003-03-0953
98. Lang, F., Abed, M., Lang, E., and Föller, M. (2014). Oxidative stress and suicidal erythrocyte death. Antioxid. Redox Signal. 21, 138-153. Doi: 10.1089/ars.2013.5747
99. Leyland-Jones, B., Semiglazov, V., Pawlicki, M., Pienkowski, T., Tjulandin, S., Manikhas, G., et al. (2005). Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J. Clin. Oncol. 23, 5960-5972. Doi: 10.1200/JCO.2005.06.150
100. Lindholm, E., Daneryd, P., Körner, U., Hyltander, A., Fouladiun, M., and Lundholm, K. (2004). Effects of recombinant erythropoietin in palliative treatment of unselected cancer patients. Clin. Cancer Res. 10, 6855-6864. Doi: 10.1158/1078-0432.CCR-04-0373
101. Ludwiczeck, S., Aigner, E., Theurl, I., and Weiss, G. (2003). Cytokine-mediated regulation of iron transport in human monocytic cells. Blood 101, 4148-4154. Doi: 10.1182/blood-2002-08-2459
102. Ludwig, H., Aapro, M., Bokemeyer, C., Macdonald, K., Soubeyran, P., Turner, M., et al. (2009). Treatment patterns and outcomes in the management of anaemia in cancer patients in Europe: findings from the Anaemia Cancer Treatment (ACT) study. Eur. J. Cancer 45, 1603-1615. Doi: 10.1016/j.ejca.2009.02.003
103. Ludwig, H., and Strasser, K. (2001). Symptomatology of anemia. Semin. Oncol. 28(2 Suppl. 8), 7-14. Doi: 10.1016/S0093-7754(01)90206-4
104. Ludwig, H., Van Belle, S., Barrett-Lee, P., Birgegård, G., Bokemeyer, C., Gascón, P., et al. (2004). The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur. J. Cancer 40, 2293-2306. Doi: 10.1016/j.ejca.2004.06.019
105. Lundholm, K., Daneryd, P., Bosaeus, I., Körner, U., and Lindholm, E. (2004). Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: effects on survival, metabolism, and function. Cancer 100, 1967-1977. Doi: 10.1002/cncr.20160
106. Macciò, A., Gramignano, G., and Madeddu, C. (2015a). A multitargeted treatment approach for anemia and cachexia in metastatic castration-resistant prostate cancer. J. Pain Symptom Manage. 50, e1-e4. Doi: 10.1016/j.jpainsymman.2015.04.014
107. Macciò, A., Gramignano, G., and Madeddu, C. (2015b). Surprising results of a supportive integrated therapy in myelofibrosis. Nutrition 31, 239-243. Doi: 10.1016/j.nut.2014.07.016
108. Macciò, A., Madeddu, C., Gramignano, G., Mulas, C., Tanca, L., Cherchi, M. C., et al. (2015c). The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study. Haematologica 100, 124-132. Doi: 10.3324/haematol.2014.112813
109. Macciò, A., Lai, P., Santona, M. C., Pagliara, L., Melis, G. B., and Mantovani, G. (1998). High serum levels of soluble IL-2 receptor, cytokines, and C reactive protein correlate with impairment of T cell response in patients with advanced epithelial ovarian cancer. Gynecol. Oncol. 69, 248-252. Doi: 10.1006/gyno.1998.4974
110. Macciò, A., and Madeddu, C. (2012). Inflammation and ovarian cancer. Cytokine 58, 133-147. Doi: 10.1016/j.cyto.2012.01.015
111. Macciò, A., Madeddu, C., Gramignano, G., Mulas, C., Floris, C., Sanna, E., et al. (2012). A randomized phase III clinical trial of a combined treatment for cachexia in patients with gynecological cancers: evaluating the impact on metabolic and inflammatory profiles and quality of life. Gynecol. Oncol. 124, 417-425. Doi: 10.1016/j.ygyno.2011.12.435
112. Macci?, A., Madeddu, C., Gramignano, G., Mulas, C., Sanna, E., and Mantovani, G. (2010). Efficacy and safety of oral lactoferrin supplementation in combination with rHuEPO-β for the treatment of anemia in advanced cancer patients undergoing chemotherapy: open-label, randomized controlled study. Oncologist 15, 894-902. Doi: 10.1634/theoncologist.2010-0020
113. Macciò, A., Madeddu, C., Massa, D., Astara, G., Farci, D., Melis, G. B., et al. (2009). Interleukin-6 and leptin as markers of energy metabolic changes in advanced ovarian cancer patients. J. Cell. Mol. Med. 13, 3951-3959. Doi: 10.1111/j.1582-4934.2008.00408.x
114. Macciò, A., Madeddu, C., Massa, D., Mudu, M. C., Lusso, M. R., Gramignano, G., et al. (2005). Hemoglobin levels correlate with interleukin-6 levels in patients with advanced untreated epithelial ovarian cancer: role of inflammation in cancer-related anemia. Blood 106, 362-367. Doi: 10.1182/blood-2005-01-0160
115. Madeddu, C., Gramignano, G., Floris, C., Murenu, G., Sollai, G., and Macciò, A. (2014). Role of inflammation and oxidative stress in post-menopausal oestrogen-dependent breast cancer. J. Cell. Mol. Med. 18, 2519-2529. Doi: 10.1111/jcmm.12413
116. Madeddu, C., Gramignano, G., Kotsonis, P., Coghe, F., Atzeni, V., Scartozzi, M., et al. (2018). Microenvironmental M1 tumor-associated macrophage polarization influences cancer-related anemia in advanced ovarian cancer: key role of Interleukin-6. Haematologica doi: 10.3324/haematol.2018.191551 [Epub ahead of print].
117. Madeddu, C., Mantovani, G., Gramignano, G., Astara, G., and Macciò, A. (2015). Muscle wasting as main evidence of energy impairment in cancer cachexia: future therapeutic approaches. Future Oncol. Doi: 10.2217/fon.15.195 [Epub ahead of print].
118. Mantovani, G., Macciò, A., Madeddu, C., Mura, L., Gramignano, G., Lusso, M. R., et al. (2003). Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress. J. Mol. Med. 81, 664-673. Doi: 10.1007/s00109-003-0476-1
119. Mantovani, G., Macció, A., Madeddu, C., Mura, L., Massa, E., Mudu, M., et al. (2001). Serum values of proinflammatory cytokines are inversely correlated with serum leptin levels in patients with advanced stage cancer at different sites. J. Mol. Med. 79, 406-414. Doi: 10.1007/s001090100234
120. Mantovani, G., Macció, A., Mura, L., Massa, E., Mudu, M. C., Mulas, C., et al. (2000). Serum levels of leptin and proinflammatory cytokines in patients with advanced-stage cancer at different sites. J. Mol. Med. 78, 554-561. Doi: 10.1007/s001090000137
121. Marini, M. A., Mannino, G. C., Fiorentino, T. V., Andreozzi, F., Perticone, F., and Sesti, G. (2017). A polymorphism at IGF1 locus is associated with anemia. Oncotarget 8, 32398-32406. Doi: 10.18632/oncotarget.16132
122. Martin, L., Senesse, P., Gioulbasanis, I., Antoun, S., Bozzetti, F., Deans, C., et al. (2015). Diagnostic criteria for the classification of cancer-associated weight loss. J. Clin. Oncol. 33, 90-99. Doi: 10.1200/JCO.2014.56.1894
123. McCammon, M. T., Epstein, C. B., Przybyla-Zawislak, B., McAlister-Henn, L., and Butow, R. A. (2003). Global transcription analysis of Krebs tricarboxylic acid cycle mutants reveals an alternating pattern of gene expression and effects on hypoxic and oxidative genes. Mol. Biol. Cell. 14, 958-972. Doi: 10.1091/mbc.e02-07-0422
124. McCranor, B. J., Kim, M. J., Cruz, N. M., Xue, Q. L., Berger, A. E., Walston, J. D., et al. (2014). Interleukin-6 directly impairs the erythroid development of human TF-1 erythroleukemic cells. Blood Cells Mol. Dis. 52, 126-133. Doi: 10.1016/j.bcmd.2013.09.004
125. McMillan, D. C. (2009). Systemic inflammation, nutritional status and survival in patients with cancer. Curr. Opin. Clin. Nutr. Metab. Care 12, 223-226. Doi: 10.1097/MCO.0b013e32832a7902
126. Means, R. T. (1995). Pathogenesis of the anemia of chronic disease: a cytokine-mediated anemia. Stem Cells 13, 32-37. Doi: 10.1002/stem.5530130105
127. Means, R. T. (2003). Recent developments in the anemia of chronic disease. Curr. Hematol. Rep. 2, 116-121.
128. Mercadante, S., Ferrara, P., Villari, P., David, F., Giarratano, A., and Riina, S. (2009). Effects of red blood transfusion on anemia-related symptoms in patients with cancer. J. Palliat. Med. 12, 60-63. Doi: 10.1089/jpm.2008.0139
129. Mhaskar, R., Wao, H., Miladinovic, B., Kumar, A., and Djulbegovic, B. (2016). The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis stimulating agents. Cochrane Database Syst. Rev. 2: CD009624. Doi: 10.1002/14651858.CD009624.pub2
130. Michallet, M., and Losem, C. (2016). Biosimilar epoetin zeta in oncology and haematology: development and experience following 6 years of use. Acta Haematol. 135, 44-52. Doi: 10.1159/000438976
131. Miller, A. H., Ancoli-Israel, S., Bower, J. E., Capuron, L., and Irwin, M. R. (2008). Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J. Clin. Oncol. 26, 971-982. Doi: 10.1200/JCO.2007.10.7805
132. Millonig, G., Ganzleben, I., Peccerella, T., Casanovas, G., Brodziak-Jarosz, L., Breitkopf-Heinlein, K., et al. (2012). Sustained submicromolar H2O2 levels induce hepcidin via signal transducer and activator of transcription 3 (STAT3). J. Biol. Chem. 287, 37472-37482. Doi: 10.1074/jbc.M112.358911
133. Molnar, M. Z., Czira, M. E., Rudas, A., Ujszaszi, A., Haromszeki, B., Kosa, J. P., et al. (2011). Association between the malnutrition-inflammation score and post-transplant anaemia. Nephrol. Dial. Transplant. 26, 2000-2006. Doi: 10.1093/ndt/gfq690
134. Montel-Hagen, A., Sitbon, M., and Taylor, N. (2009). Erythroid glucose transporters. Curr. Opin. Hematol. 16, 165-172. Doi: 10.1097/MOH.0b013e328329905c
135. Mystakidou, K., Kalaidopoulou, O., Katsouda, E., Parpa, E., Kouskouni, E., Chondros, C., et al. (2005). Evaluation of epoetin supplemented with oral iron in patients with solid malignancies and chronic anemia not receiving anticancer treatment. Anticancer Res. 25, 3495-3500.
136. Nagasawa, E., Abe, Y., Nishimura, J., Yanase, T., Nawata, H., and Muta, K. (2005). Pivotal role of peroxisome proliferator-activated receptor gamma (PPARgamma) in regulation of erythroid progenitor cell proliferation and differentiation. Exp. Hematol. 33, 857-864. Doi: 10.1016/j.exphem.2005.05.003
137. Nairz, M., Sonnweber, T., Schroll, A., Theurl, I., and Weiss, G. (2012). The pleiotropic effects of erythropoietin in infection and inflammation. Microbes Infect. 14, 238-246. Doi: 10.1016/j.micinf.2011.10.005
138. Nathan, D. G. (2015). Amino acid uptake in erythropoiesis. Sci. Signal. 8: fs9. Doi: 10.1126/scisignal.aab1203
139. Nekoui, A., and Blaise, G. (2017). Erythropoietin and nonhematopoietic effects. Am. J. Med. Sci. 353, 76-81. Doi: 10.1016/j.amjms.2016.10.009
140. Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K., et al. (2004). IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113, 1271-1276. Doi: 10.1172/JCI200420945
141. Newland, A. M., and Black, C. D. (2008). Tumor progression associated with erythropoiesis-stimulating agents. Ann. Pharmacother. 42, 1865-1870. Doi: 10.1345/aph.1L231
142. Nicolas, G., Bennoun, M., Porteu, A., Mativet, S., Beaumont, C., Grandchamp, B., et al. (2002). Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc. Natl. Acad. Sci. U.S.A. 99, 4596-4601. Doi: 10.1073/pnas.072632499
143. Nieken, J., Mulder, N. H., Buter, J., Vellenga, E., Limburg, P. C., Piers, D. A., et al. (1995). Recombinant human interleukin-6 induces a rapid and reversible anemia in cancer patients. Blood 86, 900-905.
144. Nilsson-Ehle, H., Bengtsson, B. A., Lindstedt, G., and Mellström, D. (2005). Insulin-like growth factor-1 is a predictor of blood haemoglobin concentration in 70-yr-old subjects. Eur. J. Haematol. 74, 111-116. Doi: 10.1111/j.1600-0609.2004.00374.x
145. Obermair, A., Handisurya, A., Kaider, A., Sevelda, P., Kölbl, H., and Gitsch, G. (1998). The relationship of pretreatment serum hemoglobin level to the survival of epithelial ovarian carcinoma patients: a prospective review. Cancer 83, 726-731. Doi: 10.1002/(SICI)1097-0142(19980815)83: 43.0.CO; 2-U
146. Oburoglu, L., Romano, M., Taylor, N., and Kinet, S. (2016). Metabolic regulation of hematopoietic stem cell commitment and erythroid differentiation. Curr. Opin. Hematol. 23, 198-205. Doi: 10.1097/MOH.0000000000000234
147. Oburoglu, L., Tardito, S., Fritz, V., de Barros, S. C., Merida, P., Craveiro, M., et al. (2014). Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification. Cell Stem Cell 15, 169-184. Doi: 10.1016/j.stem.2014.06.002
148. Olszewska, M., Wiatrow, J., Bober, J., Stachowska, E., Golembiewska, E., Jakubowska, K., et al. (2012). Oxidative stress modulates the organization of erythrocyte membrane cytoskeleton. Postepy Hig. Med. Dosw. 66, 534-542.
149. Palis, J. (2014). Primitive and definitive erythropoiesis in mammals. Front. Physiol. 5: 3. Doi: 10.3389/fphys.2014.00003
150. Patel, H. J., and Patel, B. M. (2017). TNF-α and cancer cachexia: molecular insights and clinical implications. Life Sci. 170, 56-63. Doi: 10.1016/j.lfs.2016.11.033
151. Patra, S. K., and Arora, S. (2012). Integrative role of neuropeptides and cytokines in cancer anorexia-cachexia syndrome. Clin. Chim. Acta 413, 1025-1034. Doi: 10.1016/j.cca.2011.12.008
152. Pedrazzoli, P., Farris, A., Del Prete, S., Del Gaizo, F., Ferrari, D., Bianchessi, C., et al. (2008). Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha. J. Clin. Oncol. 26, 1619-1625. Doi: 10.1200/JCO.2007.12.2051
153. Pfeffer, M. A., Burdmann, E. A., Chen, C. Y., Cooper, M. E., de Zeeuw, D., Eckardt, K. U., et al. (2009). A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N. Engl. J. Med. 361, 2019-2032. Doi: 10.1056/NEJMoa0907845
154. Porporato, P. E. (2016). Understanding cachexia as a cancer metabolism syndrome. Oncogenesis 5: e20. Doi: 10.1038/oncsis.2016.3
155. Preston, N. J., Hurlow, A., Brine, J., and Bennett, M. I. (2012). Blood transfusions for anaemia in patients with advanced cancer. Cochrane Database Syst. Rev. 2: CD009007. Doi: 10.1002/14651858.CD009007.pub2
156. Prince, O. D., Langdon, J. M., Layman, A. J., Prince, I. C., Sabogal, M., Mak, H. H., et al. (2012). Late stage erythroid precursor production is impaired in mice with chronic inflammation. Haematologica 97, 1648-1656. Doi: 10.3324/haematol.2011.053397
157. Pronzato, P. (2006). Cancer-related anaemia management in the 21st century. Cancer Treat. Rev. 32(Suppl. 2), S1-S3. Doi: 10.1016/j.ctrv.2006.04.008
158. Quirt, I., Robeson, C., Lau, C. Y., Kovacs, M., Burdette-Radoux, S., Dolan, S., et al. (2001). Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy. J. Clin. Oncol. 19, 4126-4134. Doi: 10.1200/JCO.2001.19.21.4126
159. Rattanasompattikul, M., Molnar, M. Z., Zaritsky, J. J., Hatamizadeh, P., Jing, J., Norris, K. C., et al. (2013). Association of malnutrition-inflammation complex and responsiveness to erythropoiesis-stimulating agents in long-term hemodialysis patients. Nephrol. Dial. Transplant. 28, 1936-1945. Doi: 10.1093/ndt/gfs368
160. Recalcati, S., Locati, M., Gammella, E., Invernizzi, P., and Cairo, G. (2012). Iron levels in polarized macrophages: regulation of immunity and autoimmunity. Autoimmun. Rev. 11, 883-889. Doi: 10.1016/j.autrev.2012.03.003
161. Reglin, B., Secomb, T. W., and Pries, A. R. (2009). Structural adaptation of microvessel diameters in response to metabolic stimuli: where are the oxygen sensors? Am. J. Physiol. Heart Circ. Physiol. 297, H2206-H2219. Doi: 10.1152/ajpheart.00348.2009
162. Ribeiro, S., Garrido, P., Fernandes, J., Vala, H., Rocha-Pereira, P., Costa, E., et al. (2016). Pathological and molecular mechanisms underlying resistance to recombinant human erythropoietin therapy in the remnant kidney rat model of chronic kidney disease associated anemia. Biochimie 125, 150-162. Doi: 10.1016/j.biochi.2016.03.012
163. Rizzo, J. D., Brouwers, M., Hurley, P., Seidenfeld, J., Arcasoy, M. O., Spivak, J. L., et al. (2010). American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood 116, 4045-4059. Doi: 10.1182/blood-2010-08-300541
164. Rodgers, G. M. III, Gilreath, J. A., Achebe, M. M., Alwan, L., Arcasoy, M., Ali Beth, S., et al. (2017). NCCN. Cancer-and Chemotherapy-Induced Anemia, Version 2.2017. Available at: http://www.nccn.org/professionals/physician-gls/pdf/anemia.pdf [accessed April 26, 2017].
165. Sailaja, Y. R., Baskar, R., and Saralakumari, D. (2003). The antioxidant status during maturation of reticulocytes to erythrocytes in type 2 diabetics. Free. Radic. Biol. Med. 35, 133-139. Doi: 10.1016/S0891-5849(03)00071-6
166. Saini, A., Al-Shanti, N., and Stewart, C. E. (2006). Waste management-cytokines, growth factors and cachexia. Cytokine Growth Factor Rev. 17, 475-486. Doi: 10.1016/j.cytogfr.2006.09.006
167. Sandler, S., Bendtzen, K., Eizirik, D. L., and Welsh, M. (1990). Interleukin-6 affects insulin secretion and glucose metabolism of rat pancreatic islets in vitro. Endocrinology 126, 1288-1294. Doi: 10.1210/endo-126-2-1288
168. Sanz Ortiz, J. (2008). Predictors of response to erythropoiesis-stimulating agents (ESA) in cancer patients: the role of baseline serum epoetin level. Clin. Transl. Oncol. 10, 486-492. Doi: 10.1007/s12094-008-0237-2
169. Schmidt, P. J. (2015). Regulation of iron metabolism by hepcidin during conditions of inflammation. J. Biol. Chem. 290, 18975-18983. Doi: 10.1074/jbc.R115.650150
170. Schwartz, R. N. (2007). Anemia in patients with cancer: incidence, causes, impact, management, and use of treatment guidelines and protocols. Am. J. Health Syst. Pharm. 64(3 Suppl. 2), S5-S13. Doi: 10.2146/ajhp060601
171. Semenza, G. L. (2000). Surviving ischemia: adaptive responses mediated by hypoxia-inducible factor 1. J. Clin. Invest. 106, 809-812. Doi: 10.1172/JCI11223
172. Shasha, D. (2001). The negative impact of anemia on radiotherapy and chemoradiation outcomes. Semin. Hematol. 38(3 Suppl. 7), 8-15. Doi: 10.1016/S0037-1963(01)90125-8
173. Shin, N. R., Lee, Y. Y., Kim, S. H., Choi, C. H., Kim, T. J., Lee, J. W., et al. (2014). Prognostic value of pretreatment hemoglobin level in patients with early cervical cancer. Obstet. Gynecol. Sci. 57, 28-36. Doi: 10.5468/ogs.2014.57.1.28
174. Shu, T., Jing, C., Lv, Z., Xie, Y., Xu, J., and Wu, J. (2014). Hepcidin in tumor-related iron deficiency anemia and tumor-related anemia of chronic disease: pathogenic mechanisms and diagnosis. Eur. J. Haematol. 94, 67-73. Doi: 10.1111/ejh.12402
175. Simon, T. L., Alverson, D. C., AuBuchon, J., Cooper, E. S., DeChristopher, P. J., Glenn, G. C., et al. (1998). Practice parameter for the use of red blood cell transfusions: developed by the Red Blood Cell Administration Practice Guideline Development Task Force of the College of American Pathologists. Arch. Pathol. Lab. Med. 122, 130-138.
176. Singh, A. K., Szczech, L., Tang, K. L., Barnhart, H., Sapp, S., Wolfson, M., et al. (2006). Correction of anemia with epoetin alfa in chronic kidney disease. N. Engl. J. Med. 355, 2085-2098. Doi: 10.1056/NEJMoa065485
177. Sitkovsky, M., and Lukashev, D. (2005). Regulation of immune cells by local-tissue oxygen tension: HIF1α and adenosine receptors. Nat. Rev. Immunol. 5, 712-721. Doi: 10.1038/nri1685
178. Smith, R. E. Jr., Aapro, M. S., Ludwig, H., Pintér, T., Smakal, M., Ciuleanu, T. E., et al. (2008). Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J. Clin. Oncol. 26, 1040-1050. Doi: 10.1200/JCO.2007.14.2885
179. Spivak, J. L. (2000). The blood in systemic disorders. Lancet 355, 1707-1712. Doi: 10.1016/S0140-6736(00)02249-2
180. Spivak, J. L. (2005). The anaemia of cancer: death by a thousand cuts. Nat. Rev. Cancer 5, 543-555. Doi: 10.1038/nrc1648
181. Spivak, J. L. (2011). Iron and the anemia of chronic disease: vindication for the Non-essential role of iron supplementation. Oncology 25, 421-423.
182. Spivak, J. L., Gascón, P., and Ludwig, H. (2009). Anemia management in oncology and hematology. Oncologist 14(Suppl. 1), 43-56. Doi: 10.1634/theoncologist.2009-S1-43
183. Steensma, D. P. (2008). Is anemia of cancer different from chemotherapy-induced anemia? Clin. Oncol. 26, 1022-1102. Doi: 10.1200/JCO.2007.15.3874
184. Steensma, D. P., Sloan, J. A., Dakhil, S. R., Dalton, R., Kahanic, S. P., Prager, D. J., et al. (2011). Phase III, randomized study of the effects of parenteral iron, oral iron, or no iron supplementation on the erythropoietic response to darbepoetin alfa for patients with chemotherapy-associated anemia. J. Clin. Oncol. 29, 97-105. Doi: 10.1200/JCO.2010.30.3644
185. Storring, P. L., Tiplady, R. J., Gaines Das, R. E., Stenning, B. E., Lamikanra, A., Rafferty, B., et al. (1998). Epoetin alfa and beta differ in their erythropoietin isoform compositions and biological properties. Br. J. Haematol. 100, 79-89. Doi: 10.1046/j.1365-2141.1998.00521.x
186. Strassmann, G., Fong, M., Kenney, J. S., and Jacob, C. O. (1992). Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J. Clin. Invest. 89, 1681-1684.
187. Succurro, E., Arturi, F., Caruso, V., Rudi, S., Sciacqua, A., Andreozzi, F., et al. (2011). Low insulin-like growth factor-1 levels are associated with anaemia in adult non-diabetic subjects. Thromb. Haemost. 105, 365-370. Doi: 10.1160/TH10-06-0379
188. Takeda, A., Toda, T., Shinohara, S., Mogi, Y., and Matsui, N. (2002). Factors contributing to higher hematocrit levels in hemodialysis patients not receiving recombinant human erythropoietin. Am. J. Kidney Dis. 40, 104-109. Doi: 10.1053/ajkd.2002.33918
189. Tanneberger, S., Melilli, G., Strocchi, E., Frenquelli, C., and Pannuti, Q. F. (2004). Use of red blood cell transfusion in palliative care services: it is still up to date or is cancer-related anemia controlled better with erythropoietic agents? Ann. Oncol. 15, 839-844. Doi: 10.1093/annonc/mdh178
190. Tarng, D. C., Huang, T. P., Chen, T. W., and Yang, W. C. (1999). Erythropoietin hyporesponsiveness: from iron deficiency to iron overload. Kidney Int. Suppl. 69, S107-S118.
191. Thomas, G. (2001). The effect of hemoglobin level on radiotherapy outcomes: the Canadian experience. Semin. Oncol. 28(2 Suppl. 8), 60-65. Doi: 10.1016/S0093-7754(01)90215-5
192. Tonia, T., Mettler, A., Robert, N., Schwarzer, G., Seidenfeld, J., Weingart, O., et al. (2012). Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst. Rev. 12: CD003407. Doi: 10.1002/14651858.CD003407.pub5
193. Torti, F. M., and Torti, S. V. (2002). Regulation of ferritin genes and protein. Blood 99, 3505-3516. Doi: 10.1182/blood.V99.10.3505
194. Toy, P., Popovsky, M. A., Abraham, E., Ambruso, D. R., Holness, L. G., Kopko, P. M., et al. (2005). Transfusion-related acute lung injury: definition and review. Crit. Care Med. 33, 721-726. Doi: 10.1097/01.CCM.0000159849.94750.51
195. Tsuboi, M., Ezaki, K., Tobinai, K., Ohashi, Y., and Saijo, N. (2009). Weekly administration of epoetin beta for chemotherapy-induced anemia in cancer patients: results of a multicenter, phase III, randomized, double-blind, placebo-controlled study. Jpn. J. Clin. Oncol. 39, 163-168. Doi: 10.1093/jjco/hyn151
196. Tsui, A. K., Marsden, P. A., Mazer, C. D., Sled, J. G., Lee, K. M., Henkelman, R. M., et al. (2014). Differential HIF and NOS responses to acute anemia: defining organ-specific hemoglobin thresholds for tissue hypoxia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R13-R25. Doi: 10.1152/ajpregu.00411.2013
197. Turnbull, A. V., Lee, S., and Rivier, C. (1998). Mechanisms of hypothalamic-pituitary-adrenal axis stimulation by immune signals in the adult rat. Ann. N. Y. Acad. Sci. 840, 434-443. Doi: 10.1111/j.1749-6632.1998.tb09582.x
198. Umemoto, Y., Tsuji, K., Yang, F. C., Ebihara, Y., Kaneko, A., Furukawa, S., et al. (1997). Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells. Blood 90, 3438-3443.
199. Vander Heiden, M. G., Cantley, L. C., and Thompson, C. B. (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033. Doi: 10.1126/science.1160809
200. Weber, R. S., Jabbour, N., and Martin, R. C. II (2008). Anemia and transfusions in patients undergoing surgery for cancer. Ann. Surg. Oncol. 15, 34-45. Doi: 10.1245/s10434-007-9502-9
201. Weiss, G., and Goodnough, L. T. (2005). Anemia of chronic disease. N. Engl. J. Med. 352, 1011-1023. Doi: 10.1056/NEJMra041809
202. Wish, J. B. (2006). Assessing iron status: beyond serum ferritin and transferrin saturation. Clin. J. Am. Soc. Nephrol. 1(Suppl. 1), S4-S8. Doi: 10.2215/CJN.01490506
203. Woodson, R. D., and Auerbach, S. (1982). Effect of increased oxygen affinity and anemia on cardiac output and its distribution. J. Appl. Physiol. 53, 1299-1313. Doi: 10.1152/jappl.1982.53.5.1299
204. Wright, J. R., Ung, Y. C., Julian, J. A., Pritchard, K. I., Whelan, T. J., Smith, C., et al. (2007). Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J. Clin. Oncol. 25, 1027-1032. Doi: 10.1200/JCO.2006.07.1514
205. Wu, H. M., Jiang, Z. F., Ding, P. S., Shao, L. J., and Liu, R. Y. (2015). Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells. Sci. Rep. 5: 12291. Doi: 10.1038/srep12291
206. Xia, Y., Jiang, L., and Zhong, T. (2018). The role of HIF-1α in chemo-/radioresistant tumors. Onco Targets Ther. 11, 3003-3011. Doi: 10.2147/OTT.S158206
207. Zhang, L. L., Zhou, G. Q., Li, Y. Y., Tang, L. L., Mao, Y. P., Lin, A. H., et al. (2017). Combined prognostic value of pretreatment anemia and cervical node necrosis in patients with nasopharyngeal carcinoma receiving intensity-modulated radiotherapy: a large-scale retrospective study. Cancer Med. 6, 2822-2831. Doi: 10.1002/cam4.1233
208. Zhang, Y., Chen, Y., Chen, D., Jiang, Y., Huang, W., Ouyang, H., et al. (2014). Impact of preoperative anemia on relapse and survival in breast cancer patients. BMC Cancer 14: 844. Doi: 10.1186/1471-2407-14-844
209. Zhu, W., and Xu, B. (2015). Association of pretreatment anemia with pathological response and survival of breast cancer patients treated with neoadjuvant chemotherapy: a population-based study. PLoS One 10: e0136268. Doi: 10.1371/journal.pone.0136268