|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 31 (November 1), 2007: pp. 4902-4908 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.2392 CNS or Bone Marrow Involvement As Risk Factors for Poor Survival in Post-Transplantation Lymphoproliferative Disorders in Children After Solid Organ Transplantation
From the Departments of Pediatric Hematology/Oncology, Pediatric Cardiology, and Pediatric Nephrology, Hannover Medical School, Hannover; Department of Pediatric Cardiology, Deutsches Herzzentrum; Department of Pediatric Nephrology, University Hospital Charité Berlin, Berlin; Departments of Pediatric Gastroenterology and Pediatric Nephrology, University Hospital Hamburg-Eppendorf, Hamburg-Eppendorf; Department of Pediatric Cardiology, University Hospital Grosshadern, Grosshadern; Department of Pediatric Gastroenterology, Dr-von-Haunersches Kinderspital, Munich; Departments of Pediatric Nephrology and Pediatric Hematology/Oncology, Olgahospital Stuttgart, Stuttgart; Department of Pediatrics, Division of Pediatric Nephrology, University Hospital Cologne, Cologne; Department of Pediatrics and Pediatric Neurology, University Hospital Essen, Essen; Division of Pediatric Nephrology, University Children's Hospital Heidelberg, Heidelberg; Departments of Pediatric Cardiology and Pediatric Hematology/Oncology, University Hospital Giessen, Giessen; Department of Pediatric Nephrology, University Hospital Freiburg, Freiburg, Germany; and Department of Pediatric Nephrology, University Hospital Zurich, Zurich, Switzerland Address reprint requests to Britta Maecker, MD, Pediatric Hematology/Oncology, Medizinische Hochschule Hannover, Carl-Neuberg-Str 1, D-30625 Hannover, Germany; e-mail: maecker.britta{at}mh-hannover.de
Purpose To identify prognostic factors of survival in pediatric post-transplantation lymphoproliferative disorder (PTLD) after solid organ transplantation. Patients and Methods A multicenter, retrospective case analysis of 55 pediatric solid organ graft recipients (kidney, liver, heart/lung) developing PTLD were reported to the German Pediatric-PTLD registry. Patient charts were analyzed for tumor characteristics (histology, immunophenotypes, cytogenetics, Epstein-Barr virus [EBV] detection), stage, treatment, and outcome. Probability of overall and event-free survival was analyzed in defined subgroups using univariate and Cox regression analyses. Results PTLD was diagnosed at a median time of 29 months after organ transplantation, with a significantly shorter lag time in liver (0.83 years) versus heart or renal graft recipients (3.33 and 3.10 years, respectively; P = .001). The 5-year overall and event-free survival was 68% and 59%, respectively, with 59% of patients surviving 10 years. Stage IV disease with bone marrow and/or CNS involvement was associated independently with poor survival (P = .0005). No differences in outcome were observed between early- and late-onset PTLD, monomorphic or polymorphic PTLD, and EBV-positive or EBV-negative PTLD, respectively. Patients with Burkitt or Burkitt-like PTLD and c-myc translocations had short survival (< 1 year). Conclusion Stage IV disease is an independent risk factor for poor survival in pediatric PTLD patients. Prospective multicenter trials are needed to delineate additional risk factors and to assess treatment approaches for pediatric PTLD.
Post-transplantation lymphoproliferative disorders (PTLDs) have been recognized as severe complications of immunosuppressive therapy after solid organ transplantation that cause significant morbidity and mortality.1,2 The development of PTLD is a result of compromised antiviral and antitumor immunosurveillance due to iatrogenic immunosuppression.3 Although primary infection with or reactivation of Epstein-Barr virus (EBV) after organ transplantation confers a high risk of developing PTLD,4,5 unique risk factors for or predictors of PTLD have yet to be defined.6 Development of PTLD has been linked to EBV disparity between donor/recipient,7,8 the use of certain immunosuppressive drugs (muromonab-CD3, antithymocyte globulin, tacrolimus),9-13 and concurrent cytomegalovirus infection.13,14 Compared with adult organ graft recipients, pediatric patients seem to be at higher risk to develop PTLD,13 given that they are less likely to have EBV-specific immunity at the time of transplantation. Incidence of PTLD in children ranges from 0.5% to 20% depending on the type of organ graft and the number of risk factors.9,12,15-18 Treatment strategies include reduced immunosuppressive therapy as tolerated,19-21 use of monoclonal antibodies (eg, anti-CD20 antibody rituximab22,23), and combination chemotherapy with cytotoxic agents.24-26 Stable remissions are observed in a number of patients (60% to 80%), but treatment also causes severe adverse effects and a significant treatment-related morbidity and mortality.24-26 Our aim was to assess pathologic, virologic, and genetic characteristics as well as prognostic factors influencing the survival of pediatric PTLD patients. We present retrospective data on 55 pediatric patients diagnosed with PTLD in Germany and Switzerland after solid organ transplantation between 1990 and 2003.
Patients and Data Collection The study was approved by our institution's review board. Patients were recruited retrospectively by inquiry to the Working Groups on Pediatric Nephrology, Pediatric Heart and Lung Transplantation, and Pediatric Liver Transplantation in Germany. Positive responses and patient data were received from 12 of 18 renal transplantation centers, four of four liver transplantation centers, and six of 15 heart transplantation centers. 50 patients were reported by these centers. Furthermore, pediatric patients (n = 12) reported to the Berlin-Frankfurt-Muenster (BFM) Non-Hodgkin's Lymphoma (NHL) study center (University of Giessen, Giessen, Germany) were included in this trial. Inclusion criteria were a history of solid organ transplantation, histologically proven PTLD between 1990 and 2003, and age at diagnosis of PTLD  18 years. Seven of 62 patients did not meet inclusion criteria because of age (n = 5) or lack of tumor biopsy (n = 2). Data were collected by retrospective chart analysis either by the treating physician or by a central data managing physician. A standardized questionnaire considered organ transplantation (underlying disease, type of organ graft, EBV serostatus at the time of transplantation, and initial immunosuppressive treatment); post-transplantation history (episodes of graft rejection, EBV infection/reactivation, or cytomegalovirus infection); and PTLD (clinical performance, histopathologic diagnosis as reviewed by the local pathologist, cytogenetic results, expression of CD20 on tumor cells, detection of EBV or EBV proteins in tumor cells, stage of disease, treatment, outcome, probability of overall survival [pOS], and probability of event-free survival [pEFS]).
Statistical Analysis
Differences in the distribution of variables among patient subsets were analyzed using the
Patient Characteristics A total of 55 patients were available for data analysis (29 male, 26 female). Transplanted organs were kidney (n = 26), heart (n = 14), heart/lung (n = 2), lung (n = 1), and liver (n = 12; Appendix Table A1, online only, lists underlying disease). None of the patients suffered from primary immunodeficiency or systemic hematologic or malignant disease before transplantation. Median age at diagnosis of PTLD was 2.8 years in liver transplantation patients, 7.5 years in heart/lung transplantation patients, and 14.0 years in renal transplantation patients. Nineteen of 55 patients developed PTLD during the first year after organ transplantation (early-onset PTLD; Fig 1A). The interval from organ transplantation to onset of PTLD was significantly shorter in liver (median, 0.83 years; Fig 1B) than in renal (3.10 years) or heart transplant (3.33 years) recipients (P = .001). This interval to PTLD was not correlated to age at the time of organ transplantation (Fig 1C). Patients had received various regimens of immunosuppressive therapy combinations. At least one episode of graft rejection before onset of PTLD was observed in 25 of 40 patients (62.5%) for whom data were available.
In the absence of standardized therapeutic regimens, treatment of PTLD was not uniform. In all patients, immunosuppressive therapy was reduced. Six patients did not receive any additional therapy and remained in continuous complete remission up to 10 years; among them, one patient had early lesion, two patients had polymorphic PTLD, and three patients had monomorphic B-cell PTLD (two patients had monoclonal disease). One patient received autologous EBV-specific T cells. The remaining patients were treated with anti-CD20 monoclonal antibody alone (n = 6), in combination with various chemotherapy regimens (n = 5), or with systemic chemotherapy alone (n = 32). Chemotherapy regimens were based mainly on BFM NHL scheme with individually adapted dose modifications (n = 24). Independent of the type of organ graft, most common recommendations were reduction of all chemotherapy components to 80% (or less; three patients); reduction of methotrexate to 50% (or less; three patients); replacement of ifosfamide by cyclophosphamide (one patient); and a reduced number of chemotherapy cycles (two patients). Except for one patient who died as a result of heart failure, there was no graft-specific toxicity. Three patients received therapy according to the German Society of Pediatric Oncology and Hematology protocol for Hodgkin's disease, and seven patients were treated according to an individualized dose-reduced chemotherapy regimen. In one patient, PTLD was diagnosed on postmortem examination; one patient died without specific treatment for PTLD because of poor performance status, and one patient was lost to follow-up shortly after diagnosis.
Survival
For renal, heart, and liver graft recipients, 5-year pEFS was 0.66, 0.69, and 0.57, respectively (Fig 3A). No significant differences were seen (P = .33 for heart/renal v liver graft recipients), indicating that the type of organ graft had no impact on survival in our patient cohort.
Histologic Classification of Tumors Forty-nine of 55 patients presented with B-cell malignancies, including one early lesion, eight patients with polymorphic PTLD, 26 patients with monomorphic B-cell PTLD, 11 patients with Burkitt or Burkitt-like PTLD, and three patients presenting with B-ALL (Table 1). Forty-three of the B-cell malignancies were stained for cell surface expression of CD20 (Table 1), which was positive in 35 tumors (81.4%); among them were all polymorphic PTLDs, Burkitt or Burkitt-like NHLs, and B-ALLs. Cytogenetic analysis was performed in 32 of 48 patients with B-cell malignancies. All polymorphic and monomorphic PTLD had a normal karyotype. In contrast, four of eight patients with Burkitt or Burkitt-like NHL revealed translocations involving chromosome 8, two patients had t(8;22), and one patient each had t(2;8) and t(8;14), respectively. In addition, one B-ALL patient presented with translocation t(8;14); in the other patients no cytogenetic analysis was performed. In two patients with t(8;14) and t(8;22), respectively, rearrangement of c-myc and immunoglobulin genes could be confirmed by fluorescent in situ hybridization. In addition, the cohort contained three patients with Hodgkin's disease and three patients with T-cell NHL. All patients with Hodgkin's disease and the patient with early lesion survived in continuous complete remission. Of the three patients with T-cell PTLD, one patient is in remission, one patient died as a result of tumor progression, and one patient was lost to follow-up.
Five-years pEFS data for patients with B-cell PTLD (polymorphic, monomorphic, and Burkitt or Burkitt-like/B-ALL) are shown in Figure 3B. Patients with Burkitt or Burkitt-like NHL and B-ALL were analyzed within the same group because of biologic similarities.27 Although poly- and monomorphic PTLD patients had similar 5-year pEFS (0.66 and 0.68, respectively; P = .58), patients with Burkitt or Burkitt-like NHL and B-ALL showed a trend toward an inferior outcome (pEFS, 0.38 at 5 years; P = .07). In this small group of 14 patients, six of whom had stage IV disease, the five patients with c-myc translocations tended to have an inferior outcome, whereas pEFS of patients without chromosomal translocations was comparable to that for patients with monomorphic B-cell PTLD (Fig 3C). These results emphasize the importance of cytogenetic analysis for disease prognosis.
Poor EFS in Patients With Stage IV Disease
Variables that showed at least a trend for prognostic value in univariate analysis were examined with Cox regression analysis: sex, stage of disease (I-III v IV), histologic diagnosis (Burkitt/B-ALL v other), number of involved sites ( 2 v > 2), EBV infection at transplantation (positive v naïve), history of graft rejection, and time to EBV seroconversion or reactivation ( 12 v > 12 months). In this analysis, stage IV disease (n = 8) was the only significant predictor of inferior survival (relative risk, 6.8; 95% CI, 1.84 to 24.8; P = .004).
Poor Response to First-Line Treatment Is Associated With Inferior EFS
Impact of EBV Infection on Development and Outcome of PTLD In immunocompetent patients, EBV elicits a strong cellular and humoral immune response controlling latent infection,31 suggesting that EBV-positive tumors may be associated with stronger immune responses and subsequently decreased mortality. However, 5-year pEFS was not significantly different between patients with EBV-negative and EBV-positive tumors (P = .13; Appendix Fig A1B). This finding differs from results by Leblond et al,28 who demonstrated inferior survival in an adult patient population with EBV-negative tumors. Similarly, there was no difference between 5-year pEFS in patients who did or did not have serologic evidence of prior EBV infection at the time of organ transplantation (5-year pEFS, 0.75 and 0.60, respectively; P = .65; Appendix Fig A1C). Thus, together with the observation that incidence of PTLD was high in EBV-naïve organ recipients, we conclude that EBV and anti-EBV immunity seem to play a role in the development of PTLD, especially in the first year after transplantation, but do not seem to have an impact on prognosis once PTLD has developed.
In our retrospective analysis, we identified several important prognostic factors affecting outcome in pediatric PTLD patients. The overall survival rates of 0.68 and 0.59 at 5 and 10 years, respectively, are in accordance with other published data.3,13,18 Stage IV disease was the only independent predictor of poor EFS. Recently, poor survival was reported in pediatric PTLD patients with CNS involvement.32,33 In adult PTLD patients, Leblond et al28 identified primary CNS involvement as a poor prognostic factor; in addition, involvement of multiple sites seems to be a risk factor for inferior outcome in this patient group.17,28,29 In our analysis there was no significant difference in survival of patients with stage I, II, or III disease, whereas patients presenting with stage IV disease had a significantly worse survival. In our cohort, eight patients did not have bone marrow examination, and 16 patients had no evaluation of CNS fluid to detect CNS involvement. The prognostic significance of correct staging for survival emphasizes the need for complete diagnostic work-up during initial staging. All histologic types of PTLD were identified including three patients with T-cell PTLD and three patients with Hodgkin's disease. However, the majority of tumors were of B-cell origin. Of note, 19% of B-cell tumors did not express the CD20 antigen, emphasizing the need for immunologic confirmation of CD20 expression before anti-CD20 immunotherapy. The importance of discriminating between polymorphic and monomorphic disease is controversial.33a Occasionally, polymorphic and monomorphic PTLDs have been detected simultaneously in the same patient.34 In our series, polymorphic PTLD was a relatively rare event (14%), possibly secondary to reporting bias, which may result in a under-reporting of polymorphic PTLD with benign course. Polymorphic and monomorphic PTLDs were associated with comparable pEFS, which is in accordance with results published by others.15,18,35 However, because of the retrospective design of our study, we cannot completely rule out sampling or interpretation bias. Furthermore, nonuniform treatment may influence survival and mask additional risk factors. Burkitt-like lymphomas and B-ALLs showed a trend toward an inferior pEFS, but because of low numbers, no statistically significant result was achieved. This trend was more substantial in patients with genetic alterations of c-myc, which has been reported anecdotally in two recent studies.36,37 Thus, c-myc translocations, if present, seem to have an adverse effect on EFS, providing compelling reasons for cytogenetic tumor analysis in each patient. To tailor effective and well-tolerated treatment strategies remains an important and open question for physicians confronted with pediatric PTLD. Effectiveness of various treatment regimens could not be analyzed in this retrospective data set because of high variability. Given that the vast majority of B-cell PTLDs expressed the pan–B-cell antigen CD20, these patients may benefit from new treatment strategies such as monoclonal antibodies (eg, rituximab) alone or in combination with (low dose) chemotherapy.26 Davis et al38 suggest that sequential treatment strategies may be feasible in pediatric PTLD. In our data set, failure to achieve remission after first-line treatment was associated with significantly worse outcome, similar to data published by Benkerrou et al.39 This clearly emphasizes the need to monitor treatment response closely. For future studies, [18F]-fluorodeoxyglucose positron emission tomography imaging may help to predict metabolic response early in the treatment course.40-42 In addition to outcome predictors of manifest PTLD, our data revealed interesting insights into factors influencing the development of PTLD. The mean interval between organ transplantation and onset of PTLD was significantly shorter in liver versus renal graft or heart recipients. In particular, no PTLD occurred in liver graft recipients beyond the fourth year. This may be attributable to the fact that immunosuppressive therapy can often be reduced to low levels or even completely stopped after the first 5 years in this patient population.43 Alternatively, the absence of prior EBV infection at the time of organ transplantation may contribute to early onset of PTLD; although not statistically significant, nine of 10 liver graft recipients were EBV naïve compared with 10 of 16 heart/renal graft recipients (P = .12). Although liver and heart graft recipients were significantly younger at transplantation than renal graft recipients (0.77 and 1.36 years v 9.72 years, respectively; P = .0001), there was no association between age at transplantation and time to onset of PTLD (Appendix Fig A2, online only). Our analysis delineates a number of factors that might be important to consider in future risk-factor–based therapeutic studies. To delineate additional rational and optimized treatment strategies, future prospective trials (ideally carried out in interdisciplinary and international consortiums) are needed.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Britta Maecker, Novartis; Christoph Klein, Novartis Testimony: N/A Other: N/A
Conception and design: Britta Maecker, Thomas Jack, Karl Welte, Michael Melter, Gisela Offner, Christoph Klein Financial support: Britta Maecker, Karl Welte, Christoph Klein Administrative support: Britta Maecker, Christoph Klein Provision of study materials or patients: Britta Maecker, Hashim Abdul-Khaliq, Martin Burdelski, Alexandra Fuchs, Peter Hoyer, Sabine Koepf, Ulrike Kraemer, Guido F. Laube, Dirk E. Müller-Wiefel, Heinrich Netz, Martin Pohl, Burkhard Toenshoff, Hans-Joachim Wagner, Michael Wallot, Michael Melter, Gisela Offner Collection and assembly of data: Britta Maecker, Thomas Jack, Hashim Abdul-Khaliq, Martin Burdelski, Alexandra Fuchs, Peter Hoyer, Sabine Koepf, Ulrike Kraemer, Guido F. Laube, Dirk E. Müller-Wiefel, Heinrich Netz, Martin Pohl, Burkhard Toenshoff, Hans-Joachim Wagner, Michael Wallot Data analysis and interpretation: Britta Maecker, Martin Zimmermann, Michael Melter, Gisela Offner, Christoph Klein Manuscript writing: Britta Maecker, Christoph Klein Final approval of manuscript: Britta Maecker, Thomas Jack, Martin Zimmermann, Hashim Abdul-Khaliq, Martin Burdelski, Alexandra Fuchs, Peter Hoyer, Sabine Koepf, Ulrike Kraemer, Guido F. Laube, Dirk E. Müller-Wiefel, Heinrich Netz, Martin Pohl, Burkhard Toenshoff, Hans-Joachim Wagner, Michael Wallot, Karl Welte, Michael Melter, Gisela Offner, Christoph Klein
We thank our patients, their parents, and their physicians for their commitment, and Annette Frank-Hoppe for study support. Jochen Ehrich, Martin Holder, Bernd Hoppe, Axel Karow, Thomas Lang, Anja Lehnhardt, Eckhard Maass, Barbara Meissner, and Miriam Zimmering are additional coauthors of this study.
Supported by research funding from the C.D. Foundation and Novartis. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Nalesnik MA: Clinicopathologic characteristics of post-transplant lymphoproliferative disorders: Recent Results Cancer Res 159 : 9 -18, 2002 2. Nalesnik MA: Clinical and pathological features of post-transplant lymphoproliferative disorders (PTLD). Springer Semin Immunopathol 20 : 325 -342, 1998[Medline] 3. Smets F, Sokal EM: Epstein-Barr virus-related lymphoproliferation in children after liver transplant: Role of immunity, diagnosis, and management. Pediatr Transplant 6 : 280 -287, 2002[CrossRef][Medline] 4. Smets F, Latinne D, Bazin H, et al: Ratio between Epstein-Barr viral load and anti-Epstein-Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease. Transplantation 73 : 1603 -1610, 2002[CrossRef][Medline] 5. Wagner HJ, Wessel M, Jabs W, et al: Patients at risk for development of posttransplant lymphoproliferative disorder: Plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation 72 : 1012 -1019, 2001[Medline] 6. Axelrod DA, Holmes R, Thomas SE, et al: Limitations of EBV-PCR monitoring to detect EBV associated post-transplant lymphoproliferative disorder. Pediatr Transplant 7 : 223 -227, 2003[CrossRef][Medline] 7. Ho M, Jaffe R, Miller G, et al: The frequency of Epstein-Barr virus infection and associated lymphoproliferative syndrome after transplantation and its manifestations in children. Transplantation 45 : 719 -727, 1988[Medline] 8. Swerdlow AJ, Higgins CD, Hunt BJ, et al: Risk of lymphoid neoplasia after cardiothoracic transplantation: A cohort study of the relation to Epstein-Barr virus. Transplantation 69 : 897 -904, 2000[CrossRef][Medline] 9. Younes BS, McDiarmid SV, Martin MG, et al: The effect of immunosuppression on posttransplant lymphoproliferative disease in pediatric liver transplant patients. Transplantation 70 : 94 -99, 2000[Medline] 10. Dharnidharka VR, Ho PL, Stablein DM, et al: Mycophenolate, tacrolimus and post-transplant lymphoproliferative disorder: A report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 6 : 396 -399, 2002[CrossRef][Medline] 11. Sokal EM, Antunes H, Beguin C, et al: Early signs and risk factors for the increased incidence of Epstein-Barr virus-related posttransplant lymphoproliferative diseases in pediatric liver transplant recipients treated with tacrolimus. Transplantation 64 : 1438 -1442, 1997[CrossRef][Medline] 12. Cox KL, Lawrence-Miyasaki LS, Garcia-Kennedy R, et al: An increased incidence of Epstein-Barr virus infection and lymphoproliferative disorder in young children on FK506 after liver transplantation. Transplantation 59 : 524 -529, 1995[Medline] 13. Caillard S, Dharnidharka V, Agodoa L, et al: Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation 80 : 1233 -1243, 2005[CrossRef][Medline] 14. Manez R, Breinig MC, Linden P, et al: Posttransplant lymphoproliferative disease in primary Epstein-Barr virus infection after liver transplantation: The role of cytomegalovirus disease. J Infect Dis 176 : 1462 -1467, 1997[Medline] 15. Pinkerton CR, Hann I, Weston CL, et al: Immunodeficiency-related lymphoproliferative disorders: Prospective data from the United Kingdom Children's Cancer Study Group Registry. Br J Haematol 118 : 456 -461, 2002[CrossRef][Medline] 16. Allen U, Hebert D, Moore D, et al: Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplant recipients, 1988-97: A Canadian multi-centre experience. Pediatr Transplant 5 : 198 -203, 2001[CrossRef][Medline] 17. Trofe J, Buell JF, Beebe TM, et al: Analysis of factors that influence survival with post-transplant lymphoproliferative disorder in renal transplant recipients: The Israel Penn International Transplant Tumor Registry experience. Am J Transplant 5 : 775 -780, 2005[CrossRef][Medline] 18. Webber SA, Naftel DC, Fricker FJ, et al: Lymphoproliferative disorders after paediatric heart transplantation: A multi-institutional study. Lancet 367 : 233 -239, 2006[CrossRef][Medline] 19. Starzl TE, Nalesnik MA, Porter KA, et al: Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1 : 583 -587, 1984[Medline] 20. Swinnen LJ: Organ transplant-related lymphoma. Curr Treat Options Oncol 2 : 301 -308, 2001[CrossRef][Medline] 21. Nepomuceno RR, Balatoni CE, Natkunam Y, et al: Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. Cancer Res 63
: 4472
-4480, 2003 22. Milpied N, Vasseur B, Parquet N, et al: Humanized anti-CD20 monoclonal antibody (Rituximab) in post transplant B-lymphoproliferative disorder: A retrospective analysis on 32 patients. Ann Oncol 11
: 113
-116, 2000
(suppl 1) 23. Serinet MO, Jacquemin E, Habes D, et al: Anti-CD20 monoclonal antibody (rituximab) treatment for Epstein-Barr virus-associated, B-cell lymphoproliferative disease in pediatric liver transplant recipients. J Pediatr Gastroenterol Nutr 34 : 389 -393, 2002[CrossRef][Medline] 24. Mamzer-Bruneel MF, Lome C, Morelon E, et al: Durable remission after aggressive chemotherapy for very late post-kidney transplant lymphoproliferation: A report of 16 cases observed in a single center. J Clin Oncol 18
: 3622
-3632, 2000 25. Smets F, Vajro P, Cornu G, et al: Indications and results of chemotherapy in children with posttransplant lymphoproliferative disease after liver transplantation. Transplantation 69 : 982 -984, 2000[Medline] 26. Gross TG, Bucuvalas JC, Park JR, et al: Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation. J Clin Oncol 23
: 6481
-6488, 2005 27. Ferry JA: Burkitt's lymphoma: Clinicopathologic features and differential diagnosis. Oncologist 11
: 375
-383, 2006 28. Leblond V, Dhedin N, Mamzer Bruneel MF, et al: Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders. J Clin Oncol 19
: 772
-778, 2001 29. Ghobrial IM, Habermann TM, Maurer MJ, et al: Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders. J Clin Oncol 23
: 7574
-7582, 2005 30. Cohen JI: Benign and malignant Epstein-Barr virus-associated B-cell lymphoproliferative diseases. Semin Hematol 40 : 116 -123, 2003[CrossRef][Medline] 31. Cohen JI: Epstein-Barr virus infection. N Engl J Med 343
: 481
-492, 2000 32. Buell JF, Gross TG, Hanaway MJ, et al: Posttransplant lymphoproliferative disorder: Significance of central nervous system involvement. Transplant Proc 37 : 954 -955, 2005[CrossRef][Medline] 33. Traum AZ, Rodig NM, Pilichowska ME, et al: Central nervous system lymphoproliferative disorder in pediatric kidney transplant recipients. Pediatr Transplant 10 : 505 -512, 2006[CrossRef][Medline] 33. Ghobrial IM, Habermann TM, Macon WR, et al: Differences between early and late posttransplant lymphoproliferative disorders in solid organ transplant patients: Are they two different diseases? Transplantation 79 : 244 -247, 2005[CrossRef][Medline] 34. Chadburn A, Cesarman E, Liu YF, et al: Molecular genetic analysis demonstrates that multiple posttransplantation lymphoproliferative disorders occurring in one anatomic site in a single patient represent distinct primary lymphoid neoplasms. Cancer 75 : 2747 -2756, 1995[CrossRef][Medline] 35. Paranjothi S, Yusen RD, Kraus MD, et al: Lymphoproliferative disease after lung transplantation: Comparison of presentation and outcome of early and late cases. J Heart Lung Transplant 20 : 1054 -1063, 2001[CrossRef][Medline] 36. Djokic M, Le Beau MM, Swinnen LJ, et al: Post-transplant lymphoproliferative disorder subtypes correlate with different recurring chromosomal abnormalities. Genes Chromosomes Cancer 45 : 313 -318, 2006[CrossRef][Medline] 37. Delecluse HJ, Rouault JP, Ffrench M, et al: Post-transplant lymphoproliferative disorders with genetic abnormalities commonly found in malignant tumours. Br J Haematol 89 : 90 -97, 1995[Medline] 38. Davis CL, Wood BL, Sabath DE, et al: Interferon-alpha treatment of posttransplant lymphoproliferative disorder in recipients of solid organ transplants. Transplantation 66 : 1770 -1779, 1998[CrossRef][Medline] 39. Benkerrou M, Jais JP, Leblond V, et al: Anti-B-cell monoclonal antibody treatment of severe posttransplant B-lymphoproliferative disorder: Prognostic factors and long-term outcome. Blood 92
: 3137
-3147, 1998 40. von Falck C, Maecker B, Schirg E, et al: Post transplant lymphoproliferative disease in paediatric solid organ transplant patients: A possible role for [18F]-FDG-PET(/CT) during initial staging and therapy monitoring. Eur J Radiol 63 : 427 -435, 2007[CrossRef][Medline] 41. Bakker NA, Pruim J, de Graaf W, et al: PTLD visualization by FDG-PET: Improved detection of extranodal localizations. Am J Transplant 6 : 1984 -1985, 2006[CrossRef][Medline] 42. O'Conner AR, Franc BL: FDG PET imaging in the evaluation of post-transplant lymphoproliferative disorder following renal transplantation. Nucl Med Commun 26 : 1107 -1111, 2005[CrossRef][Medline] 43. Bucuvalas JC, Ryckman FC: Long-term outcome after liver transplantation in children. Pediatr Transplant 6 : 30 -36, 2002[CrossRef][Medline] Submitted December 6, 2006; accepted August 10, 2007.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 test for categorized variables, and with t test or the Wilcoxon rank sum test for continuous variables. The statistical analysis was carried out using SAS for PC, version 9.1 (SAS Institute Inc, Cary, NC). 
