scholarly journals Posttransplant Lymphoproliferative Disorders in Neuronal Xenotransplanted Macaques

2016 ◽  
Vol 54 (2) ◽  
pp. 336-344 ◽  
Author(s):  
L. Cavicchioli ◽  
S. Ferraresso ◽  
S. Westmoreland ◽  
S. Kaliyaperumal ◽  
H. Knight ◽  
...  
Keyword(s):  
Cell Function ◽  
Solid Organ Transplantation ◽  
Lymphoproliferative Disorders ◽  
World Health ◽  
Nuclear Antigen ◽  
Solid Organ ◽  
Double Labeling ◽  
Hematopoietic Stem ◽  
Health Organization ◽  
Posttransplant Lymphoproliferative Disorders

Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations that occur in the setting of depressed T-cell function due to immunosuppressive therapy used following solid organ transplantation, hematopoietic stem cell transplantation, and also xenotransplantation. In the present study, 28 immunosuppressed parkinsonian Macaca fascicularis were intracerebrally injected with wild-type or CTLA4-Ig transgenic porcine xenografts to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Nine of 28 (32%) immunosuppressed primates developed masses compatible with PTLD, located mainly in the gastrointestinal tract and/or nasal cavity. The masses were classified as monomorphic PTLD according to the World Health Organization classification. Immunohistochemistry and polymerase chain reaction (PCR) analyses revealed that the PTLDs were associated with macaca lymphocryptovirus as confirmed by double-labeling immunohistochemistry for CD20 and Epstein-Barr nuclear antigen 2 (EBNA-2), where the viral protein was located within the CD20+ neoplastic B cells. In sera from 3 distinct phases of the experimental life of the primates, testing by quantitative PCR revealed a progression of the viral load that paralleled the PTLD progression and no evidence of zoonotic transmission of porcine lymphotropic herpesvirus through xenoneuronal grafts. These data suggest that monitoring the variation of macaca lymphocryptovirus DNA in primates could be used as a possible early diagnostic tool for PTLD progression, allowing preemptive treatment such as immunosuppression therapy reduction.

Hodgkin Lymphoma–like Posttransplantation Lymphoproliferative Disorder

2006 ◽  
Vol 130 (4) ◽  
pp. 558-560 ◽  
Author(s):  
Barbara Semakula; ◽  
Jon V. Rittenbach ◽  
Jun Wang
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Lymphoproliferative Disorder ◽  
Molecular Genetic ◽  
Lymphoproliferative Disorders ◽  
World Health ◽  
Solid Organ ◽  
World Health Organization Classification ◽  
Health Organization ◽  
Posttransplantation Lymphoproliferative Disorder

Abstract Posttransplantation lymphoproliferative disorders (PTLD) are a heterogeneous group of monoclonal or polyclonal lymphoproliferative lesions that occur in immunosuppressed recipients following solid organ or bone marrow transplantation, including 4 categories: (1) early lesions (reactive plasmacytic hyperplasia, and infectious-mononucleosis–like PTLD), (2) polymorphic PTLD, (3) monomorphic PTLD (including B-cell neoplasms and T-cell neoplasms), and (4) Hodgkin lymphoma (HL) and HL-like PTLD in the current World Health Organization classification. Although HL-like PTLD has been grouped with classic HL PTLD, controversy remains as to whether it is truly a form of HL or whether it should be more appropriately considered as a form of B-cell PTLD. The current available literature data indicate the presence of important immunophenotypic, molecular genetic, and clinical differences between HL PTLD and HL-like PTLD, suggesting that HL-like PTLD is in fact most often a form of B-cell PTLD. Distinction from true HL may be important for clinical management and prognosis.

Posttransplant Lymphoproliferative Disorders in Pediatric Solid Organ Recipients: A Multicenter Retrospective Analysis of Patients from 1990 to 2003.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1929-1929
Author(s):  
B. Maecker ◽  
T. Jack ◽  
H. Abdul-Khaliq ◽  
M. Burdelski ◽  
J. Ehrich ◽  
...  
Keyword(s):  
Lung Transplantation ◽  
Immunosuppressive Therapy ◽  
Retrospective Analysis ◽  
Organ Transplantation ◽  
Median Time ◽  
Solid Organ Transplantation ◽  
Lymphoproliferative Disorders ◽  
Solid Organ ◽  
Hodgkin's Lymphomas ◽  
Posttransplant Lymphoproliferative Disorders

Abstract Posttransplant lymphoproliferative disorders (PTLD) have been recognized as severe side effects of immunosuppressive therapy after organ transplantation. However, no standard diagnostic and therapeutic approaches have been defined. Furthermore, few interdisciplinary perspectives comparing patients with heart/liver/kidney transplants are available. Here, we present results of a multicenter, retrospective analysis of pediatric patients treated for PTLD in Germany and Switzerland from 1990 to 2003. Patients were recruited by surveys through the working groups of pediatric renal, liver, and heart/lung transplantation as well as from the registry of pediatric Non-Hodgkin’s lymphomas (NHL-BFM). Inclusion criteria consisted of a history of solid organ transplantation, biopsy-proven diagnosis of PTLD, and age at onset of PTLD 18 years of less. Patient charts were analyzed for clinical course from transplant to onset of PTLD, virus serology, treatment regimen, and outcome. A total of 53 patients from 19 centers could be included, among them 25 renal graft recipients, 14 heart-, 11 liver-, and 1 lung transplant recipients as well as 2 patients after combined heart/lung transplantation. PTLD was diagnosed at a median time of 34 months [range 2 – 119 months] post organ transplantation. Histological evaluation based on the WHO classification showed 2 early lesion PTLD, 8 polymorphic PTLD, 26 high-grade B-cell lymphomas, 12 Burkitt-like lymphomas, 3 cases of Hodgkin’s disease and 2 T-cell lymphomas. Cytogenetic analysis revealed translocations involving chromosome 8 in five patients with Burkitt-like lymphomas. EBV gene products were detected in 31 tumors by in situ hybridization or immunohistochemistry, while 13 tumors were EBV negative (no data available on 9 tumors). EBV serology was negative in 55% of patients at the time of organ transplantation. However, in 29 patients EBV primary infection/reactivation was documented after organ transplantation (median time to infection/reactivation 5.9 months). In all patients immunosuppressive therapy was reduced. Treatment and follow up data were available in 51 patients: six patients remained in complete remission without additional treatment, in one patient autologous EBV-specific T-cells were infused. 41 patients received monoclonal antibodies (anti-CD20; n=7), chemotherapy (n=28), or a combination thereof (n=5). Fifteen of 51 patients died of progressing PTLD (n=7; among them 3 patients in which treatment was refused), treatment-related mortality (n=7), or fatal graft failure (n=2). Mortality was higher in patients with Burkitt-like lymphomas (7 of 12 patients) compared to all other entities (8 of 39 patients; p=0.026). Patients with stage IV disease had an inferior outcome compared to patients with stage I-III disease (mortality 6 of 7 vs. 9 of 44 patients, p=0.002). Thus, pediatric PTLD is a heterogeneous disease often associated with fatal outcome. The PED-PTLD study group has initiated a prospective multicenter trial of standardized diagnosis and treatment of PTLD after solid organ transplantation in children.

Viral induction and targeted inhibition of galectin-1 in EBV+ posttransplant lymphoproliferative disorders

Blood ◽  
2011 ◽  
Vol 117 (16) ◽  
pp. 4315-4322 ◽  
Author(s):  
Jing Ouyang ◽  
Przemyslaw Juszczynski ◽  
Scott J. Rodig ◽  
Michael R. Green ◽  
Evan O'Donnell ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cytotoxic T Cells ◽  
Treatment Strategies ◽  
Lymphoproliferative Disorders ◽  
Luciferase Expression ◽  
Carbohydrate Binding ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Posttransplant Lymphoproliferative Disorders

Abstract Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBV-driven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV proteins, including latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV-transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy, and administration of EBV-specific cytotoxic T cells. In the present study, we report that EBV-transformed lymphoblastoid B-cell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydrate-binding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4+ Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression, and the combination of LMP2A and LMP1 was additive. In addition, small interfering RNA (siRNA)–mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was dependent on both activating protein 1 (AP-1) and PI3K. A newly developed neutralizing Gal1 mAb selectively inhibited Gal1-mediated apoptosis of EBV-specific CD8+ T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors.

The Impact of the World Health Organization Classification and Clonality Assessment of Posttransplant Lymphoproliferative Disorders on Disease Management

2006 ◽  
Vol 130 (11) ◽  
pp. 1649-1653
Author(s):  
Walid A. Mourad ◽  
Asma Tulabah ◽  
Adher Al Sayed ◽  
Madras Raja ◽  
Yasser Khafaga ◽  
...  
Keyword(s):  
World Health Organization ◽  
Lymphoproliferative Disorders ◽  
World Health ◽  
World Health Organization Classification ◽  
The World ◽  
Health Organization ◽  
Type 3 ◽  
Posttransplant Lymphoproliferative Disorders

Abstract Context.—The World Health Organization classification of posttransplant lymphoproliferative disorders divides them into 4 main categories. Objective.—To classify cases of posttransplant lymphoproliferative disorders diagnosed in our institution according to the World Health Organization scheme and correlate the classification and clonality with clinical data. Design.—Cases of posttransplant lymphoproliferative disorders were reviewed. They were classified according to the World Health Organization scheme. Clonality was determined by flow cytometry and/or polymerase chain reaction. Patients' charts were reviewed. Results.—Thirty-one cases were identified. Median age was 33 years. There were 19 cases of kidney, 8 cases of liver, and 4 cases of bone marrow transplant. Immunosuppression consisted of cyclosporin A and prednisone (N = 24) or FK506 and prednisone (N = 7). Twenty cases (63%) were World Health Organization type 3, 7 cases (23%) type 2, 3 cases (6.4%) type 1, and 1 case type 4 posttransplant lymphoproliferative disorder. Ten patients received chemotherapy, 20 patients had reduction of immunosuppression, and 1 had no treatment. Follow-up was available on 25 patients. Seven (43.75%) of 16 with type 3 lesions with available follow-up died of their disease. Five of these patients received reduction of immunosuppression alone. Only 2 of 9 patients with type 3 disease who received chemotherapy died of disease. Two patients with type 2 disease died of unrelated causes. One patient is alive with disease; the remaining patients with types 1 and 2 disease are alive with no disease. Conclusions.—The World Health Organization classification of posttransplant lymphoproliferative disorders is valuable in the identification of subtypes. It helps identify early lesions (1 and 2) requiring reduction of immunosuppression and type 3 disease, which requires chemotherapy from the outset.

Predicting Risk of Infection and Graft vs. Host Disease (GvHD), and Response to Immunosuppression (ISP) in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Patients (pts) Using the Cylex®ImmuKnow® Assay: A Pilot Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5325-5325
Author(s):  
Elias J. Anaissie ◽  
Jose A. Diaz ◽  
Monica L. Grazziutti ◽  
Marisa H. Miceli ◽  
Michele Fox-Cottler ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Function ◽  
Solid Organ Transplantation ◽  
Myelogenous Leukemia ◽  
Functional Assay ◽  
Solid Organ ◽  
Cell Transplant ◽  
Infection Prophylaxis ◽  
Hematopoietic Stem ◽  
Atp Production

Abstract Background: GvHD, intensity of ISP and infection are major causes of toxicity post-HSCT. Yet, no method reliably predicts these complications. A functional assay for immunity, which predicts risk of GvHD and infection and allows tailoring ISP and infection prophylaxis, is needed. The ImmuKnow is an assay of global T-cell function that measures increased ATP production after stimulating CD4+ T-helper cells and has been shown useful for managing ISP therapies in solid-organ transplantation. We hypothesized that ImmuKnow could assist in predicting risk of GvHD and infection and response to ISP post-HSCT. Patients and Methods: Between January 2003 and May 2006, 34 adult allogeneic HSCT pts [mean age 47 years (range 22–71); 53% females; acute myelogenous leukemia, 8 pts; myeloma, 6 pts;] underwent blood sampling for determining ImmuKnow at various times post-HSCT (238 assays, mean of 7/pt). Results were correlated with clinical course (infection, stable, GvHD, response to ISP). Results: During the testing period, GvHD was documented in 16 pts [(acute, n=7 pts; chronic, n=9 pts] and 53 infections occurred [CMV viremia (n=20); bacteremia (n=20); others (n=13)]. The median immune function (ng/mL ATP) of GvHD pts was significantly higher than that of clinically stable pts (342 +/−105 vs. 167 ng/mL +/−136 respectively), p<0.001. Pts with infections had a median 89 ng/mL ATP (+/−119), also statistically different (p=0.002) from stable pts. A pt with ATP value ≥ 300 ng/mL was more likely (RR=4) to develop GvHD than one with lower immune response. Similarly, there was a higher risk (RR=5) for infection in pts with an ATP ≤ 80 ng/mL. Relative risk curves for infection and GvHD intersected in the low immune response zone (140 ng/mL ATP). Following therapy for GvHD in 10 pts, ATP values rapidly decreased (193 ng/mL ATP +/−122) over 17 days (range 3–35) and were associated with improvement, while stable or increasing values (50 ng/mL ATP +/−99) were observed among 6 pts who failed to respond to GvHD therapy. Conclusions: these data suggest that the FDA-approved ImmuKnow assay is an objective marker of risk for infection and GvHD, and of responsiveness to ISP therapy post-HSCT. Tailoring intensity and duration of ISP to risks of GvHD and infection in an individual pt may be possible and may improve outcomes. Validation of these preliminary data is ongoing.

scholarly journals Late-Onset Posttransplant Lymphoproliferative Disorders after Solid Organ Transplantation in Adults: A Case Series and Review of the Literature

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
S. Gandhi ◽  
E. Behling ◽  
D. Behrens ◽  
A. Ferber ◽  
R. Schwarting ◽  
...  
Keyword(s):  
Organ Transplantation ◽  
Late Onset ◽  
Solid Organ Transplantation ◽  
Case Series ◽  
Lymphoproliferative Disorders ◽  
Solid Organ ◽  
Review Of The Literature ◽  
Histological Features ◽  
Histological Types ◽  
Posttransplant Lymphoproliferative Disorders

The posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of neoplasms that have wide variety of clinical and histological presentations. The management of PTLDs is challenging due to variety of involvement sites and histological types. The length and type of immunosuppression are correlated with the emergence of PTLDs, and most of the cases appear within the first two years after transplant. This case series describes five late-onset PTLDs with rare histological features and multiorgan involvement.

scholarly journals Rituximab therapy is effective for posttransplant lymphoproliferative disorders after solid organ transplantation

Cancer ◽  
2005 ◽  
Vol 104 (8) ◽  
pp. 1661-1667 ◽  
Author(s):  
Anne H. Blaes ◽  
Bruce A. Peterson ◽  
Nancy Bartlett ◽  
David L. Dunn ◽  
Vicki A. Morrison
Keyword(s):  
Organ Transplantation ◽  
Solid Organ Transplantation ◽  
Lymphoproliferative Disorders ◽  
Solid Organ ◽  
Posttransplant Lymphoproliferative Disorders

scholarly journals MON-LB114 CGM in Cystic Fibrosis Patients to Predict Cystic Fibrosis-Related Diabetes Onset

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Mariana Zorron Mei Hsia Pu ◽  
José D Ribeiro ◽  
André M Morcillo ◽  
Aline C Gonçalves ◽  
Antonio F Ribeiro ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Colorimetric Method ◽  
Solid Organ Transplantation ◽  
Forced Expiratory Volume ◽  
World Health ◽  
Solid Organ ◽  
Early Diabetes ◽  
Diabetes Onset ◽  
Health Organization

Abstract Background: Therapeutic progress and improvement on resources enabled the emergence of new comorbidities in cystic fibrosis (CF), such as cystic fibrosis-related diabetes (CFRD). About 20% of adolescents and 40-50% of adults are affected. CFRD and glucose intolerance reduce life expectancy in this population, highlighting the importance of early diagnosis and treatment. Up to 15% of CF patients have hypoglycemia during OGTT and its etiology remains unclear. Some authors associate hypoglycemia with CFRD onset, while others do not agree with this association. Objective: To determine whether abnormal CGM (hypo/hyperglycemia) can predict CFRD onset, pulmonary function and BMI decline in CF patients. Methods: Prospective single center study. All CF patients between 10-19yo from our outpatient clinic were screened for CFRD through OGTT following the World Health Organization (WHO) protocol. The enzymatic colorimetric method was used to classify them as per the ADA. Non-diabetic CF patients performed 3-day CGM, forced expiratory volume in the first second (FEV1), BMI and OGTT. All tests except for CGM were then reassessed after a long follow-up. The WHO’s 2006 curve was used to calculate the z scores for individuals ≤19yo and WHO cut-off values for &gt;19yo. Oral corticoid use during data collection, pregnancy and solid organ transplantation were exclusion criteria. Results: Thirty-nine patients were recruited and 34 completed an average of 3.1 years (±0.51) follow-up. No clinical or laboratory variables could predict diabetes progression or hypoglycemic events. The cohort had an increase in mean BMI (17.80±3.65 vs 18.36±3.49; p=0.025) and a reduction in mean FEV1 (66.91±25.79% vs 56.32±29.57%; p=0.001) between the two evaluations. Patients who developed diabetes showed statistically significant worse FEV1 in the end of the follow-up (22.67±5 vs 59.58±28.9; p=0.041), and lower BMI at both start (14.37±1.23 vs 18.13±3.65; p=0.049) and end (14.81±0.66 vs 18.71±3.46; p=0.029) of follow-up. A logistic regression of the effect of time adjusted for independent variables for progression to CFRD was conducted. A higher possibility of evolution among participants with IGT (odds ratio [OR] 21.67; 95% confidence interval [CI] 7.03-67.36; p&lt;0.01), and a lower possibility among participants with NGT (OR 1.84; 95% CI 1.06-3.19; p=0.031). Conclusion: CGM was not a useful tool to predict early diabetes onset in this population with the current cut-off values. However, the IGT group seems to be the riskiest group. The CF population has particular characteristics and may not have the same diagnostic criteria for DM as the non-CF population. More studies are necessary to determine the appropriate CGM cut-off values for CFRD.

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