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• W2013212118 abstract "Hodgkin lymphoma (HL) is a hematologic malignancy of the lymphoid tissue that mainly affects young adults.1Bhatia S. Meadows A.T. Long-term follow-up of childhood cancer survivors: future directions for clinical care and research.Pediatr Blood Cancer. 2006; 46: 143-148Crossref PubMed Scopus (89) Google Scholar Standard treatment for subdiaphragmatic stages I and II combines chemotherapy regimen followed by dose-reduced involved-field irradiation (including mediastinum). Adverse effects of treatment include early death, second neoplasm, and organ dysfunction.1Bhatia S. Meadows A.T. Long-term follow-up of childhood cancer survivors: future directions for clinical care and research.Pediatr Blood Cancer. 2006; 46: 143-148Crossref PubMed Scopus (89) Google Scholar The consequences of HL treatments on thymus involution remain poorly explored.2Watanabe N. De Rosa S.C. Cmelak A. Hoppe R. Herzenberg L.A. Roederer M. Long-term depletion of naive T cells in patients treated for Hodgkin's disease.Blood. 1997; 90: 3662-3672PubMed Google Scholar Here, we investigated the long-term effects of thymic irradiation on the naive T-cell compartment in 30 patients with HL, 7 to 19 years after mediastinal radiotherapy (all in complete remission of Hodgkin disease), compared with 60 age- and sex-matched healthy controls (HCs) (summarized in Table E1 in this article's Online Repository at www.jacionline.org). Lymphocyte distribution was analyzed by using fluorescence-activated cell sorting, and thymic output was analyzed by measuring (1) T-cell receptor excision circles (TRECs) and (2) the frequency of naive thymic CD4+ CD45RA+ CD31+ T cells, which have higher TREC levels than do peripherally expanded CD4+ CD31− central T cells3Kimmig S. Przybylski G.K. Schmidt C.A. Laurisch K. Mowes B. Radbruch A. et al.Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood.J Exp Med. 2002; 195: 789-794Crossref PubMed Scopus (378) Google Scholar, 4Kohler S. Thiel A. Life after the thymus: CD31+ and CD31− human naive CD4+ T-cell subsets.Blood. 2009; 113: 769-774Crossref PubMed Scopus (245) Google Scholar (see this article's Methods section in the Online Repository at www.jacionline.org). Results showed that the CD3+ and CD3+ TCRαβ+ T-cell counts were significantly reduced in patients with HL than in matched HCs (P = .02 and P = .01, respectively), while the total lymphocyte counts were similar in both populations (Fig 1, A, and Table I). The CD4+ T-cell counts were dramatically lower in patients than in HCs (P < .001; mean decrease of 32%) while the CD8+ T-cell counts were equivalent in both groups. Patients with HL exhibited (1) an increase in B-cell counts (P = .01), with a decreased frequency of memory B cells, indicating an increase in naive B-cell counts, and (2) a marginal increase in natural killer cell frequency (P = .04) (Fig 1, A, and Table I).Table IImmunologic characteristics of patients with HL and HCsCharacteristicMean ± SDP valueHealthy subjectsPatients with HLLymphocytes (cells/mm3)2123 ± 5762065 ± 1106.24CD3+1531 ± 4251231 ± 649.02CD3+ CD4+ CD8−954 ± 302633 ± 293<.001CD3+ CD8+ CD4−492 ± 197493 ± 334.45CD3+ CD4+ CD28−18 ± 2330 ± 53.35CD4+ CD28−/CD4+ (%)2 ± 2.84 ± 6.02CD3+ CD4− CD8− TCRαβ+16 ± 1011 ± 6.01CD4+/CD8+ ratio in TCRαβ+2.4 ± 1.21.6 ± 0.6.003CD3+ TCRαβ+ CD4− CD8+448 ± 177444 ± 316<.001CD3+ TCRαβ+ CD8− CD4+949 ± 302630 ± 293<.001CD3+ TCRγδ+ CD4− CD8−48 ± 4664 ± 45<.001CD3+ CD4+ CD45RA+512 ± 304202 ± 154<.001CD3+ CD4+ CD45RA+ CD31+335 ± 195134 ± 125<.001CD3+ CD4+ CD45RA+ CD31−177 ± 14667 ± 46<.001CD4+ CD45RA+ CD31+/CD4+ CD45RA+ CD31− T-cell ratio2.3 ± 1.162 ± 1.29.27CD3+ CD4+ CD45RO+475 ± 153454 ± 249.21CD3− (CD56+ and/or CD16+)294 ± 159372 ± 307.16CD3− (CD56+ and/or CD16+)/lymphocytes (%)13.8 ± 617.5 ± 10.04CD19+265 ± 112382 ± 301.01CD19+/lymphocytes (%)12 ± 3.517.7 ± 7<.001CD19+ CD27+/CD19+ (%)30.9 ± 1219 ± 9<.001TREC numbers/106 WBCs At least 100n = 55n = 12 <100n = 5n = 18Mean ± SD1057 ± 1108647 ± 1750<.001Median (interquartile range)610 (345-1470)0 (0-598)WBC, White blood cell.P values in boldface are < .05. Open table in a new tab WBC, White blood cell. P values in boldface are < .05. We next evaluated the long-term effect of treatments on CD4+ T-cell homeostasis and thymic activity. Patients with HL exhibited a profound decrease in naive CD4+CD45RA+ T-cell numbers (P < .001; mean decrease of 57%), whereas patients in both groups had equivalent memory CD4+ CD45RO+ T-cell numbers (P = .21) (Fig 1, A, and Table I). The frequency of CD4+ CD28− T cells was significantly increased in patients with HL than in HCs (P = .02) (Table I), indicative of chronic T-cell activation.5Thewissen M. Somers V. Hellings N. Fraussen J. Damoiseaux J. Stinissen P. CD4+CD28null T cells in autoimmune disease: pathogenic features and decreased susceptibility to immunoregulation.J Immunol. 2007; 179: 6514-6523Crossref PubMed Scopus (149) Google Scholar, 6Parish S.T. Wu J.E. Effros R.B. Sustained CD28 expression delays multiple features of replicative senescence in human CD8 T lymphocytes.J Clin Immunol. 2010; 30: 798-805Crossref PubMed Scopus (51) Google Scholar Seven to 19 years post-treatment, patients with HL have lower absolute numbers of CD4+ CD45RA+ CD31+ T cells (P < .001; mean decrease of 59%) (Fig 1, A, and Table I; see Table E2 in this article's Online Repository at www.jacionline.org). Accordingly, TREC levels in peripheral leukocytes were lower in patients than in HCs (P < .001) (Fig 1, B, and Table 1; see Table E2); 18 of the 30 patients had undetectable levels of TRECs (<100 TRECs/106 white blood cells) compared with 5 of 60 matched HCs (Fig 1, B). During aging, the decrease in CD4+CD45RA+CD31+ T cells correlates with the decline in TRECs.3Kimmig S. Przybylski G.K. Schmidt C.A. Laurisch K. Mowes B. Radbruch A. et al.Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood.J Exp Med. 2002; 195: 789-794Crossref PubMed Scopus (378) Google Scholar, 7den Braber I. Mugwagwa T. Vrisekoop N. Westera L. Mogling R. de Boer A.B. et al.Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans.Immunity. 2012; 36: 288-297Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar, 8Kilpatrick R.D. Rickabaugh T. Hultin L.E. Hultin P. Hausner M.A. Detels R. et al.Homeostasis of the naive CD4+ T cell compartment during aging.J Immunol. 2008; 180: 1499-1507Crossref PubMed Scopus (170) Google Scholar Association between CD4+CD45RA+CD31+ T cells (Fig 1, C) or TREC levels (Fig 1, D), as dependent variables, and age at analysis (22-72 years), revealed an age-dependent decline in CD4+CD45RA+CD31+ T cells and TRECs in patients and controls, which was not significantly different between patients and controls (P = .06 for CD4+CD45RA+CD31+ T cells and P = .11 for TRECs). However, CD4+CD45RA+CD31+ T cells (Fig 1, C) and TREC levels (Fig 1, D) became lower in patients with HL earlier in life than in HCs. TREC levels were undetectable in 48-year-old patients but still detectable in HCs at age 70 years and beyond (Fig 1, D). In patients with HL, the number of CD4+CD45RA+CD31− central T cells was dramatically lower than in HCs (P < .001) (Fig 1, A, and Table I) and the CD31+/CD31− T-cell ratio was not significantly affected in patients with HL (P = .27) (Table I). Finally, we evaluated the effect of doses, time since radiotherapy, age at treatment, modalities of chemotherapy, and disease stage on the CD4+CD45RA+CD31+ thymic T-cell numbers and TREC levels. Patients receiving radiation doses of 40 Gy exhibited a more pronounced decrease in thymic output than did patients receiving a dose of less than 40 Gy (P = .044 for CD4+ CD45RA+ CD31+ T cells; P = .004 for TREC levels) (Fig 1, E and F). Patients treated at older ages had a more pronounced decrease in TREC levels than did patients treated younger (in univariate [P = .002] and multivariate analysis; see Table E2), and most of the patients treated after age 34 years had undetectable TREC levels (see Fig E1 in this article's Online Repository at www.jacionline.org). The cutoff value for age at treatment associated with a lower number of CD4+CD45RA+CD31+ T cells was explored using receiver operating characteristic analysis of sensitivity and specificity at different cutoff values. The number of CD4+CD45RA+CD31+ T cells was lower in patients treated after the age of 34 years than in patients treated younger (area under the receiver operating characteristic curve = 0.73). Although TREC levels were slightly lower in patients with HL treated with doxorubicin, bleomycin, vinblastine, and dacarbazine than in those treated with other types of chemotherapy (P = .007), CD4+CD45RA+CD31+ T-cell number was not dependent on the type of chemotherapy (P = .33) (see Fig E1). Finally, multivariate analysis showed that male patients had higher levels of CD4+ CD45RA+ CD31+ T cells than did female patients (P = .007) (see Table E2). No association was observed between the decrease in thymic ouput and time since radiotherapy and the stage of HL. In conclusion, long after treatment, patients with HL exhibit a persistent and dramatic alteration in CD4+ T-cell homeostasis and in thymic function, evidenced by a decrease in naive thymic CD4+ CD45RA+ CD31+ T-cell numbers and TREC levels, while memory CD4+ T-cell counts remained unaffected. Signs of immune senescence (decrease in naive T cells and TRECs and increase in CD28− CD4+ T cells) occur earlier in patients. High doses of radiotherapy and treatment after the age of 34 years exacerbate the reduction in thymus output. The premature loss of thymic function in patients suggests that, with aging, they could be more vulnerable to infections and aging-associated immune disorders. However, we did not observe an increased incidence of such pathologies in our patients with HL, suggesting that the detailed analysis of T-cell populations may not be required, unless they suffer from autoimmunity or severe infectious complications. We thank Mrs Marie-Line Loiry, Sophie Chaudet, Anne Huet, and Catherine Daniel for expert technical assistance, Dr Stephane Supiot for advice on radiotherapy, Joanne Walker for English language advice, and Professor Norbert Ifrah for advice on Hodgkin lymphoma. We thank all the patients and healthy volunteers who willingly took part in this study. Written informed consent was obtained from patients treated for HL and from age- and sex-matched HCs. The study was conducted after approval by the Institutional Review Board of Angers University Hospital, France. A cohort of 30 patients who survived HL, diagnosed during childhood or adulthood, was prospectively monitored between January 2011 and June 2011 at Angers University Hospital. Patients were eligible for enrollment if they had received a treatment associating chemotherapy with mediastinum radiotherapy (at least 20 Gy) and had a follow-up period longer than 5 years. Sixty age-matched and sex-matched HCs recruited from acquaintances, without a history of cancer or treatment by radiotherapy, were included and served as the reference group. We collected data on baseline characteristics: number of infections with antibiotherapy per year, number of second cancer, autoimmunity, and other sequelae. Patients were selected on the basis of their age at the moment of treatment with a repartition as follows: 8 patients treated between the age of 5 and 19 years, 8 patients between the age of 20 and 30 years, 8 patients between the age of 31 and 45 years, and 6 patients older than 46 years. The time from radiotherapy to study ranged from 7 to 19 years, and radiation dose levels ranged from 20 to 40 Gy on mediastinum. The immunologic reconstitution was analyzed by using flow cytometry (fluorescence-activated cell sorting). Fresh venous blood samples, collected on EDTA, were gently mixed and incubated with fluorochrome-labeled mAbs for 20 minutes at room temperature in the dark. No-wash lysis and fixation were then performed using the TQ-Prep Workstation and IMMUNOPREP reagents (Beckman Coulter, Villepinte, France). Fluorescence was then analyzed within 1 hour on a FACSCANTO II cytofluorometer, driven by the FACSDIVA software (BD Biosciences, Pont de Clay, France). Absolute CD3+ cell count was determined using Trucount Tubes (BD Biosciences), and absolute counts of other cell populations were calculated from this value. Thymopoiesis was assessed by quantifying TRECs per T cells using real-time quantitative PCR, as previously described.E1Chan K. Puck J.M. Development of population-based newborn screening for severe combined immunodeficiency.J Allergy Clin Immunol. 2005; 115: 391-398Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar DNA was extracted from 5 mL whole blood, using the iPrep gDNA blood kit (Invitrogen, Carlsbad, Calif), and the concentration was determined using a Nanodrop spectrophotometer (Thermo Scientific, Wilmington, Del). Quantitative PCR was performed with a quantity of DNA adjusted between 0.15 and 0.35 μg/reaction and using primers and probes, as described by Chan and Puck.E1Chan K. Puck J.M. Development of population-based newborn screening for severe combined immunodeficiency.J Allergy Clin Immunol. 2005; 115: 391-398Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar Each sample was tested in duplicate; if a negative result was obtained, the sample was retested using a higher quantity of DNA. The number of copies/reaction, expressed as a number of copies/106 white blood cells (WBCs), was determined using a standard curve established with the Douek's plasmid.E2Douek D.C. McFarland R.D. Keiser P.H. Gage E.A. Massey J.M. Haynes B.F. et al.Changes in thymic function with age and during the treatment of HIV infection.Nature. 1998; 396: 690-695Crossref PubMed Scopus (1574) Google Scholar Values of less than 100 copies of TRECs/106 WBCs were considered as undetectable by this technique. Descriptive statistics were used to summarize the characteristics of patients with HL and HCs. Variables related to disease and biological, demographic, and immunologic characteristics were analyzed and described. Continuous variables were summarized as mean ± SD or median (with interquartile ranges), and categorical variables as frequency (percentage). Bonferroni corrections were performed to account for multiple statistical parameters for calculating statistical significance. The 2 groups were first analyzed and described separately. All immunologic characteristics were first analyzed separately for patients with HL and HCs. Separate univariate models were performed to explore the immunologic characteristics of patients with HL and HCs and to explore the biological and clinical characteristics of both groups. Univariate linear regression models were used to analyze immunologic characteristics. Mixed linear models were used to take the matching of patients with HL with HCs into account and to compare immunologic characteristics between both groups. Generalized estimating equations were used to examine potential factors associated between TREC status (number of copies <100/106 WBCs) in both groups. Logistic regression was used to explore factors associated with TREC status among patients with HL. Interaction between the 2 groups and age at analysis were tested for CD31+thymic naive T cells, TREC status, and CD4+ CD31−central naive T cells. All statistical tests were from 2-sided tests. Data were analyzed using the Stata Software version 12.1 (Stata Corporation, College Station, Tex).Table E1Characteristics of patients with HL and HCsCharacteristicHCsPatients with HLP valueSex Male22111 Female3819Age at analysisMean age (y), ± SD44.1 ± 15.543.8 ± 15.2 20-301571 31-45148 >453115Stage of HL∗Patients were staged according to the Ann Arbor classification (stage II, involvement of ≥2 lymph node regions on the same side of the diaphragm; stage III, involvement of lymph node regions on both sides of the diaphragm, which may include the spleen). IINA7NA IIINA23Chemotherapy regimen†ABVD: Doxorubicin, bleomycin, vinblastine, dacarbazine; VB-VP: vinblastine, bleomycin, etoposide (VP16), and prednisone; Other: EBVM (epirubicin, bleomycin, vinblastin, methotrexate), VABEM (vindesine doxorubicin, carmustine, etoposide, methylprednisolone), BEACOPP baseline (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), OPPA (vincristine, doxorubicin, prednisone, procarbacine), BEAM (carmustine, etoposide, cytosine arabinoside, melphalan). ABVDNA22NA VB-VPNA4 OtherNA8Autoimmunity‡Autoimmunity is defined with an autoimmune disease such as systemic lupus erythematosus or rheumatoid arthritis. Yes12.25 No5928Thyroid abnormality§Hypothyroidism or hyperthyroidism measured by thyroid function tests. Yes719.0001 No529 NA12Numbers of infections per yearNumbers of infections are defined as respiratory infections (eg, sinusitis, otitis, and bronchitis) in 1 year and the need for antibiotics. Fewer than 2 infections5823.03 ≥2 infections15 NA12NA, Not applicable/available.P values in boldface are < .05.∗ Patients were staged according to the Ann Arbor classification (stage II, involvement of ≥2 lymph node regions on the same side of the diaphragm; stage III, involvement of lymph node regions on both sides of the diaphragm, which may include the spleen).† ABVD: Doxorubicin, bleomycin, vinblastine, dacarbazine; VB-VP: vinblastine, bleomycin, etoposide (VP16), and prednisone; Other: EBVM (epirubicin, bleomycin, vinblastin, methotrexate), VABEM (vindesine doxorubicin, carmustine, etoposide, methylprednisolone), BEACOPP baseline (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), OPPA (vincristine, doxorubicin, prednisone, procarbacine), BEAM (carmustine, etoposide, cytosine arabinoside, melphalan).‡ Autoimmunity is defined with an autoimmune disease such as systemic lupus erythematosus or rheumatoid arthritis.§ Hypothyroidism or hyperthyroidism measured by thyroid function tests.|| Numbers of infections are defined as respiratory infections (eg, sinusitis, otitis, and bronchitis) in 1 year and the need for antibiotics. Open table in a new tab Table E2Factors associated with the number of CD31+thymic naive cells and the TREC status in multivariate analysis∗This multivariate analysis describes different factors associated with the number of CD31+thymic naive cells (A and B) and with a small amount of TRECs (C and D) in the population including either patients with HL and HCs (A and C) or patients with HL (B and D). A positive regression coefficient means that the factor is associated with higher levels of CD31+thymic naive cells or a risk of having a small amount of TRECs. A negative coefficient means a decrease in these parameters.FactorCoefficientP value95% CIA. Factors associated with the number of CD31+thymic naive cells in patients with HL and HCs Male96.80.00726.2-167.4 Age at analysis−3.60.002−5.8 to −1.3 HL−202.70.000−268.9 to −136.5B. Factors associated with the number of CD31+thymic naive cells in patients with HL Age at treatment−5.10.000−7.2 to −3 Thyroid abnormality−72.30.030−137 to −7.6C. Factors associated with a small amount of TRECs (<100 copies/106 WBCs) in patients with HL and HCs Male−1.45†With TREC status analysis, the coefficients have a special meaning: the antilogarithm of the coefficient equals the odds ratio..081−3.09 to 0.17 Age at analysis0.10†With TREC status analysis, the coefficients have a special meaning: the antilogarithm of the coefficient equals the odds ratio..0020.03-0.17 HL4.06†With TREC status analysis, the coefficients have a special meaning: the antilogarithm of the coefficient equals the odds ratio..0002.08-6.05D. Factors associated with a small amount of TRECs (<100 copies/106 WBCs) in patients with HL Age at treatment0.15†With TREC status analysis, the coefficients have a special meaning: the antilogarithm of the coefficient equals the odds ratio..0070.04-0.27 Thyroid abnormality1.47†With TREC status analysis, the coefficients have a special meaning: the antilogarithm of the coefficient equals the odds ratio..231−0.94 to 3.89 Number of previous chemotherapies0.80†With TREC status analysis, the coefficients have a special meaning: the antilogarithm of the coefficient equals the odds ratio..519−1.63 to 3.23∗ This multivariate analysis describes different factors associated with the number of CD31+thymic naive cells (A and B) and with a small amount of TRECs (C and D) in the population including either patients with HL and HCs (A and C) or patients with HL (B and D). A positive regression coefficient means that the factor is associated with higher levels of CD31+thymic naive cells or a risk of having a small amount of TRECs. A negative coefficient means a decrease in these parameters.† With TREC status analysis, the coefficients have a special meaning: the antilogarithm of the coefficient equals the odds ratio. Open table in a new tab NA, Not applicable/available. P values in boldface are < .05." @default.
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• W2013212118 title "Long-term consequences of Hodgkin lymphoma therapy on T-cell lymphopoiesis" @default.
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