Abstract
22 min readWaldenström’s macroglobulinaemia (WM) is a rare disease that accounts for 1%–2% of non-Hodgkin lymphomas. The reported age-adjusted incidence rate is 3.4 per million among the male population and 1.7 per million among the female population in the United States, and 7.3 and 4.2 per million, respectively, in the European standard population [1.Groves F.D. Travis L.B. Devesa S.S. et al.Waldenstrom's macroglobulinemia: incidence patterns in the United States, 1988–1994.Cancer. 1998; 82: 1078-1081Crossref PubMed Scopus (159) Google Scholar, 2.Phekoo K.J. Jack R.H. Davies E. et al.The incidence and survival of Waldenstrom's macroglobulinaemia in South East England.Leuk Res. 2008; 32: 55-59Crossref PubMed Scopus (36) Google Scholar]. In contrast to multiple myeloma, WM prevalence is higher among Caucasians than among African-Americans (IRR: 1.75) [3.Teras L.R. DeSantis C.E. Cerhan J.R. Morton L.M. Jemal A. Flowers C.R. 2016 US lymphoid malignancy statistics by World Health Organization subtypes.CA Cancer J Clin. 2016; 66: 443-459Crossref PubMed Scopus (605) Google Scholar]. WM is a disease of the elderly, with the median age at the time of diagnosis being 63–75 years in different series [3.Teras L.R. DeSantis C.E. Cerhan J.R. Morton L.M. Jemal A. Flowers C.R. 2016 US lymphoid malignancy statistics by World Health Organization subtypes.CA Cancer J Clin. 2016; 66: 443-459Crossref PubMed Scopus (605) Google Scholar, 4.Kastritis E. Kyrtsonis M.C. Morel P. et al.Competing risk survival analysis in patients with symptomatic Waldenstrom macroglobulinemia: the impact of disease unrelated mortality and of rituximab-based primary therapy.Haematologica. 2015; 100: e446-e449Crossref PubMed Scopus (31) Google Scholar, 5.Treon S.P. How I treat Waldenstrom macroglobulinemia.Blood. 2009; 114: 2375-2385Crossref PubMed Scopus (166) Google Scholar]. A strong familial predisposition has been reported [6.McMaster M.L. Familial Waldenstrom's macroglobulinemia.Semin Oncol. 2003; 30: 146-152Crossref PubMed Scopus (59) Google Scholar, 7.Treon S.P. Hunter Z.R. Aggarwal A. et al.Characterization of familial Waldenstrom's macroglobulinemia.Ann Oncol. 2006; 17: 488-494Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 8.Treon S.P. Tripsas C. Hanzis C. et al.Familial disease predisposition impacts treatment outcome in patients with Waldenstrom macroglobulinemia.Clin Lymphoma Myeloma Leuk. 2012; 12: 433-437Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar] and first degree relatives of WM patients have up to 20-fold increased risk for developing WM (and also increased risk but at lower level for other B-cell disorders) [9.Kristinsson S.Y. Bjorkholm M. Goldin L.R. et al.Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden.Blood. 2008; 112: 3052-3056Crossref PubMed Scopus (119) Google Scholar]. The diagnosis of WM is based on the histopathological confirmation of bone marrow (BM) infiltration by lymphoplasmacytic cells/lymphoplasmacytic lymphoma (LPL) and the detection of any amount of monoclonal immunoglobulin M (IgM) protein [10.Owen R.G. Treon S.P. Al-Katib A. et al.Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's macroglobulinemia.Semin Oncol. 2003; 30: 110-115Crossref PubMed Scopus (732) Google Scholar, 11.WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2. WHO Press, Geneva2017Google Scholar], which should always be confirmed by immunofixation. The presence of monoclonal IgM without the histopathological diagnosis of LPL in the BM is not considered as WM, because this situation could correspond to monoclonal gammopathy of undetermined significance (MGUS), or to a nodal LPL without BM infiltration. A diagnosis of LPL without detection of monoclonal IgM does not fulfil the criteria for WM. The clonal lymphoplasmacytic cell population in the BM (which contains a population with lymphocytic differentiation and one with plasmacytic differentiation) should be documented by a trephine biopsy and/or aspiration and confirmed by immunophenotypic studies (immunohistochemistry or flow cytometry) showing expression of CD19, CD20, CD22 and CD79a on the lymphocytic as well as CD38 on the plasmacytic component (small variations can occur) [10.Owen R.G. Treon S.P. Al-Katib A. et al.Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's macroglobulinemia.Semin Oncol. 2003; 30: 110-115Crossref PubMed Scopus (732) Google Scholar, 11.WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2. WHO Press, Geneva2017Google Scholar]. Multiparametric flow cytometry may provide additional data on the immunophenotypic characterisation of WM showing accumulation of light-chain-isotype-positive B cells with a characteristic phenotype [CD22(+dim)/CD25+/CD27+/IgM+] that differs from other B-lymphomas by negative expression of CD5, CD10, CD11c or CD103 [12.Paiva B. Montes M.C. Garcia-Sanz R. et al.Multiparameter flow cytometry for the identification of the Waldenstrom's clone in IgM-MGUS and Waldenstrom's macroglobulinemia: new criteria for differential diagnosis and risk stratification.Leukemia. 2014; 28: 166-173Crossref PubMed Scopus (67) Google Scholar]. About 90% of patients with WM harbour the myeloid differentiation primary response MYD88L265P gene mutation in their lymphoplasmacytic cells [13.Treon S.P. Xu L. Yang G. et al.MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia.N Engl J Med. 2012; 367: 826-833Crossref PubMed Scopus (920) Google Scholar], which can be helpful for the differential diagnosis from other morphologically similar diseases (such as multiple myeloma). The MYD88L265P mutation alone is not diagnostic of WM. This mutation is also found in 50%–80% of patients with IgM MGUS and may also be found in other lymphomas such as marginal zone lymphoma. Furthermore, 5%–10% of patients who fulfil the immunophenotypic and clinical criteria of WM do not have the MYD88L265P mutation (they may either have other MYD88 mutations [14.Treon S.P. Xu L. Hunter Z. MYD88 mutations and response to ibrutinib in Waldenstrom's macroglobulinemia.N Engl J Med. 2015; 373: 584-586Crossref PubMed Scopus (177) Google Scholar] or may have wild type MYD88). Diagnostics for the detection of MYD88L265P have not been standardised but should be based on BM sampling, because peripheral blood detection may give false-negative results [15.Xu L. Hunter Z.R. Yang G. et al.Detection of MYD88 L265P in peripheral blood of patients with Waldenstrom's macroglobulinemia and IgM monoclonal gammopathy of undetermined significance.Leukemia. 2014; 28: 1698-1704Crossref PubMed Scopus (79) Google Scholar]. A sensitive method, such as allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) is recommended and each laboratory should report the method and detection limits. The use of molecular methods for MYD88L265P detection and flow cytometry may also be useful for the diagnosis of cases with extranodal involvement (pleura, central nervous system, etc.) [16.Poulain S. Boyle E.M. Roumier C. et al.MYD88 L265P mutation contributes to the diagnosis of Bing Neel syndrome.Br J Haematol. 2014; 167: 506-513Crossref PubMed Scopus (59) Google Scholar]. Activating C–X–C chemokine receptor type 4 (CXCR4) mutations are found in ∼30% of patients with WM [13.Treon S.P. Xu L. Yang G. et al.MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia.N Engl J Med. 2012; 367: 826-833Crossref PubMed Scopus (920) Google Scholar]. More than 30 different CXCR4 mutations have been described in WM, complicating diagnostic standardisation. Since there are as yet no therapeutic implications outside clinical trials, diagnostic testing for the presence or the absence of CXCR4 mutations is not routinely recommended. However, in patients considered for treatment with ibrutinib, CXCR4 mutational status may be evaluated given the effects in depth and response kinetics in those with CXCR4 mutations [17.Treon S.P. Tripsas C.K. Meid K. et al.Ibrutinib in previously treated Waldenstrom's macroglobulinemia.N Engl J Med. 2015; 372: 1430-1440Crossref PubMed Scopus (658) Google Scholar, 18.Dimopoulos M.A. Trotman J. Tedeschi A. et al.Ibrutinib for patients with rituximab-refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial.Lancet Oncol. 2017; 18: 241-250Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar]. Besides patient history and documentation of symptoms, initial evaluation should include a complete blood count (CBC) with differential and and may be the for and with WM and not to other disorders should be confirmed by evaluation of status or additional The level should be is a for survival and a component of the International for WM P. A. P. et for Waldenstrom macroglobulinemia.Blood. 2009; PubMed Scopus Google Scholar]. protein and and of are at initial The of IgM can be based either on or on IgM by may be E. of monoclonal and 2009; PubMed Scopus Google Scholar]. response the method should be for the of IgM for an in the laboratory as and can as well R.G. et in Waldenstrom from the International J Haematol. PubMed Scopus Google Scholar, Garcia-Sanz R. E. et for the diagnosis and initial evaluation of patients with Waldenstrom a from the International Workshop on Waldenstrom J Haematol. 2016; PubMed Scopus Google Scholar]. The of of chain in patients with WM is and is recommended in there is of chain or or in the rare of a patient with but (and IgM However, in patients with the evaluation of may be of and in patients with J 2008; PubMed Scopus Google Scholar]. protein and/or for of should be and familial history for WM and other B cell lymphoproliferative of symptoms, peripheral IgM is and is blood and with and aspiration and for cytometry not for MYD88L265P gene of the and and in patients being considered for for protein with and bone B WM, Waldenström’s in a new and bone B WM, Waldenström’s to IgM is in WM. may be considered in patients with of or but does not well with the clinical of the showing of the is a of Treon S.P. to the of and the of in patients with Waldenstrom's macroglobulinemia.Clin Lymphoma 2009; Full Text PDF PubMed Scopus Google a of the may for However, the of should also such as or that may or to the for and should be at diagnosis in patients with or laboratory of their should be that the presence of or may the of IgM testing and are with of In patients with symptoms, of the or testing for should be In of for disease should be for B and and and is is in patients with WM and an for treatment of other unrelated for may also The clinical is a peripheral the S. et and of IgM and peripheral recommendations from the consensus J Haematol. 2017; PubMed Scopus Google Scholar]. are in the of of patients and should be evaluated A. J. et in Waldenstrom's 2006; PubMed Scopus Google Scholar]. may also be evaluated L. S. et of IgM monoclonal gammopathy with and a 2015; PubMed Scopus Google Scholar]. may be found in patients with or can also be In patients with peripheral with a and evaluation studies should be considered S. et and of IgM and peripheral recommendations from the consensus J Haematol. 2017; PubMed Scopus Google Scholar]. are not is an of WM and peripheral P. G. Haematol. 2016; PubMed Scopus Google Scholar, S. M. G. et study clinical and criteria in monoclonal immunoglobulin chain Oncol. 2016; PubMed Scopus Google Scholar]. is the type in WM, but other such as A have been a and evaluation of the BM biopsy with can the with and rate and should be studies should be in the evaluation to and/or with or does not to additional R. K. et al.The of in Waldenstrom J PubMed Scopus Google Scholar] to an lymphoma or malignancy is in which a biopsy of the is is based on the P. A. P. et for Waldenstrom macroglobulinemia.Blood. 2009; PubMed Scopus Google this for symptomatic of WM from for age 3 and IgM risk not in include and or or immunoglobulin International for Waldenström’s WM, Waldenström’s for age 3 and IgM risk not in include and in a new immunoglobulin International for Waldenström’s WM, Waldenström’s 3 to with disease should be without Treon S.P. R. et and criteria to in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's macroglobulinemia.Semin Oncol. 2003; 30: PubMed Scopus Google Scholar, L. C. et of the of immunoglobulin M a survival for patients with immunoglobulin M monoclonal gammopathy of undetermined Cancer Res. PubMed Scopus Google Scholar, E. R. et recommendations from the International Workshop on Waldenstrom's macroglobulinemia.Blood. 2016; PubMed Scopus Google Scholar]. 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However, a study that IgM are with risk of symptomatic and are considered to be a treatment Meid K. et IgM level as of symptomatic in patients with Waldenstrom J Haematol. 2017; PubMed Scopus Google Scholar]. The for treatment include B and other such as and are for of in patients with WM for of either symptomatic or in and/or and/or or to for of and/or to to immunoglobulin WM, Waldenström’s in a new immunoglobulin WM, Waldenström’s in clinical is for given the treatment and new is by the clinical of the disease or treatment response without BM infiltration or with disease (such as 4 and the of symptomatic should be with the E. R. et recommendations from the International Workshop on Waldenstrom's macroglobulinemia.Blood. 2016; PubMed Scopus Google Scholar, P. R. et and of Waldenstrom macroglobulinemia: of macroglobulinemia and Oncol. 2017; PubMed Scopus Google in first to disease for to WM, Waldenström’s in a new WM, Waldenström’s are the of A of IgM in of patients treated with rituximab-based which may M.A. C. A. et of Waldenstrom's macroglobulinemia with Oncol. PubMed Scopus Google Scholar, R. et immunoglobulin M in patients with Waldenstrom macroglobulinemia: an PubMed Scopus Google Scholar]. use of may be considered in symptomatic patients with of IgM and at risk for or of with or and for higher response than but complete are is with a survival of 3 a 4 years and median survival of years with and E. M. Kyrtsonis M.C. et and as primary treatment of Waldenstrom macroglobulinemia: analysis of a phase 2015; PubMed Scopus Google Scholar]. or similar are primary for patients with and with for to is with and than with based on a of a study G. et as treatment for patients with and an multicentre, phase 3 Full Text Full Text PDF PubMed Scopus Google Scholar]. of should be to the of the patients by the of and/or by the per has not been with but is a primary for patients with no data are to the of in patients with alone or in with is in WM M. Garcia-Sanz R. E. et in patients with analysis of a phase study a of 2017; PubMed Scopus Google Scholar, S. et of in with in patients with Waldenstrom J PubMed Scopus Google Scholar, S.P. L. et of Waldenstrom macroglobulinemia with and clinical Oncol. 2009; PubMed Scopus Google Scholar] and should be given and at of a phase study of for has a median of median of response of years and rate of at years M. Garcia-Sanz R. 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S. et of a of for patients with Waldenstrom marginal zone or lymphoplasmacytic Oncol. PubMed Scopus (119) Google Scholar]. a has and is with response in patients with WM, as the in WM [17.Treon S.P. Tripsas C.K. Meid K. et al.Ibrutinib in previously treated Waldenstrom's macroglobulinemia.N Engl J Med. 2015; 372: 1430-1440Crossref PubMed Scopus (658) Google Scholar, 18.Dimopoulos M.A. Trotman J. Tedeschi A. et al.Ibrutinib for patients with rituximab-refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial.Lancet Oncol. 2017; 18: 241-250Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar]. has been by the European for patients with WM who have primary and for the treatment of patients who are for The results of the study in which the of ibrutinib with with in patients who no treatment or in patients M.A. Tedeschi A. Trotman J. et 3 of ibrutinib in macroglobulinemia.N Engl J Med. of Scopus Google Scholar]. 30 the rate with with with at a response in of the for also in patients previously M.A. Tedeschi A. Trotman J. et 3 of ibrutinib in macroglobulinemia.N Engl J Med. of Scopus Google Scholar]. A phase study in patients with ibrutinib has also been but with S.P. J. Meid K. et al.Ibrutinib is as first in symptomatic Waldenstrom's macroglobulinemia.Blood. 2017; Scholar]. ibrutinib could be a treatment for patients with not no of data has been yet for the use of ibrutinib in in any or treatment with could provide clinical to data S.P. Hanzis C. et is with clinical outcome in patients with Waldenstrom macroglobulinaemia who to a J Haematol. PubMed Scopus Google Scholar], be recommended in WM to the of data on the in patients and on data in rituximab-refractory patients M.A. Trotman J. Tedeschi A. et al.Ibrutinib for patients with rituximab-refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial.Lancet Oncol. 2017; 18: 241-250Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar], ibrutinib is recommended for patients who their rituximab-refractory patients with MYD88 may have no from this is based on data from of Furthermore, patients with mutation may also from ibrutinib [14.Treon S.P. Xu L. Hunter Z. MYD88 mutations and response to ibrutinib in Waldenstrom's macroglobulinemia.N Engl J Med. 2015; 373: 584-586Crossref PubMed Scopus (177) Google Scholar]. should be given disease and are of the is the risk of such as may be in patients who and 3 ibrutinib is an treatment rituximab-based be considered in patients who are not for ibrutinib or who in this time patients who years a rituximab-based an rituximab-based may be with with either or either with or without or may be E. M. Kyrtsonis M.C. et and as primary treatment of Waldenstrom macroglobulinemia: analysis of a phase 2015; PubMed Scopus Google Scholar]. with is an but also and should be patients who a with their primary the may also be considered E. M. Kyrtsonis M.C. et and as primary treatment of Waldenstrom macroglobulinemia: analysis of a phase 2015; PubMed Scopus Google Scholar]. may also be a treatment for patients with with cell has a for the of patients with disease but also and a C. C. et and in Waldenstrom macroglobulinemia: the Lymphoma of the European for and Oncol. 28: PubMed Scopus Google Scholar]. In patients disease to may also be of the treatment The of cell is outside clinical and should be considered in patients with who have or are to C. C. et in patients with Waldenstrom macroglobulinemia: report from the Lymphoma of the European for and Oncol. 28: PubMed Scopus Google Scholar, C. R.H. et for cell in patients with Waldenstrom's macroglobulinemia: a of the Lymphoma for Waldenstrom's macroglobulinemia Waldenstrom's macroglobulinemia 2017; Scholar]. evaluation in WM is based on of monoclonal IgM in the and on or of IgM R.G. et in Waldenstrom from the International J Haematol. PubMed Scopus Google Scholar]. is not to an IgM as disease BM are not routinely recommended for response for of R.G. et in Waldenstrom from the International J Haematol. PubMed Scopus Google in the of clinical trials, is to have BM results in of IgM and BM infiltration have been reported with [17.Treon S.P. Tripsas C.K. Meid K. et al.Ibrutinib in previously treated Waldenstrom's macroglobulinemia.N Engl J Med. 2015; 372: 1430-1440Crossref PubMed Scopus (658) Google Scholar, S.P. Meid K. Tripsas C. et clinical of as primary in Waldenstrom macroglobulinemia Cancer Res. 2017; PubMed Scopus Google Scholar, S.P. Hunter Z.R. J. et clinical of in Waldenstrom's macroglobulinemia: results of Cancer Res. PubMed Scopus Google Scholar, C. et in or Waldenstrom's macroglobulinemia.Clin Lymphoma 2009; Full Text PDF PubMed Scopus Google Scholar]. by should be in patients with or or a of the disease with is based on clinical A is not in and criteria response of monoclonal IgM protein by IgM should be confirmed by a of and at bone marrow and trephine response monoclonal IgM 90% in IgM level from in IgM may be either by IgM protein by or IgM by of new or of response monoclonal IgM but 90% in IgM level from in IgM may be either by IgM protein by or IgM by in at new or of response monoclonal IgM but in IgM level from in IgM may be either by IgM protein by or IgM by new or of disease monoclonal IgM and in IgM level from in IgM may be either by IgM protein by or IgM by in new or of disease in IgM should be confirmed by a from in clinical to the immunoglobulin IgM should be confirmed by a in IgM may be either by IgM protein by or IgM by in a new immunoglobulin M. is to molecular that could to status of MYD88 and CXCR4 may response and kinetics of response to ibrutinib [14.Treon S.P. Xu L. Hunter Z. MYD88 mutations and response to ibrutinib in Waldenstrom's macroglobulinemia.N Engl J Med. 2015; 373: 584-586Crossref PubMed Scopus (177) Google Scholar, 18.Dimopoulos M.A. Trotman J. Tedeschi A. et al.Ibrutinib for patients with rituximab-refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial.Lancet Oncol. 2017; 18: 241-250Abstract Full Text Full Text PDF PubMed Scopus (185) Google data on their mutational status may the of other or such as or the definition of the treatment for different in WM. In the MYD88 or CXCR4 no impact on the of the M.A. Tedeschi A. Trotman J. et 3 of ibrutinib in macroglobulinemia.N Engl J Med. of Scopus Google Scholar]. in WM should be based on patient and disease should include blood and of IgM 3 for for an additional 3 and with to and is not recommended. survival for patients for the median survival is but a to unrelated to the WM E. Kyrtsonis M.C. Morel P. et al.Competing risk survival analysis in patients with symptomatic Waldenstrom macroglobulinemia: the impact of disease unrelated mortality and of rituximab-based primary therapy.Haematologica. 2015; 100: e446-e449Crossref PubMed Scopus (31) Google Scholar]. and of are not in S. S. et of a of for patients with Waldenstrom marginal zone or lymphoplasmacytic Oncol. PubMed Scopus (119) Google Scholar, J. Meid K. et to B-cell lymphoma in patients with Waldenstrom J 2016; PubMed Scopus Google Scholar] and in S. S. et of a of for patients with Waldenstrom marginal zone or lymphoplasmacytic Oncol. PubMed Scopus (119) Google Scholar, J. A. et incidence of and in patients with Waldenstrom macroglobulinemia treated with Oncol. 2009; PubMed Scopus Google Scholar] of patients with WM, Second may also in in patients S. S. et of a of for patients with Waldenstrom marginal zone or lymphoplasmacytic Oncol. PubMed Scopus (119) Google Scholar, Hunter Z.R. et of among patients with Waldenstrom macroglobulinemia: an analysis of the 2015; PubMed Scopus Google Scholar]. in with the standard for The has been by the A of recommendations is in of and of have been the in without considered standard clinical by the and the This has been to an of diagnosis of WM histopathological confirmation of BM infiltration by monoclonal lymphoplasmacytic cells and monoclonal IgM of any confirmed by cells are for CD19, CD20, CD22 and 90% of WM cases are for the MYD88L265P which can be helpful for WM from other lymphoma and IgM multiple and risk evaluation a protein and IgM patients with of is and status should be considered in patients with is of a is recommended may not always be is an in WM a with and and should be studies should be in the initial evaluation or is based on the patients should not be treated but the level of monoclonal IgM alone is not an to treatment should be for the of with for include the presence of B or symptomatic or of with or or or with are primary treatment with or or is considered for patients for treatment with is not recommended for patients with WM patients who have from rituximab-refractory ibrutinib is the treatment of patients for at ibrutinib may be considered patients with an or a or ibrutinib may be with may be considered in patients with in clinical is for either in first or of and bone complete blood immunoglobulin International for Waldenström’s WM, Waldenström’s in a new of and of from the of Health of the of of from at one of for or of without or with a of or of such or of with studies or without of for with a clinical or for but with a clinical for or does not the risk or the or for not or for of the of of the for among cell PubMed Scopus Google Scholar]. in a new and bone complete blood immunoglobulin International for Waldenström’s WM, Waldenström’s has from and and from and has from and and has reported being a for and has from in for and has reported in for and and for and has for and from and has from and and has reported being an for and has reported in for and has from and and from and for treatment and of PDF to for treatment and of PDF
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