Successful treatment of angiomatosis with thalidomide and interferon α. A description of five cases and overview of treatment of angiomatosis and proliferating hemangiomas

Česká verzia

Authors: Z. Adam ¹; L. Pour ¹; M. Krejčí ¹; E. Pourová ²; O. Synek ²; L. Zahradová ¹; M. Navrátil ¹; M. Mechl ³; T. Nebeský ³; J. Neubauer ³; J. Feit ⁴; J. Vokurková ⁵; Z. Král ¹; O. Bednařík ¹; P. Šlampa ⁶; H. Doležalová ⁶; R. Hájek ¹; J. Mayer ¹
Authors place of work: Interní hematoonkologická klinika Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jiří Vorlíček, CSc. ¹; Interní oddělení nemocnice Vyškov, přednosta prim. MUDr. Oldřich Synek ²; Radiologická klinika Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Vlastimil A. Válek, CSc. ³; Ústav patologie Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta doc. MUDr. Josef Feit, CSc. ⁴; Klinika popálenin a rekonstrukční chirurgie Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Pavel Brychta, CSc. ⁵; Radioterapeutická klinika Lékařské fakulty MU a Masarykova onkologického ústavu Brno, přednosta prof. MUDr. Pavel Šlampa, CSc. ⁶
Published in the journal: Vnitř Lék 2010; 56(8): 810-823
Category: Case Reports

Summary

Our paper describes 5 patients with a vascular malformation – angiomatosis. In the first patient, a young man, angiomatosis affected the stomach, intestine, the area of mesenterium and retroperitoneum as well as mediastinum. Angiomatous mass had invaded pelvic bones and vertebrae. Treatment was initiated with interferon α in a maximum tolerated dose of 3 million units 3 times a week. Because of low efficacy of interferon α, thalidomide was added at a dose of 100 mg per day. Bone pain disappeared following a few applications of zoledronate administered in regular monthly intervals. After 3 years of concomitant administration of interferon α and thalidomide, we changed the regimen due to adverse effects and are administering thalidomide and interferon alternatively in 4-monthly intervals. Treatment has resulted in 50% reduction, according to imaging, of angiomatous mass, reduced intensity of disseminated intravascular coagulation and disappearance of clinical signs. The second was a case of multiple angiomatosis affecting the intestine only (multiple intestinal angiodysplasias) where we used thalidomide monotherapy. This treatment reduced blood losses and haemoglobin concentrations rose to normal levels. This male patient had consumed 120 transfusion units per year before the initiation of thalidomide. The third case was a slowly progressing vascular malformation of the face. This vascular malformation troubled its sufferer by spontaneous shortening that could not be resolved surgically because of its fragility. Two years of combined treatment with interferon α 6 million unites 3 times a week and thalidomide 100 mg daily led to a reduction and flattening of the malformation, paling of its colour and ceasing of spontaneous bleeding. This development enabled minor surgery – partial excision of this large vascular malformation. Histology examination confirmed that there was no evidence of new capillary formation. Histological examination thus confirmed efficacy of the treatment. The fourth case involved a patient with large vascular malformations affecting supraclavicular region of the neck and nape in whom radiotherapy was applied (54 Gy) leading to a reduction of the malformation mass by a at least 50%. The fifth is a case of an extensive periorbital lymphangioma that diminished following treatment with interferon α. These cases illustrate the benefits of combined treatment including thalidomide and interferon α in patients with multiple angiomatosis or large proliferating hemangioma (vascular malformation). If combined treatment with thalidomide and interferon α is not possible, it is beneficial to use thalidomide monotherapy. Radiotherapy is another alternative, although it is necessary to apply doses exceeding 50 Gy which may not be always possible.

Key words:
vascular malformation – angiomatosis – hemangiomatosis – hemangioma – angiodysplasia – lymphangioma – thalidomide – lenalidomide – interferon α – zoledronate – bevacizumab – antiangiogenic treatment – radiotherapy – monoclonal gammopathy

Zdroje

1. Weiss SW, Goldblum J, Enzinger FM et al. Hemangiomas and angiomatosis. In: Christopher DM, Krishnan UK, Fredrik M (eds). WHO classification of tumours: pathology and genetics of tumours of soft tissue and bone. Lyon: IARC Press 2002: 161–168.

2. Adam Z, Křikavová L, Krejčí M et al. Léčba mnohočetné angiomatózy postihující skelet, břišní i hrudní dutinu interferonem alfa, thalidomidem a zoledronatem. Vnitř Lék 2008; 54: 653–664.

3. Sundine MJ, Wirth GA. Hemangiomas: an overview. Clin Pediatr (Phila) 2007; 46: 206–221.

4. Argenta LC, David LR, Sanger C et al. Advances in hemangioma evaluation and treatment. J Craniofac Surg 2006; 17: 748–755.

5. Werner JA, Eivazi B, Folz BJ et al. State of art zur Klassifikation, diagnostik und therapie von zervikofazialen Hämangiomen und vaskulären Malformationen. Laryngo-Rhino-Otol 2006; 85: 883–891.

6. Srbová J. Hemangiomatóza. Sestra 2005; 15: 46.

7. Metry DW, Hawroth A, Altman C et al. Association of solitary, segmental hemangiomas of the skin with visceral hemangiomatosis. Arch Dermatol 2004; 140: 591–596.

8. Vevaina JR, Mark EJ. Thoracic hemangiomatosis masquerading as interstitial lung disease. Chest 1988; 93: 657–659.

9. Sullivan A, Chmura K, Cool CD et al. Pulmonary capillary hemangiomatosis: an immunohistochemical analysis of vascular remodeling. Eur J Med Res 2006; 11: 187–193.

10. Cioffi U, De Simone M, Pavoni M et al. Pulmonary capillary hemangiomatosis in an asymptomatic elderly patient. Int Surg 1999; 84: 168–170.

11. Fugo K, Matsuno Y, Okamoto K et al. Solitary capillary hemangioma of the lung: report of 2 resected cases detected by high‑resolution CT. Am J Surg Pathol 2006; 30: 750–753.

12. Ito K, Ichiki T, Ohi K et al. Pulmonary capillary hemangiomatosis with severe pulmonary hypertension. Circ J 2003; 67: 793–795.

13. Levy AD, Abbott RM, Rohrmann CA Jr et al. Gastrointestinal hemangiomas: imaging findings with pathologic correlation in pediatric and adult patients. AJR Am J Roentgenol 2001; 177: 1073–1081.

14. Lyon DT, Mantia AG. Large-bowel hemangiomas. Dis Colon Rectum 1984; 27: 404–414.

15. Park DD, Ricketts RR. Infantile gastrointestinal hemangioma as a cause of chronic anemia. South Med J 1992; 85: 201–205.

16. Mills CS, Lloyd TV, van Aman ME et al. Diffuse hemangiomatosis of the colon. J Clin Gastroenterol 1985; 7: 416–421.

17. Mottl H, Koutecký J, Buncová M et al. Sdružený výskyt preaurikulárního hemangiomu s hemangiomatózou tenkého střeva a mesenteria. Čes Slov Pediatr 1985; 40: 523–526.

18. Lakhkar B, Abubacker S. Duodeno‑jejunal hemangiomatosis. Indian J Pediatr 2000; 67: 931–933.

19. Djouhri H, Arrive L, Bouras T et al. Diffuse cavernous hemangiomatosis of the rectosigmoid colon: imaging findings. J Comput Assist Tomogr 1998; 22: 851–855.

20. Dobozi BM, Rockey DC. Diffuse colonic hemangiomatosis. Gastrointest Endosc 2004; 60: 799.

21. Elsayes KM, Menias CO, Dillman JR et al. Vascular malformation and hemangiomatosis syndromes: spectrum of imaging manifestations. AJR Am J Roentgenol 2008; 190: 1291–1299.

22. Hsu RM, Horton KM, Fishman EK. Diffuse cavernous hemangiomatosis of the colon: findings on three-dimensional CT colonography. AJR Am J Roentgenol 2002; 179: 1042–1044.

23. Scafidi DE, McLeary MS, Young LW. Diffuse neonatal gastrointestinal hemangiomatosis. CT finding. Pediatr Radiol 1998; 28: 512–518.

24. Schulze PJ, Langendorff G. Extensive, diffuse haemangiomatosis of the skeleton. Rofo 1979; 131: 67–71.

25. Seelhoff A, Schumacher B. 72‑year-old woman with anemia and suspected intestinal blood loss. Dtsch Med Wochenschr 2009; 134: 1819–1820.

26. Parker WT, Harper JG, Rivera DE et al. Mesenteric cavernous hemangioma involving small bowel and appendix: a rare presentation of a vascular tumor. Am Surg 2009; 75: 811–816.

27. Marinis A, Kairi E, Theodosopoulos T et al. Right colon and liver hemangiomatosis: a case report and a review of the literature. World J Gastroenterol 2006; 12: 6405–6407.

28. Ibarguen E, Sharp HL, Snyder CL et al. Hemangiomatosis of the colon and peritoneum: case report and management discussion. Clin Pediatr (Phila) 1988; 27: 425–430.

29. Bláhová K, Mottl M, Tůma S. Hemangiomatóza jater u tříměsíčního kojence. Čes Slov Pediatr 1991; 46: 434–436.

30. Moon WS, Yuy HC, Lee JM et al. Diffuse hepatic hemangiomatosis in an adult. J Korean Med Sci 2000; 15: 471–474.

31. Langer C, Thonhofer R, Hagenbarth K et al. Difuse Hämangiomatose von Leber und Milz bei Erwachsenen. Pathologie 2001; 22: 424–428.

32. Kalousová J. Komplexní léčba hemangiomatózy jater. Čes Slov Pediatr 1994; 49: 698–699.

33. Kim JD, Chang UI, Yang JM Clinical challenges and images in GI. Diffuse hepatic hemangiomatosis involving the entire liver. Gastroenterology 2008; 134: 1830, 2197.

34. D’Antonio A, Boscaino A, de Dominicis G et al. Splenic hemangiomatosis. A report of two cases and review of literature. Adv Clin Path 2002; 6: 119–124.

35. Kairi‑Vassilatou E, Grapsa D, Kontogianni‑Katsarou K et al. Clinicopathological features of unusual vascular lesions of the pelvis, retroperitoneum and colon in females: a report of five cases and review of the literature. Eur J Gynaecol Oncol 2006; 27: 250–255.

36. Dixit VK, Sharma H, Ratnakar KS. Splenic hemangiomatosis with osseous involvement. Indian J Gastroenterol 1993; 12: 105–106.

37. Lin CH, Hsieh HF, Yu JC et al. Spontaneous rupture of a large exogastric hemangioma. complicated by hemoperitoneum and sepsis. J Formos Med Assoc 2006; 105: 1027–1030.

38. Valentini V, Nicolai G, Lorè B et al. Intraosseous hemangiomas. J Craniofac Surg 2008; 19: 1459–1464.

39. Plowman PN. Skeletal haemangiomatosis presenting with spinal cord compression – postoperative management of pro-gressive disease. Br J Radiol 1997; 70: 429–431.

40. Bandiera S, Gasbarrini A, De Iure F et al. Symptomatic vertebral hemangioma: the treatment of 23 cases and a review of the literature. Chir Organi Mov 2002; 87: 1–15.

41. Janecek M, Dufek P. Generalized hemangiomatosis in relation to the synovial membrane. Acta Chir Orthop Traumatol Cech 1985; 52: 155–160.

42. Dufau JP, le Tourneau A, Audouin J et al. Isolated diffuse hemangiomatosis of the spleen with Kasabach‑Merrit‑like syndrome. Histopathology 1999; 35: 337–344.

43. Lantuéjoul S, Sheppard MN, Corrin B et al. Pulmonary veno‑occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol 2006; 30: 850–857.

44. Junquera F, Saperas E, de Torres I et al. Increased expression of angiogenic factors in human colonic dysplasia. Am J Gastroenterol 1999; 94: 1070–1076.

45. Cirulli A, Liso A, D’Ovidio F et al. Vascular endothelial growth factor serum levels are elevated in patients with hereditary hemorrhagic telangiectasia. Acta Haematol 2003; 110: 29–32.

46. Ozawa CR, Banfi A, Glazer NL et al. Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis. J Clin Invest 2004; 113: 516–527.

47. Lee RJ, Springer ML, Blanco-Bose WE et al. VEGF gene delivery do myocardium: deleterious effects of unregulated expression. Circulation 2000; 102: 898–901.

48. Bauditz J, Lochs H, Voderholzer W. Macroscopic appearance of intestinal angiodysplasias under antiangiogenic treatment with thalidomide. Endoscopy 2006; 38: 1036–1039.

49. Vase P. Estrogen treatment of hereditary hemorrhatic telangiectasia. A double blind controlled trial. Acta Med Scand 1981; 209: 393–396.

50. Junquera F, Feu F, Papo M et al. A multicenter, randomized, clinical trial of hormonal therapy in the prevention of rebleeding from gastrointestinal angiodysplasia. Gastroenterology 2001; 121: 1073–1079.

51. Wettstein AR, Meagher AP. Thalidomide in Crohn’s disease. Lancet 1997; 350: 1445–1446.

52. Pérez-Encinas M, Rabuñal Martínez MJ, Bello López JL. Is thalidomide effective for the treatment of gastrointestinal bleeding in hereditary hemorhagic telangiectasia? Haematologica 2002; 87: 34–35.

53. Bauditz J, Schachschal G, Wedel S et al. Thalidomie for treatment of severe intestinal bleeding. Gut 2004; 53: 609–612.

54. Bauditz J. Angiogeneseinhibitoren zur Behandlung Angiodysplasie assoziirter gastrointestinaler Blutungen. Dtsch Med Wochenschr 2009; 134: 1893–1896.

55. Madhusudan S, Deplanque G, Braybrooke JP et al. Antiangiogenic therapy for Hippel Lindau disease. JAMA 2004; 291: 943–944.

56. Mahajan D, Miller C, Hirose K et al. Incidental reduction of the size of liver hemangioma following use of VEGF inhibitor bevacizumab. J Hepatol 2008; 49: 867–870.

57. Šlampa P, Petera J et al. Radiační onkologie. Praha: Galén 2007, 30–32, 418–419.

58. Blei F, Orlow SJ, Geronemus R. Multimodal management of diffuse neonatal hemangiomatosis. J Am Acad Dermatol 1997; 37: 1019–1021.

59. Gozal D, Saad N, Bader D et al. Diffuse neonatal haemangiomatosis: successful management with high dose corticosteroids. Eur J Pediatr 1990; 149: 321–324.

60. Hasan Q, Tan ST, Gush J et al. Steroid therapy of a proliferating hemangioma: histochemical and molecular changes. Pediatrics 2000; 105: 117–120.

61. Haxhija EQ, Lackner H, Höllwarth ME. Medical treatment of children with hemangiomas and its limitations. Handchir Mikrochir Plast Chir 2009; 41: 78–82.

62. Mulliken JB, Boon LM, Takahashi K et al. Pharmacologic therapy for endangering hemangiomas. Curr Opin Dermatol 1995; 2: 109–113.

63. Musumeci ML, Schlecht K, Perrotta R et al. Management of cutaneous hemangiomas in pediatric patients. Cutis 2008; 81: 315–322.

64. Roganovic J. An update on the treatment of high‑risk hemangiomas in infants. Eur J Pediatr Surg 2007; 17: 147.

65. Uysal KM, Olgun N, Erbay A et al. High dose oral methylprednisolone therapy in childhood hemangiomas. Pediatr Hematol Oncol 2001; 18: 335–341.

66. Wilson MW, Hoehn ME, Haik BG et al. Low‑dose cyclophosphamide and interferon alfa 2a for the treatment of capillary hemangioma of the orbit. Ophthalmology 2007; 114: 1007–1011.

67. Drucker AM, Pope E, Mahant S et al. Vincristine and corticosteroids as first‑line treatment of Kasabach‑Merritt syndrome in kaposiform hemangioendothelioma. J Cutan Med Surg 2009; 13: 155–159.

68. Gottschling S, Schneider G, Meyer S et al. Two infants with life-threatening diffuse neonatal hemangiomatosis treated with cyclophosphamide. Pediatr Blood Cancer 2006; 46: 239–242.

69. Hara K, Yoshida T, Kajiume T et al. Successful treatment of Kasabach-Merritt syndrome with vincristine and diagnosis of the hemangioma using three-dimensional imaging. Pediatr Hematol Oncol 2009; 26: 375–380.

70. Hurvitz SA, Hurvitz CH, Sloninsky L et al. Successful treatment with cyclophosphamide of life-threatening diffuse hemangiomatosis involving the liver. J Pediatr Hematol Oncol 2000; 22: 527–532.

71. Hauer J, Graubner U, Konstantopoulos Net al. Effective treatment of kaposiform hemangioendotheliomas associated with Kasabach-Merritt phenomenon using four-drug regimen. Pediatr Blood Cancer 2007; 49: 852–854.

72. Harper L, Michel JL, Enjolras O et al. Successful management of a retroperitoneal kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon using alpha-interferon. Eur J Pediatr Surg 2006; 16: 369–372.

73. Hartman KR, Moncur JT, Minniti CP et al Mediastinal Kaposiform hemangioendothelioma and Kasabach-Merritt phenomenon in an infant: treatment with interferon. J Pediatr Hematol Oncol 2009; 31: 690–692.

74. Chao YH, Liang DC, Chen SH et al. Interferon‑alpha for alarming hemangiomas in infants: experience of a single institution. Pediatr Int 2009; 51: 469–473.

75. Jiménez-Hernández E, Dueñas-González MT, Quintero‑Curiel JL et al. Treatment with interferon‑alpha-2b in children with life-threatening hemangiomas. Dermatol Surg 2008; 34: 640–647.

76. Lindner DJ. Interferons as antiangiogenic agents. Curr Oncol Rep 2002; 4: 510–514.

77. Nevolová P, Bláhová K, Kabelka Z. Úspěchy léčby rozsáhlé hemangiomatózy u 17měsíčního dítěte po podání interferonu alfa. Ref výběr Dermatovenereol 1996; 2: 83.

78. Radzikowska E, Szczepulska-Wójcik E, Roszkowski K. Pulmonary epithelioid haemangioendothelioma – interferon 2‑alpha treatment – case report. Pneumonol Alergol Pol 2008; 76: 281–285.

79. Schiavetti A, De Pasquale MD, Di Salvo S et al. Recombinant interferon alfa 2a in hepatic hemangiomatosis with congestive heart failure: a case report. Pediatr Hematol Oncol 2003; 20: 161–165.

80. Stratte EG, Tope WD, Johnson CL et al. Multimodal management of diffuse neonatal hemangiomatosis. J Am Acad Dermatol 1996; 34: 337–342.

81. Suskan E, Tekin D, Atay G et al. Airway haemangioma treated with interferon‑alpha 2a. Acta Paediatr 2008; 97: 393–394.

82. Szymik-Kantorowicz S, Kobylarz K, Krysta M et al. Interferon‑alpha in the treatment of high‑risk haemangiomas in infants. Eur J Pediatr Surg 2005; 15: 11–16.

83. White CW. Treatment of hemangiomatosis with recombinant interferon alfa. Semin Hematol 1990; 27 (3 Suppl 4): 15–22.

84. Wu JM, Lin CS, Wang JN et al. Pulmonary cavernous hemangiomatosis treated with interferon alfa‑2a. Pediatr Cardiol 1996; 17: 332–334.

85. Kaselas C, Tsikopoulos G, Papouis G et al. Intralesional administration of interferon A for the management of severe haemangiomas. Pediatr Surg Int 2007; 23: 215–218.

86. Eichler A, Ukena D, Wilkens H et al. Interferon alfa‑2a in the treatment of diffuse thoracic angiomatosis in adulthood. Pneumologie 2000; 54: 243–248.

87. Sardi I, Sanzo M, Giordano F et al. Monotherapy with thalidomide for treatment of spinal cord hemangioblastomas in a patient with von Hippel-Lindau disease. Pediatr Blood Cancer 2009; 53: 464–467.

88. Takahashi A, Ogawa C, Kanazawa T et al. Remission induced by interferon alfa in a patient with massive osteolysis and extension of lymph-hemangiomatosis: a severe case of Gorham‑Stout syndrome. J Pediatr Surg 2005; 40: E47–E50.

89. Or R, Feferman R, Shoshan S. Thalidomide reduces vascular density in granulomatous tissue of subcutaneously implanted polyvinyl alcohol sponges in guinea pigs. Exp Hematol 1998; 26: 217–221.

90. Vacca A, Scavelli C, Montefusco V et al. Thalidomide down regulates angiogenic genes in bone marrow endothelial cells of patients with multiple myeloma. J Clin Oncol 2005; 23: 5334–5346.

91. Rajkumar SV, Witzig TE. A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma. Cancer Treat Rev 2000; 26: 351–362.

92. Bauer KS, Dixon SC, Figg WD. Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species dependent. Biochem Pharmacol 1998; 55: 1827–1834.

93. D’Amato RJ, Loughnan MS, Flynn E et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994; 91: 4082–4085.

94. Kenyon BM, Browne F, D’Amato RJ. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res 1997; 64: 971–978.

95. Piribauer M, Czech T, Dieckmann K et al. Stabilization of a progressive hemangioblastoma under treatment with thalidomide. J Neurooncol 2004; 66: 295–299.

96. Mascarenhas RC, Sanghvi AN, Friedlander L et al. Thalidomide inhibits the growth and progression of hepatic epithelioid hemangioendothelioma. Oncology 2004; 67: 471–475.

97. Frei-Jones M, McKinstry RC, Perry A et al. Use of thalidomide to diminish growth velocity in a life-threatening congenital intracranial hemangioma. J Neurosurg Pediatr 2008; 2: 125–129.

98. Jarvi K, Roebuck DJ, Sebire NJ et al. Successful treatment of extensive infantile hemangiomatosis of the small bowel in a 3-month-old with thalidomide and somatostatin analog. J Pediatr Gastroenterol Nutr 2008; 46: 593–597.

99. Almadi M, Ghali PM, Constantin A et al. A. Recurrent obscure gastrointestinal bleeding: dilemmas and success with pharmacological therapies. Case series and review. Can J Gastroenterol 2009; 23: 625–631.

100. Bauditz J, Lochs H. Angiogenesis and vascular malformations: antiangiogenic drugs for treatment of gastrointestinal bleeding. World J Gastroenterol 2007; 13: 5979–5984.

101. Kirkham SE, Lindley KJ, Elawad MA et al. Treatment of multiple small bowel angiodysplasias causing severe life-threatening bleeding with thalidomide. J Pediatr Gastroenterol Nutr 2006; 42: 585–587.

102. Mimidis K, Kaliontzidou M, Tzimas T at al. Thalidomide for treatment of bleeding angiodysplasias during hemodialysis. Ren Fail 2008; 30: 1040–1041.

103. Alberto SF, Felix J, de Deus J. Thalidomide for the treatment of severe intestinal bleeding. Endoscopy 2008; 40: 788.

104. Selinger CP, Ang YS. Gastric antral vascular ectasia (GAVE): an update on clinical presentation, pathophysiology and treatment. Digestion 2008; 77: 131–137.

105. Dunne KA, Hill J, Dillon JF. Treatment of chronic transfusion‑dependent gastric antral vascular ectasia (watermelon stomach) with thalidomide. Eur J Gastroenterol Hepatol 2006; 18: 455–456.

106. Hirri HM, Green PJ, Lindsay J. Von Willebrand’s disease and angiodysplasia treated with thalidomide. Haemophilia 2006; 12: 285–286.

107. Fraiman G, Ganti AK, Potti A et al. Angiosarcoma of the small intestine: a possible role for thalidomide? Med Oncol 2003; 20: 397–402.

108. Shurafa M, Kamboj G. Thalidomide for the treatment of bleeding angiodysplasias. Am J Gastroenterol 2003; 98: 221–222.

109. Dabak V, Kuriakose P, Kamboj G et al. A pilot study of thalidomide in recurrent GI bleeding due to angiodysplasias. Dig Dis Sci 2008; 53: 1632–1635.

110. Heidt J, Langers AM, van der Meer FJ et al. Thalidomide as treatment for digestive tract angiodysplasias. Neth J Med 2006; 64: 425–428.

111. Ma L, del Soldato P, Wallace JL. Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing. Shifting the antiogenic balance. Proc Natl Acad Sci USA 2002; 99: 13243–13247.

112. Masferrer JL, Leahy KM, Koki AT et al. Antiangiogenic and antitumor activities of cyclooxygenase‑2 inhibitors. Cancer Res 2000; 60: 1306–1311.

113. Meyerle CB, Freund KB, Iturralde D et al. Intravitreal bevacizumab (Avastin) for retinal angiomatous proliferation. Retina 2007; 27: 451–457.

114. Ziemssen F, Voelker M, Inhoffen W et al. Combined treatment of juxtapapillary retinal capillary haemagnioma with intravitreal bevacizumab and photodynamic therapy. Eye 2007; 21: 1125–1126.

115. von Buelow M, Pape S, Hoerauf H. Systemic bevacizumab treatment of a juxtapappillary retinal haemangioma. Acta Ophthalmol Scand 2007; 85: 114–116.

116. Joeres S, Heussen FM, Treziak T et al. Bevacizumab (Avastin) treatment in patients with retinal angiomatous proliferation. Graefes Arch Clin Exp Ophthalmol 2007; 245: 1597–1602.

117. Belmont L, Zemoura L, Couderc LJ. Pulmonary epithelioid haemangioendothelioma and bevacizumab. J Thorac Oncol 2008; 3: 557–558.

118. Gilheeney SW, Scott, RM, Turner C et al. Treatment of Von Hippel Lindau associated hemangioblastoma in pediatric patients with bevacizumab (Avastin). Neurolo‑Oncology 2007; 9. Abstract 168.

119. Nelson SC, Bostrom BC. Successful use of bevacizumab in live threatening steroid‑resistant infantile hepatic hemangioendotelioma. Pediatr Blood Cancer 2007; 48. Abstract 611.

120. Kline RM, Buck LM. Bevacizumab treatment in multifocal lymphangioendotheliomatosis with thrombocytopenia. Pediatr Blood Cancer 2009; 52: 534–536.

121. Smith AR, Jane H, Margaret HK et al. Reversible bony changes after treatment with bevacizumab in a child with cutaneovisceral angiomatosis with thrombocytopenia syndrome: A case report and review of the literature. Blood 2007; 110: 1323.

122. Bose P, Holter JL, Selby GB et al. Use of bevacizumab in hereditary hemorhagic telangiectasia. Blood 2008; 112 (Suppl). Abstract 3928.

123. Mitchell A, Adams LA, MacQuillan Get al. Bevacizumab reverse need for liver transplantation in hereditary hemorhagic telangiectasia. Liver Transplant 2008; 14: 210–213.

124. Smith AR, Hennessy JM, Kurth MA et al. Reversible skeletal changes after treatment with bevacizumab in a child with cutaneovisceral angiomatosis with thrombocytopenia syndrome. Pediatr Blood Cancer 2008; 51: 418–420.

125. Ramasamy K, Stephen LW, Jackie C et al. Bevacizumab for POEMS syndrome. Blood 2006; 108. Abstract 366B.

126. Misri R, Kharkar V, Dandale A et al. Multiple capillary hemangiomas: a distinctive lesion of multicentric Castleman’s disease and POEMS syndrome. Indian J Dermatol Venereol Leprol 2008; 74: 364–366.

127. Bellahcène A, Chaplet M, Bonjean K et al. Zoledronate inhibits alphavbeta3 and alphavbeta5 integrin cell surface expression in endothelial cells. Endothelium 2007; 14: 123–130.

128. Croucher PI, De Hendrik R, Perry MJet al. 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 2003; 18: 482–492.

129. Fournier P, Boissier S, Filleur S et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone‑stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002; 62: 6538–6544.

130. Hasmim M, Bieler G, Rüegg C. Zoledronate inhibits endothelial cell adhesion, migration and survival through the suppression of multiple, prenylation‑dependent signaling pathways. J Thromb Haemost 2007; 5: 166–173.

131. Li EC, Davis LE. Zoledronic acid: a new parenteral bisphosphonate. Clin Ther 2003; 25: 2669–2708.

132. Wood J, Bonjean K, Ruetz S et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002; 302: 1055–1061.

133. Yu H, Qin A. Could local delivery of bisphosphonates be a new therapeutic choice for hemangiomas? Med Hypotheses 2009; 73: 495–497.

134. Nardone G, Rocco A, Balzano T et al. The efficacy of octreotide therapy in chronic bleeding due to vascular abnormalities of the gastrointestinal tract. Aliment Pharmacol Ther 1999; 13: 1429–1436.

135. Scaglione G, Pietrini L, Russo F et al. Long acting octreotide as rescue therapy in chronic bleeding from gastrointestinal angiodysplasia. Aliment Pharmacol Ther 2007; 26: 935–942.

136. Nardone G, Rocco A, Balzano T et al. The efficacy of octreotide therapy in chronic bleeding due to vascular abnormalities of the gastrointestinal tract. Aliment Pharmacol Ther 1999; 13: 1429–1436.

137. Loo WJ, Lanigan SW. Recent advances in laser therapy for the treatment of cutaneous vascular disorders. Lasers Med Sci 2002; 17: 9–12.

138. Winter H, Dräger E, Sterry W. Sclerotherapy for treatment of hemangiomas. Dermatol Surg 2000; 26: 105–108.

139. Colella G, Vuolo G, Siniscalchi G et al. Radiotherapy for maxillo‑facial hemangiomas in children. Dental and periodontal long term effects. Minerva Stomatol 2005; 54: 509–516.

140. Kwok-Williams M, Perez Z, Squire Ret al. Radiotherapy for life-threatening mediastinal hemangioma with Kasabach-Merritt syndrome. Pediatr Blood Cancer 2007; 49: 739–744.

141. Leong E, Bydder S. Use of radiotherapy to treat life‑threatening Kasabach‑Merritt syndrome. J Med Imaging Radiat Oncol 2009; 53: 87–91.

142. Blatný J, Štěrba J, Magnová O. Léčba život ohrožujícího krvácení u kojence s hemangiomatózou a s projevy Kasabacha‑Merritové pomocí rekombinantního faktoru VIIA. Čes Slov Pediatr 2002; 57: 401–402.

143. McLaughlin ER, Morris R, Weiss SW et al. Diffuse dermal angiomatosis of the breast: response to isotretinoin. J Am Acad Dermatol 2001; 45: 462–465.

144. van Heeckeren WJ, Sanborn SL, Narayan A et al. Complication from vascular disrupting agents and angiogenesis inhibitors: aberrant control for hemostasis and thrombosis. Curr Opin Hematol 2007; 14: 468–480.