Vnitr Lek 2022, 68(1):41-53 | DOI: 10.36290/vnl.2022.006

Multicentric Castleman's disease. Symptoms, diagnostics and therapy

Zdeněk Adam1, Zdeněk Řehák2, Zuzana Adamová3, Renata Koukalová2, Luděk Pour1, Marta Krejčí1, Ivanna Boichuk1, Viera Sandecká1, Martin Krejčí1, Martin Štork1, Sabina Ševčíková4, Zdeněk Král1
1 Interní hematologická a onkologická klinika LF MU a FN Brno
2 Oddělení nukleární medicíny Masarykův onkologický ústav Brno
3 Chirurgické oddělení nemocnice Frýdek-Místek
4 Ústav patologické fyziologie LF MU, Brno

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric (UCD) or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor. In this paper, we briefly report about symptoms of iMCD and about the International, evidence‑based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease and International evidence based consensus treatment guidelines for idiopathic multicentric Castleman disease.

Keywords: Castleman disease, siltuximab.

Published: February 14, 2022  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Adam Z, Řehák Z, Adamová Z, Koukalová R, Pour L, Krejčí M, et al.. Multicentric Castleman's disease. Symptoms, diagnostics and therapy. Vnitr Lek. 2022;68(1):41-53. doi: 10.36290/vnl.2022.006.
Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. Munshi N, Mehra M. van de Velde H, Desai A et al. Use of a claims database to characterize and estimate the incidence rate for Castleman disease. Leuk Lymphoma 2015; 56(5):1252-1260. Go to original source... Go to PubMed...
    2. Adam Z, Pour L, Krejčí M et al. Lokalizovaná (unicentrická) forma Castlemanovy nemoci. Klinické projevy, diagnostika a léčba dle mezinárodních doporučení z roku 2020. Vnitř Lék 2021;67(8):462-471. Go to original source...
    3. Fajgenbaum DC, vanRhee F, Nabel ChS. HHV-8 negative idiopathic multicentric Castleman disease: novel insight into biology pathogenesis and therapy. Blood 2014;123 (19):2924-2933. Go to original source... Go to PubMed...
    4. Bower M, Pria AD, Coyle C et al. Diagnostic criteria schemes for multicentric Castleman disease in 75 cases. J Acquir Immune Defic Syndr. 2014;65(2):e80-e82. Go to original source... Go to PubMed...
    5. Jakubíková M, Piťha J, Latta J, et al. Myasthenia gravis, Castleman disease, pemphigus, and anti‑phospholipid syndrome Muscle and nerve. 2013;47(3):447-451. Go to original source... Go to PubMed...
    6. Cibičková Ľ, Soukup T, Bradna P et al. Asociace revmatoidní artritidy a Castlemanovy choroby. Česká revmatologie. 2005;13(3):106-109.
    7. Sun DP, Chen WM, Wang L et al. Clinical characteristics and immunological abnormalities of Castleman disease complicated with autoimmune diseases. J Cancer Res Clin Oncol. 2021;147(7):2107-2115. Go to original source... Go to PubMed...
    8. El Karoui K, Vuiblet V, Dion D et al. Renal involvement in Castleman disease. Nephrol Dial Transplant 2011;26(2):599-609. Go to original source... Go to PubMed...
    9. Sydor A, Madura M, Wagrowska‑Danilewicz M. Amyloid a amyloidosis and renal failure in a course of Castleman disease. Nephrology (Carlton). 2007;12(6):620-621. Go to original source... Go to PubMed...
    10. Dispenzieri A, Armitage J O, Loes M J et al. The clinical spectrum of Castleman's disease. Amer J Hematol 2012;87:997-1002. Go to original source... Go to PubMed...
    11. Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood. 2020;135(16):1353-1364. Go to original source... Go to PubMed...
    12. Dispenzieri A. POEMS syndrome: 2014 update on diagnosis, risk‑stratification, and management. Am J Hematol 2014;89(2):214-223. Go to original source... Go to PubMed...
    13. Fajgenbaum DC, Rosenbach M, van Rhee F, et al. Eruptive cherry hemangiomatosis associated with multicentric Castleman disease: a case report and diagnostic clue. JAMA Dermatol. 2013 Feb;149(2):204-208. Go to original source... Go to PubMed...
    14. Garcia T, Dafer R, Hocker S, Schneck M et al. Recurrent strokes in two patients with POEMS syndrome and Castleman's disease. J Stroke Cerebrovasc, DiS. 2007;16(6):278-284. Go to original source... Go to PubMed...
    15. Huang J, Wang L, Zhou W, Jin J. Hyaline vascular Castleman disease associated with POEMS syndrome and cerebral infarction. Ann Hematol 86(1):59-61. Go to PubMed...
    16. Szalat R, Munshi NC. Diagnosis of Castleman Disease. Hematol Oncol Clin North Am. 2018;32(1):53-64. doi: 10.1016/j.hoc.2017. 09. 005. Go to original source... Go to PubMed...
    17. Ferda J, Ferdová E, Záhlava J et al. Fever of unknown origin: a value of (18)F‑FDG‑PET/CT with integrated full diagnostic isotropic CT imaging.European journal of radiology. 2010;73(3):518-525.
    18. Koa B et al. Emerging role of 18 F‑FDG PET/CT in Castleman disease: a review Insights Imaging.2021;12:35. Go to original source... Go to PubMed...
    19. Koukalová R, Selingerová I, Řehák Z. FDG‑PET/ CT v diagnostice a hodnocení léčebné odpovědi Castlemanovy choroby - retrospektivní studie 29 případů z jednoho centra. Klinická onkologie. 2021;34(2):120-127. Go to PubMed...
    20. Fajgenbaum DC, Uldrick TS, Bagg A et al. International, evidence‑based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood 2017;129(12):1646-1657. Go to original source... Go to PubMed...
    21. Cronin DM, Warnke RA. Castleman disease: an update on classification and the spectrum of associated lesions. Adv Anat Pathol. 2009;16:236-246. Go to original source... Go to PubMed...
    22. Masaki Y, Nakajima A, Iwao H et al. Japanese variant of multicentric castleman's disease associated with serositis and thrombocytopenia--a report of two cases: is TAFRO syndrome (Castleman- Kojima disease) a distinct clinicopathological entity? J Clin Exp Hematop 2013;53(1):79-85. Go to original source... Go to PubMed...
    23. Kawabata H, Takai K, Kojima M et al. Castleman‑Kojima disease (TAFRO syndrome): a novel systemic inflammatory disease characterized by a constellation of symptoms, namely, thrombocytopenia, ascites (anasarca), microcytic anemia, myelofibrosis, renal dysfunction, and organomegaly: J Clin Exp Hematop 2013;53(1):57-61. Go to original source... Go to PubMed...
    24. Inoue M, Ankou M, Hua J et al. Complete resolution of TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) after immunosuppressive therapies using corticosteroids and cyclosporin A: a case report. J Clin Exp Hematop. 2013;53(1):95-99. Go to original source... Go to PubMed...
    25. Tedesco S, Postacchini L, Manfredi L et al. Successful treatment of a Caucasian case of multifocal Castleman's disease with TAFRO syndrome with pathophysiology targeted therapy- case report. Exp Hematol Oncol 2015;4(1):3-10. Go to original source... Go to PubMed...
    26. Masaki Y, Kawabata H, Takai K et al. Proposed diagnostic criteria, disease severity classification and treatment stratedy for Tafro syndrom, 2015 version. Int. J. Hematol 2016;103:686-692. Go to original source... Go to PubMed...
    27. Yu L, Shi M, Cai Q et al. A Novel Predictive Model for Idiopathic Multicentric Castleman Disease: The International Castleman Disease Consortium Study. Oncologist. 2020;25(11):963-973. Go to original source... Go to PubMed...
    28. Fang X, Sun Z, Xu‑Monette ZY et al. Model for Idiopathic Multicentric Castleman Disease Supporting Treatment Decisions. Oncologist. 2021;26(1):4-6. Go to original source... Go to PubMed...
    29. Wu D, Lim MS, Jaffe ES. Pathology of Castleman Disease. Hematol Oncol Clin North Am. 2018;32(1):37-52. Go to original source... Go to PubMed...
    30. van Rhee F, Greenway A, Stone K. Treatment of Idiopathic Castleman Disease. Hematol Oncol Clin North Am. 2018;32(1):89-106. doi: 10.1016/j.hoc.2017. 09. 008. Go to original source... Go to PubMed...
    31. Van Rhee F, Voorhees P, Dispenzieri A et al al. International evidence based consensus treatment guidelines for idiopahtic multicentric Castleman disease. Blood 2018;132 (20):2115-2124.Další literatura u autora a na www.casopisvnitrnilekarstvi.cz Go to original source... Go to PubMed...
    32. Herrada J, Cabanillas F, Rice L et al. The clinical behavior of localized and multicentric Castleman disease Ann Intern Med 1998;128(8):657-662. Go to original source... Go to PubMed...
    33. Chronowski G M, Ha C S, Wilder RB et al. Treatment of unicentric and multicentric Castleman disease and the role of radiotherapy Cancer 2001;92(3):670-676. Go to original source...
    34. Zhu S H, Yu Y H, Zhang Y et al.Clinical features and outcome of patients with HIV‑negative multicentric Castleman's disease treated with combination chemotherapy: a report on 10 patients Med Oncol 2013;30(1):492-498. Go to original source... Go to PubMed...
    35. Dong Y, Zhang L, Nong L et al. Effectiveness of rituximab‑containing treatment regimens in idiopathic multicentric Castleman disease. Ann Hematol. 2018;97(9):1641-1647. Go to original source... Go to PubMed...
    36. Liu AY, Nabel CS, Finkelman BS et al. Idiopathic multicentric Castleman's disease: a systematic literature review. Lancet Haematol 2016;3(4):e163-e175. Go to original source... Go to PubMed...
    37. Ide M, Kawachi Y, Izumi Y, Kasagi K et al. Long‑term remission in HIV‑negative patients with multicentric Castleman's disease using rituximab. Eur J Haematol. 2006;76(2):119-123 Go to original source... Go to PubMed...
    38. Kaegi C, Wuest B, Schreiner J et al. Systematic Review of Safety and Efficacy of Rituximab in Treating Immune‑Mediated Disorders. Front Immunol. 2019;10:1990. doi:10.3389/fimmu.2019.01990. Go to original source... Go to PubMed...
    39. Gérard L, Bérezné A, Galicier L et al. Prospective study of rituximab in chemotherapy‑dependent human immunodeficiency virus associated multicentric Castleman's disease: ANRS 117 Castleman B Trial. J Clin Oncol 2007;25(22):3350-3356. Go to original source... Go to PubMed...
    40. Gérard L, Michot JM, Burcheri S et al. Rituximab decreases the risk of lymphoma in patients with HIV‑associated multicentric Castleman disease.Blood 2012 8;119(10):2228-2233. Go to original source... Go to PubMed...
    41. Adam Z. Szturz P, Křen L. PET‑CT dokumentovaný rychlý nástup léčebné odpovědi cyklofosfamidu, thalidomidu a dexametazonu u multicentrické formy Castlemanovy nemoci. Popis případu a přehled informací o léčbě Vnitřní lékařství. 2013;59(4):301-312.
    42. Jung CP, Emmerich B, Goebel FD et al. Successful treatment of a patient with HIV‑associated multicentric Castleman disease (MCD) with thalidomide. Am J Hematol. 2004;75:176-177. Go to original source... Go to PubMed...
    43. Lee FC, Merchant SH. Alleviation of systemic manifestations of multicentric Castleman's disease by thalidomide. Am J Hematol. 2003;73:48-53. Go to original source... Go to PubMed...
    44. Ramasamy K, Gandhi S, Flowers MT et al. Rituximab and thalidomide combination therapy for Castleman Disease. Brit J Haematol 2012;158(3):421-423. Go to original source... Go to PubMed...
    45. Stary G, Kohrgruber N, Herneth AM et al. Complete regression of HIV‑associated multicentric Castleman disease treated with rituximab and thalidomide. AIDS. 2008;22(10): 1232-1234.
    46. Zhang L, Zhao AL, Duan MH et al. Phase 2 study using oral thalidomide‑cyclophosphamide‑prednisone for idiopathic multicentric Castleman disease. Blood. 2019;133(16):1720-1728. Go to original source... Go to PubMed...
    47. Zhao X, Shi R, Jin X, Zheng J. Diffuse hyperpigmented plaques as cutaneous manifestation of multicentric Castleman disease and treatment with thalidomide: report of three cases. J Am Acad Dermatol. 2011 Aug;65(2):430-432. Go to original source... Go to PubMed...
    48. Adam Z, Pour L, Krejčí M. Účinnost lenalidomidu u vzácných krevních chorob: u histiocytózy z Langerhansových buněk, multicentrické Castlemanovy choroby, POEMS syndromu, Erdheimovy‑Chesterovy choroby a angiomatózy. Popis případů a přehled literatury Vnitřní lékařství. 2012;58(11):856-866.
    49. Szturz P, Adam Z, Chovancová J et al. Lenalidomide: a new treatment option for Castleman disease. Leuk Lymphoma. 2012;53(10):2089-2091. Go to original source... Go to PubMed...
    50. Zhou X, Wei J, Lou Y et al. Salvage therapy with lenalidomide containing regimen for relapsed/refractory Castleman disease: a report of three cases. Front Med. 2017;11(2):287-292. Go to original source... Go to PubMed...
    51. Cai S, Zhong Z, Li X et al. Treatment of multicentric Castleman disease through combination of tocilizumab, lenalidomide and glucocorticoids: Case report. Medicine (Baltimore). 2019;98(46):e17681. doi:10.1097/MD.0000000000017681 Go to original source... Go to PubMed...
    52. Hess G, Wagner V Kreft A et al. Effects of bortezomib on proinflamatory cytokine levels and transfusion dependency in patient with multicentric Castleman disease. Brit J Haematol 2006;134:602-605. Go to original source... Go to PubMed...
    53. Sobas MA, Alonso Vence N, Diaz Arias J et al. Efficacy of bortezomib in refractory form of multicentric Castleman disease associated to POEMS syndrome (MCD‑POEMS variant). Ann Hematol. 2010;89(2):217-219. Go to original source... Go to PubMed...
    54. Wang X, Ye S et al. Successful treatment with bortezomib and thalidomide for POEMS syndrome associated with multicentric mixed‑type Castleman's disease. Jpn J Clin Oncol. 2011;41(10):1221-1224. Go to original source... Go to PubMed...
    55. Xia P, Zhang L, Zou M et al. Acute Kidney Injury Caused by TAFRO Syndrome in a Chinese Patient: Efficacy of Long‑Term Corticosteroids Combined with Bortezomib and Cyclophosphamide.Kidney Blood Press Res. 2020;45(4):623-630. Go to original source... Go to PubMed...
    56. Lin Q, Fang B, Huang H et al. Efficacy of bortezomib and thalidomide in the recrudescent form of multicentric mixed‑type Castleman's disease. Blood Cancer J. 2015;5(3):e298. doi:10.1038/bcj.2015. 12. PMID: Go to original source...
    57. Khan AA, Siraj F, Bhargava M et al. Successful treatment of multicentric Castleman's disease accompanying myeloma with bortezomib. BMJ Case Rep. 2012;2012:bcr2012007646. Go to original source... Go to PubMed...
    58. Song SN, Tomosugi N, Kawabata H et al. Down‑regulation of hepcidin resulting from long‑term treatment with an anti‑IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood. 2010; 116 (18): 3627-3634. Go to original source... Go to PubMed...
    59. Robey RC, Mletzko S, Colley C et al. The use of monoclonal antibodies to treat Castleman's disease. Immunotherapy. 2014;6(2):211-219. Go to original source... Go to PubMed...
    60. Kurzrock R, Voorhees PM, Casper C, et al A phase I, open‑label study of siltuximab, an anti‑IL-6 monoclonal antibody, in patients with B‑cell non‑Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin Cancer Res 2013;19(13):3659-3670. Go to original source... Go to PubMed...
    61. Van Rhee F, Wong RS, Munshi N et al. Siltuximab for multicentric Castleman's disease. A randomized double blind placebo controlled trial. Lancet Oncol 2014;15(9):966-974. Go to original source... Go to PubMed...
    62. Van Rhee F, Casper C, Voorhees PM et al. Phase 2 open labaled multicenter study of long term safety of Siltuximab in patients with multicentric Castleman's disease. Oncotarget, 2015;6(30):30408-30419. Go to original source... Go to PubMed...
    63. van Rhee F, Rossi JF, Simpson D et al. Newly diagnosed and previously treated multicentric Castleman disease respond equally to siltuximab. Br J Haematol. 2021;192(1):e28-e31. Go to original source... Go to PubMed...
    64. Tonialini L, Bonfichi M, Ferrero S et al. Siltuximab in relapsed/refractory multicentric Castleman disease: Experience of the Italian NPP program. Hematol Oncol. 2018;36(4):689-692. Go to original source... Go to PubMed...
    65. Ostrowska B, Szymczyk A, Olszewska‑Szopa M et al. Efficacy of siltuximab in the treatment of idiopathic multicentric Castleman disease, the first Polish, real‑world experience with long‑term observation. Leuk Lymphoma. 2021 Jun 23:1-4. doi: 10.1080/10428194.2021.1941926. Epub ahead of prind. Go to original source... Go to PubMed...
    66. Ebisawa K, Shimura A, Honda A et al. Hemoglobin and C‑reactive protein levels as predictive factors for long‑term successful glucocorticoid treatment for multicentric Castleman's disease. Leuk Lymphoma. 2021;62(3):614-619. Go to original source... Go to PubMed...
    67. Morra DE, Pierson SK, Shilling D et al. Predictors of response to anti‑IL6 monoclonal antibody therapy (siltuximab) in idiopathic multicentric Castleman disease: secondary analyses of phase II clinical trial data. Br J Haematol. 2019;184(2):232-241. Go to original source... Go to PubMed...
    68. Sun Y, Wang D, Salvadore G. The effects of interleukin-6 neutralizing antibodies on symptoms of depressed mood and anhedonia in patients with rheumatoid arthritis and multicentric Castleman's disease. Brain Behav Immun. 2017;66:156-164. Go to original source... Go to PubMed...
    69. Galeotti C, Tran TA, Franchi‑Abella S et al. IL-1RA agonist (anakinra) in the treatment of multifocal castleman disease: case report. J Pediatr Hematol Oncol 2008;30(12):920-924. Go to original source... Go to PubMed...
    70. El‑Osta H, Janku F, Kurzrock R. Successful treatment of Castleman's disease with interleukin-1 receptor antagonist (Anakinra). Mol Cancer Ther. 2010;9(6):1485-1488. Go to original source... Go to PubMed...
    71. Jouvray M, Terriou L, Meignin V et al. Pseudo‑adult Still's disease, anasarca, thrombotic thrombocytopenic purpura and dysautonomia: An atypical presentation of multicentric Castleman's disease. Discussion of TAFRO syndrome. Rev Med Interne 2016;37(1):53-57. Go to original source... Go to PubMed...
    72. Ferrero S, Ragaini S. Dichotomic response to interleukin-6 blockade in idiopathic multicentric Castleman disease: two case reports. J Med Case Rep. 2021 Mar 7;15(1):105. doi: 10.1186/s13256-021-02726-4. Go to original source... Go to PubMed...
    73. Lanzillotta M, Sant'Angelo M, Kaneko N, Pillai S, Ponzoni M, Della‑Torre E. Treating life‑threatening TAFRO syndrome with interleukin-1 inhibition. Eur J Intern Med. 2021;87:121-123. Go to original source... Go to PubMed...
    74. Borocco C, Ballot‑Schmit C et al. The French paediatric cohort of Castleman disease: a retrospective report of 23 patients. Orphanet J Rare, DiS. 2020;15(1):95.doi: 10.1186/s13023-020-1345-5. Go to original source... Go to PubMed...
    75. Soudet S, Fajgenbaum D, Delattre C et al. Schnitzler syndrome co‑occurring with idiopathic multicentric Castleman disease that responds to anti‑IL-1 therapy: A case report and clue to pathophysiology. Curr Res Transl Med. 2018;66(3):83-86.
    76. Yamaga Y, Tokuyama K, Kato T et al. Successful treatment with cyclosporin A in tocilizumab‑resistant TAFRO syndrome. Intern Med 2016;55(2):185-190. Go to original source... Go to PubMed...
    77. Fajgenbaum DC. Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018;132(22):2323-2330. Go to original source... Go to PubMed...
    78. Koga T, Hagimori N, Takemori S, Randomized, double‑blind, placebo‑controlled, parallel‑group trial of sirolimus for tocilizumab‑resistant idiopathic multicentric Castleman disease: Study protocol for clinical trial.Medicine (Baltimore). 2020;99(30):e20710. doi:10.1097/MD.0000000000020710. Go to original source... Go to PubMed...
    79. Stern RM, Berliner N. Targeting the mTOR pathway in idiopathic multicentric Castleman disease. J Clin Invest. 2019;129(10):4086-4088. Go to original source... Go to PubMed...
    80. Repetto L, Jaiprakash MP, Selby PJ et al. Aggressive angiofollicular lymph node hyperplasia (Castleman's disease) treated with high dose melphalan and autologous bone marrow transplantation. Hematol Oncol 1986;4(3):213-217.) Go to original source... Go to PubMed...
    81. Ganti AK, Pipinos I, Culcea E et al. Successful hematopoietic stem‑cell transplantation in multicentric Castleman disease complicated by POEMS syndrome. Am J Hematol 2005;79(3):206-210. Go to original source... Go to PubMed...
    82. Tal Y, Haber G, Cohen MJ et al. Autologous stem cell transplantation in a rare multicentric Castleman disease of the plasma cell variant. 1. Int J Hematol 2011;93(5):677-680. Go to original source... Go to PubMed...
    83. Wang Z, Yang S, Zhu Z, Lei P, Yang J, Zhang P, Sun K. A Case of Successful Allogeneic Hematopoietic Stem Cell Transplantation for HHV8-Positive Castleman's Disease with a Review of the Literature. Cell Transplant. 2020;29:963689720943571. doi: 10.1177/0963689720943571. Go to original source... Go to PubMed...
    84. Fujimoto S, Kawabata H, Sakai T et al. Optimal treatmentsfor TAFRO syndrome: a retrospective surveillance study in Japan. Int J Hematol. 2021 Jan;113(1):73-80. Go to original source... Go to PubMed...
    85. Zhao EJ, Cheng CV, Mattman A et al. Polyclonal hypergammaglobulinaemia: assessment, clinical interpretation, and management. Lancet Haematol. 2021;8(5):e365-e375. doi: 10.1016/S2352-3026(21)00056-9. Go to original source... Go to PubMed...

    Return to the content


    Vnitřní lékařství

    Madam, Sir,
    please be aware that the website on which you intend to enter, not the general public because it contains technical information about medicines, including advertisements relating to medicinal products. This information and communication professionals are solely under §2 of the Act n.40/1995 Coll. Is active persons authorized to prescribe or supply (hereinafter expert).
    Take note that if you are not an expert, you run the risk of danger to their health or the health of other persons, if you the obtained information improperly understood or interpreted, and especially advertising which may be part of this site, or whether you used it for self-diagnosis or medical treatment, whether in relation to each other in person or in relation to others.

    I declare:

    1. that I have met the above instruction
    2. I'm an expert within the meaning of the Act n.40/1995 Coll. the regulation of advertising, as amended, and I am aware of the risks that would be a person other than the expert input to these sites exhibited

    No
    Yes

    If your statement is not true, please be aware
    that brings the risk of danger to their health or the health of others.