Oncology Reviews

, Volume 1, Issue 3, pp 141–151 | Cite as

Bisphosphonates: from preclinical evidence to survival data in the oncologic setting

  • Daniele Santini
  • Sara Galluzzo
  • Maria Elisabetta Fratto
  • Bruno Vincenzi
  • Silvia Angeletti
  • Giordano Dicuonzo
  • Gaia Schiavon
  • Giuseppe Tonini
Review
  • 19 Downloads

Abstract

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. In vivo pre-clinical data suggest that bisphosphonates may exert an antitumor effect and preliminary clinical data show promising activity on metastatic disease in cancer patients. This review will describe the pre-clinical evidence of action of bisphosphonates on osteoclasts and tumor cells, in both in vitro and animal models. In addition, the effects of principal bisphosphonates on skeletal disease progression in patients with cancers in different sites, including breast cancer, prostate cancer and non-small cell lung cancer will be reported. The preliminary clinical data from retrospective trials on the effect of bisphosphonates on survival will be described and the ongoing adjuvant phase III trial will be analyzed. This review will describe the preliminary clinical evidences from prospective studies on the effect of zoledronic acid treatment on the prevention of bone metastases.

Key words

Bisphosphonates Bone metastases Survival Preclinical 

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References

  1. 1.
    Shinoda H, Adamek G, FELIX R et al (1983) Structure-activity relationship of various bisphosphonates. Calcif Tissue Int 35:87–99PubMedCrossRefGoogle Scholar
  2. 2.
    Widler R, Jaeggi K, Glatt M et al (2002) Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa). J Med Chem 45:3721–3738PubMedCrossRefGoogle Scholar
  3. 3.
    Benford HL, Frith JC, Auriola S et al (1999) Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Mol Pharmacol 56:131–140PubMedGoogle Scholar
  4. 4.
    Luckman SP, Coxon FP, Ebetino FH et al (1998) Heterocycle-containing bisphosphonates cause apoptosis and inhibit bone resorption by preventing protein prenylation: evidence from structure-activity relationships in J774 macrophages. J Bone Miner Res 13:1668–1678PubMedCrossRefGoogle Scholar
  5. 5.
    Russell RG, Rogers MJ, Frith JC et al (1999) The pharmacology of bisphosphonates and new insights into their mechanisms of action. J Bone Miner Res 14 S2:53–65Google Scholar
  6. 6.
    Luckman SP, Hughes DE, Coxon FP et al (1998) Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13:581–589PubMedCrossRefGoogle Scholar
  7. 7.
    Lehenkari PP, Kellinsalmi M, Napankangas JP et al (2002) Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol Pharmacol 61:1255–1262PubMedCrossRefGoogle Scholar
  8. 8.
    Selander KS, Monkkonen J, Karhukorpi EK et al (1996) Characteristics of clodronate-induced apoptosis in osteoclasts and macrophages. Mol Pharmacol 50:1127–1138PubMedGoogle Scholar
  9. 9.
    Rackoff Pj, Sebba A (2005) Optimizing administration of bisphosphonates in women with postmenopausal osteoporosis. Treat. Endocrinol 4:245–251PubMedCrossRefGoogle Scholar
  10. 10.
    Cranney A, Adachi JD (2002) Corticosteroid-induced osteoporosis: a guide to optimum management. Treat Endocrinol 1:271–279PubMedCrossRefGoogle Scholar
  11. 11.
    Reid IR, Miller P, Lyles K et al (2005) Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med 353:898–908PubMedCrossRefGoogle Scholar
  12. 12.
    Fleisch H (1991) Bisphosphonates. Pharmacology and use in the treatment of tumor-induced hypercalcemic and metastatic bone disease. Drugs 42:919–944PubMedCrossRefGoogle Scholar
  13. 13.
    Mccloskey EV, Maclennan CM, Drayson MT et al (1998) A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. MRC Working Party on Leukaemia in Adults. Br J Haematol 100:317–325PubMedCrossRefGoogle Scholar
  14. 14.
    Santini D, Fratto ME, Vincenzi B et al (2006) Zoledronic acid in the management of metastatic bone disease Expert Opin Biol Ther 6:1333–1348PubMedCrossRefGoogle Scholar
  15. 15.
    Hasmin M, Bieler G, Ruegg G (2007) Zoledronate inhibits endothelial cell adhesion, migration and survival through the suppression of multiple, prenylation-dependent signalling pathways. J Thromb Haemost 5:166–173CrossRefGoogle Scholar
  16. 16.
    Clezardin P (2002) The antitumor potential of bisphosphonates. Semin Oncol 29:33–42PubMedGoogle Scholar
  17. 17.
    Croucher Pi, De Hendrik R, Perry Mj et al (2003) Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res 18:482–492PubMedCrossRefGoogle Scholar
  18. 18.
    Kunzmann V, Bauer E, Feurle J et al (2000) Stimulation of gamma/delta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood 96:384–392PubMedGoogle Scholar
  19. 19.
    Dieli F, Gebbia N, Poccia F et al (2003) Induction of gamma/delta T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo. Blood 102:2310–2311PubMedCrossRefGoogle Scholar
  20. 20.
    Caraglia M, Santini D, Marra M et al (2006) Emerging anti-cancer molecular mechanisms of aminobisphosphonates. Endocr Relat Cancer 13:7–26PubMedCrossRefGoogle Scholar
  21. 21.
    Green JR (2004) Bisphosphonates: preclinical review. Oncologist 9[Suppl 4]: S3–S13CrossRefGoogle Scholar
  22. 22.
    Fromigue O, Lagneaux L, Body JJ (2000) Bisphosphonates induce breast cancer cell death in vitro. J Bone Miner Res 15:2211–2221PubMedCrossRefGoogle Scholar
  23. 23.
    Senaratne SG et al (2002) The bisphosphonate zoledronic acid impairs Ras membrane localisation and induces cytochrome c release in breast cancer cells. Br J Cancer 86:1479–1486PubMedCrossRefGoogle Scholar
  24. 24.
    Lowik CW, van der Pluijm G, van der Wee-Pals LJA et al (1988) Migration and phenotypic transformation of osteoclast precursors into mature osteoclasts: the effect of a bisphosphonate. J Bone Miner Res 3:185–192PubMedCrossRefGoogle Scholar
  25. 25.
    Colucci S, Minielli V, Zambonin G et al (1998) Alendronate reduces adhesion of human osteoclast-like cells to bone and bone protein-coated surfaces. Calcif Tissue Int 63:230–235PubMedCrossRefGoogle Scholar
  26. 26.
    Boissier S, Ferreras M, Peyruchaud O et al (2000) Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 60:2949–2954PubMedGoogle Scholar
  27. 27.
    van der Pluijm G, Vloedgraven H, van Beek E et al (1996) Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest 98:698–705PubMedCrossRefGoogle Scholar
  28. 28.
    Pickering LM, Mansi JL, Colston KW (2003) Adhesion of breast cancer cells to extracellular matrices is inhibited by zoledronic acid and enhanced by aberrant Ras signalling. Proc Am Soc Clin Oncol 22:863Google Scholar
  29. 29.
    Hauschka PV, Mavrakos AE, Iafrati MD et al (1986) Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin sepharose. J Biol Chem 261:12665–12674PubMedGoogle Scholar
  30. 30.
    Pfeilshifter J, Mundy GR (1987) Modulation of type b transforming growth factor activity in bone cultures by osteotropic hormones. Proc Natl Acad Sci USA 84:2024–2028CrossRefGoogle Scholar
  31. 31.
    Hiraga T, Nakajima T, Ozawa H (1995) Bone resorption induced by a metastatic human melanoma cell line. Bone 16:349–356PubMedCrossRefGoogle Scholar
  32. 32.
    Guise TA (1997) Parathyroid hormonerelated protein and bone metastases. Cancer 80:1572–1580PubMedCrossRefGoogle Scholar
  33. 33.
    Croucher P, Jagdev S and Coleman R (2003) The anti-tumor potential of zoledronic acid. The Breast [Suppl 2], S30–S36Google Scholar
  34. 34.
    Gouin F, Gory B, Redini F, Heymann D (2006) Zoledronic acid slows down rat primary chondrosarcoma development, recurrent tumor progression after intralesional curretage and increases overall survival. Int J Cancer 119:980–984PubMedCrossRefGoogle Scholar
  35. 35.
    Yaccoby S, Pearse RN, Johnson CL et al (2002) Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity. Br J Haematol 116:278–290PubMedCrossRefGoogle Scholar
  36. 36.
    Morgan C, Lewis PD, Jones RM et al (2007) The in vitro anti-tumour activity of zoledronic acid and docetaxel at clinically achievable concentrations in prostate cancer. Acta Oncol 46:669–677PubMedCrossRefGoogle Scholar
  37. 37.
    Hiraga T, Williams Pj, Ueda A, Tamura D, Yoneda T (2004) Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model. Clin Cancer Res 10:4559–4567PubMedCrossRefGoogle Scholar
  38. 38.
    Daubiné F, Le Gall C, Gasser J et al (2007) Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis J Natl Cancer Inst 99:322–330PubMedCrossRefGoogle Scholar
  39. 39.
    Bezzi M, Hasmim M, Bieler G et al (2003) Zoledronate sensitizes endothelial cells to tumor necrosis factorinduced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt. J Biol Chem 278:43603–43614PubMedCrossRefGoogle Scholar
  40. 40.
    Wood J, Bonjean K, Ruetz S et al (2002) Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 302:1055–1061PubMedCrossRefGoogle Scholar
  41. 41.
    Fournier P, Boissier S, Filleur S et al. (2002) Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 62:6538–6544PubMedGoogle Scholar
  42. 42.
    Bonjean K, Bellahcene A, Locigno R et al (2001) Zoledronate modulates endothelial cell surface receptors involved in angiogenesis. Proc Am Assoc Cancer Res 42:106Google Scholar
  43. 43.
    Santini D, Vincenzi B, Avvisati G et al (2002) Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 8:1080–1084PubMedGoogle Scholar
  44. 44.
    Santini D, Vincenzi B, Dicuonzo G et al (2003) Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 9:2893–2897PubMedGoogle Scholar
  45. 45.
    Vincenzi B, Santini D, Dicuonzo G et al (2005) Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients. J Interferon Cytokine Res 25:144–151PubMedCrossRefGoogle Scholar
  46. 46.
    Santini D, Schiavon G, Angeletti S (2006) Last generation of amino-bisphosphonates (N-BPs) and cancer angiogenesis: a new role for these drugs? Recent patents on Anti-Cancer Drug Discovery 383–396Google Scholar
  47. 47.
    Salerno A, Dieli F (1998) Role of gamma delta T lymphocytes in immune responses in humans and mice. Crit Rev Immunol 18:327–357PubMedGoogle Scholar
  48. 48.
    Porcelli S, Brenner MB, Band H (1999) Biology of the human T-cell receptor. Immunol Rev 120:137–183CrossRefGoogle Scholar
  49. 49.
    Constant P, Davodeau F, Peyrat MA et al (1994) Stimulation of human T-cells by nonpeptidic mycobacterial ligands. Science 264:267–270PubMedCrossRefGoogle Scholar
  50. 50.
    Bukowski JF, Morita CT, Brenner MB (1999) Human gamma delta T cells recognize alkylamines derived from microbes, edible plants and tea: implications for innate immunity. Immunity 11:57–65PubMedCrossRefGoogle Scholar
  51. 51.
    Roelofs AJ, Thompson K, Gordon S, Rogers MJ (2006) Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 12:6222s–6230s.PubMedCrossRefGoogle Scholar
  52. 52.
    Tassone P, Forciniti S, Galea E et al (2000) Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines. Leukemia 14:841–844PubMedCrossRefGoogle Scholar
  53. 53.
    Jagdev SP, Coleman RE, Shipman CM et al (2001) The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer 84:1126–1134PubMedCrossRefGoogle Scholar
  54. 54.
    Ullen A, Lennartsson L, Hjelm-Eriksson M et al (2003) Additive/synergistic anti-tumoral effects on prostate cancer cells in vitro following treatment with a combination of gemcitabine and zoledronic acid [abstract #1737]. Proc Am Soc Clin Oncol 22:432Google Scholar
  55. 55.
    Hiraga T, Ueda A, Tamura D et al (2003) Effects of oral UFT combined with or without zoledronic acid on bone metastasis in the 4T1/luc mouse breast cancer. Int J Cancer 106: 973–979PubMedCrossRefGoogle Scholar
  56. 56.
    Vogt U, Bielawski KP, Bosse U, Schlotter CM (2004) Breast tumour growth inhibition in vitro through the combination of cyclophosphamide/metotrexate/5-fluorouracil, epirubicin/cyclophosphamide, epirubicin/paclitaxel, and epirubicin/docetaxel with the bisphosphonates ibandronate and zoledronic acid. Oncol Rep 12:1109–1114PubMedGoogle Scholar
  57. 57.
    Kimura S, Kuroda J, Segawa H (2004) Antiproliferative efficacy of the third-generation bisphosphonate, zoledronic acid, combined with other anticancer drugs in leukemic cell lines. Int J Hematol 79:37–43PubMedGoogle Scholar
  58. 58.
    Neville-Webbe HL, Rostami-Hodjegan A, Evans CA et al (2005) Sequenceand schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells. Int J Cancer 113:364–371PubMedCrossRefGoogle Scholar
  59. 59.
    Neville-Webbe HL, Coleman R, Holen I (2005) Understanding drug-sequence-dependent synergistic induction of apoptosis by zoledronic acid (ZOL) and doxorubicin (DOX) in breast cancer. Cancer Treat Rev, 31:[Suppl 1]. Abs 45 pp 28.Google Scholar
  60. 60.
    Woodward J, Coleman R, Neville-Webbe HL, Holen I (2005) The combined effects of zoledronic acid (ZOL) and doxorubicin (DOX) on breast cancer cell invasion in vitro. Anticancer Drugs 16:845–854PubMedCrossRefGoogle Scholar
  61. 61.
    Trojan J, Kim SZ, Engels K et al (2005) In vitro chemosensitivity to gemcitabine, oxaliplatin and zoledronic acid predicts treatment response in metastatic gastric cancer. Anticancer Drugs 16:87–91PubMedCrossRefGoogle Scholar
  62. 62.
    Algur E, Macklis RM, Hafeli UO (2005) Synergistic cytotoxic effects of zoledronic acid and radiation in human prostate cancer and myeloma cell lines. Int J Radiat Oncol Biol Phys 61:535–542PubMedCrossRefGoogle Scholar
  63. 63.
    Matsumoto S, Kimura S, Segawa H et al (2005) Efficacy of the third-generation bisphosphonate, zoledronic acid alone and combined with anti-cancer agents against small cell lung cancer cell lines. Lung Cancer 47:31–39PubMedCrossRefGoogle Scholar
  64. 64.
    Kim SJ, Uehara H, Yazici S et al (2005) Modulation of bone microenvironment with zoledronate enhances the therapeutic effects of STI571 and paclitaxel against experimental bone metastasis of human prostate cancer. Cancer Res 65:3707–3715PubMedCrossRefGoogle Scholar
  65. 65.
    Heymann D, Ory B, Blanchard F et al (2005) Enhanced tumor regression and tissue repair when zoledronic acid is combined with ifosfamide in rat osteosarcoma. Bone 37:74–86PubMedCrossRefGoogle Scholar
  66. 66.
    Zhou Z, Guan H, Duan X, Kleinerman ES (2005) Zoledronic acid inhibits primary bone tumor growth in Ewing sarcoma. Cancer 104:1730–1720CrossRefGoogle Scholar
  67. 67.
    Yildiz M, Celik-Ozenci C, Akan S, Akan I et al (2006) Zoledronic acid is synergic with vinblastine to induce apoptosis in a multidrug resistance protein-1 dependent way: an in vitro study. Cell Biol Int 30:278–282PubMedCrossRefGoogle Scholar
  68. 68.
    Budman DR, Calabro A (2006) Zoledronic acid (Zometa) enhances the cytotoxic effect of gemcitabine and fluvastatin: in vitro isobologram studies with conventional and nonconventional cytotoxic agents. Oncology 70:147–153PubMedCrossRefGoogle Scholar
  69. 69.
    Ozturk OH, Bozcuk H, Burgucu D (2007) Cisplatin cytotoxicity is enhanced with zoledronic acid in A549 lung cancer cell line: preliminary results of an in vitro study. Cell Biol Int 31:1069–1071PubMedCrossRefGoogle Scholar
  70. 70.
    Caraglia M, D’Alessandro AM, Marra M et al (2004) The farnesyl transferase inhibitor R115777 (Zarnestra) synergistically enhances growth inhibition and apoptosis induced on epidermoid cancer cells by Zoledronic acid (Zometa) and Pamidronate. Oncogene 23:6900–6913PubMedCrossRefGoogle Scholar
  71. 71.
    Druker BJ, Sawyers CL, Kantarjian H et al (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukaemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042PubMedCrossRefGoogle Scholar
  72. 72.
    Fang JY and Richardson BC (2005) The MAPK signalling pathways and colorectal cancer. Lancet Oncol 6:322–327PubMedCrossRefGoogle Scholar
  73. 73.
    Witters LM, Crispino J, Fraterrigo T et al (2003) Effect of the combination of docetaxel, zoledronic acid, and a COX-2 inhibitor on the growth of human breast cancer cell lines. Am J Clin Oncology 26:S92–S97Google Scholar
  74. 74.
    Lennernäs B, Albertsson P, Damber JE, Norrby K (2004) Antiangiogenic effect of metronomic paclitaxel treatment in prostate cancer and non-tumor tissue in the same animals: a quantitative study. APMIS 112:201–209PubMedCrossRefGoogle Scholar
  75. 75.
    Andela VB, Rosenblatt JD, Schwarz EM et al (2002) Synergism of aminobisphosphonates and farnesyl transferase inhibitors on tumor metastasis. Clin Irthopaedics Related Res 397:228–239CrossRefGoogle Scholar
  76. 76.
    Yata K, Otsuki T, Yamada O et al (2002) Synergistic growth inhibition of YM529 with biologic response modifiers (BRMs) in myeloma cells. Int J Hematol 75:534–539PubMedGoogle Scholar
  77. 77.
    Kuroda J, Kimura S, Segawa H, et al (2003) The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate. Blood 102:2229–2235PubMedCrossRefGoogle Scholar
  78. 78.
    Zhang PL, Lun M, Siegelmann-Danieli N et al (2004) Pamidronate resistance and associated low ras levels in breast cancer cells: a role for combinatorial therapy. Ann Clin Lab Sci 34:263–270PubMedGoogle Scholar
  79. 79.
    Yuasa T, Nogawa M, Kimura S et al (2005) A third-generation bisphosphonate, minodronic acid (YM529), augments the interferon alpha/beta-mediated inhibition of renal cell cancer cell growth both in vitro and in vivo. Clin Cancer Res 15:853–859Google Scholar
  80. 80.
    Segawa H, Kimura S, Kuroda J et al (2005) Zoledronate synergises with imatinib mesylate to inhibit Ph primary leukaemic cell growth. Br J Haematol 130:558–560PubMedCrossRefGoogle Scholar
  81. 81.
    Caraglia M, Marra M, Leonetti C et al (2007) R115777 (Zarnestra)/Zoledronic acid (Zometa) cooperation on inhibition of prostate cancer proliferation is paralleled by Erk/Akt inactivation and reduced Bcl-2 and bad phosphorylation. J Cell Physiol 211:533–543PubMedCrossRefGoogle Scholar
  82. 82.
    Costa L, Demers LM, Gouveia-Oliveira A et al (2002) Prospective evaluation of the peptide-bound collagen Type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status. J Clin Oncol 20:850–856PubMedCrossRefGoogle Scholar
  83. 83.
    Brown J, Cook R, Coleman RE et al (2003) The role of bone turnover markers in predicting clinical events in metastatic bone disease. Proc Am Soc Clin Oncol 22:738Google Scholar
  84. 84.
    Saad F (2006) Benefits of zoledronic acid in the treatment of prostate cancer: Survival and antitumor effects. J Clin Oncol 24[suppl]:230s. Abstract 4555.Google Scholar
  85. 85.
    Bertelli G, Heouaine A, Arena G et al (2006) Weekly docetaxel and zoledronic acid every 4 weeks in hormonerefractory prostate cancer patients. Cancer Chemother Pharmacol 57:46–51. Saad et al. J Clin Oncol. 2006;24[suppl]:230s. Abstract 4555.PubMedCrossRefGoogle Scholar
  86. 86.
    Mystakidou K, Katsouda E, Parpa E et al (2005) Randomized, open label, prospective study on the effect of zoledronic acid on the prevention of bone metastases in patients with recurrent solid tumors that did not present with bone metastases at baseline. Med Oncol 22:195–201PubMedCrossRefGoogle Scholar
  87. 87.
    Lipton A, Zheng M, Seaman J (2003) Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer. 98:962–969PubMedCrossRefGoogle Scholar
  88. 88.
    Janni W, Hepp F, Rjosk D et al (2001) The fate and prognostic value of occult metastatic cells in the bone marrow of patients with breast carcinoma between primary treatment and recurrence. Cancer 92:46–53PubMedCrossRefGoogle Scholar
  89. 89.
    Rack BK, Janni W, Schindlbeck C et al (2004) Effect of zoledronate on persisting isolated tumor cells (ITC) in the bone marrow (BM) of patients without recurrence of early breast cancer. Proc Am Soc Clin Oncol 23:834. Abstract 9515Google Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Daniele Santini
    • 1
  • Sara Galluzzo
    • 1
  • Maria Elisabetta Fratto
    • 1
  • Bruno Vincenzi
    • 1
  • Silvia Angeletti
    • 2
  • Giordano Dicuonzo
    • 2
  • Gaia Schiavon
    • 1
  • Giuseppe Tonini
    • 1
  1. 1.Medical OncologyUniversity Campus Bio-MedicoRomeItaly
  2. 2.Clinical PathologyUniversity Campus Bio-MedicoRomeItaly

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