Natural Killer Cells in Post-Transplant Lymphoproliferative Disorders.
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ABSTRACT:
SUBMITTER: Nakid-Cordero C
PROVIDER: S-EPMC8068932 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:It is unknown whether pediatric monomorphic post-transplant lymphoproliferative disorders (mPTLD) display similar genetic features than the immunocompetent counterpart and if they resemble adult mPTLD. We have investigated 39 pediatric mPTLD, 33 diffuse large B-cell lymphoma (DLBCL) and six Burkitt lymphoma (BL), by an integrated approach, including fluorescence in situ hybridization, cell of origin determination (COO), targeted gene sequencing and copy-number arrays. According to COO, 24/28 DLBCL (86%) were classified as activated B-cell (ABC) and all six BL were germinal center B cell (GCB)-type. Thirty-three out of 37 investigated mPTLD were positive for EBV infection. Overall, PTLD-BL carried mutations in MYC in addition to ID3 and DDX3X, ARID1A or CCND3 and a higher mutational burden than PTLD-DLBCL (12.3 vs 6.2, P = 0.01). CN profile of PTLD-BL was less complex than in IC-BL (1 vs 6.26; P < 0.005). PTLD-DLBCL showed a very heterogeneous genomic profile characterized by a lower number of mutations (2.4 vs 6.5, P=0.01) and less CNA (2.10 vs 4.36 ; P < 0.05) than in IC patients. Pathway enrichment analysis revealed that epigenetic modifiers and Notch pathway (4 cases each) were the most recurrently affected. In conclusion, these findings further unravel for the first time the molecular heterogeneity of pediatric mPTLD and provide new parameters for the design of more effective therapeutic strategies.
2023-12-19 | GSE198253 | GEO
Project description:Post-transplant lymphoproliferative disorders of T- or NK-cell origin (T/NK-PTLD) are rare entities and their genetic basis is unclear. We performed targeted sequencing of 465 cancer-related genes and high-resolution copy number analysis in 17 T-PTLD and 2 NK-PTLD cases. Overall, 377 variants were detected, with an average of 20 variants per case. Mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, KDM6B, n=11). and inactivation of TP53 by mutation and/or deletion(n=6) were the most frequent alterations, seen across disease subtypes, followed by mutations of JAK/STAT pathway genes (n=5). Novel variants, including mutations in TBX3 (n=3), MED12 (n=3) and MTOR (n=1), were observed as well. High-level microsatellite instability was seen in 1 of 14 (7%) cases, which had a heterozygous PMS2 mutation. Complex copy number changes were detected in 8 of 16 (50%) cases and disease subtype-specific aberrations were also identified. In contrast to B-cell PTLDs, the molecular and genomic alterations observed in T/NK-PTLD appear similar to those reported for peripheral T-cell lymphomas occurring in immunocompetent hosts, which may suggest common genetic mechanisms of lymphoma development.
| S-EPMC5122338 | biostudies-literature
Project description:Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication of both allogeneic solid organ (SOT) and hematopoietic cell transplantation (HCT). The histology of PTLD ranges from benign polyclonal lymphoproliferation to a lesion indistinguishable from classic monoclonal lymphoma. Most commonly, PTLDs are Epstein-Barr virus (EBV) positive and result from loss of immune surveillance over EBV. Treatment for PTLD differs from the treatment for typical non-Hodgkin lymphoma because prognostic factors are different, resistance to treatment is unique, and there are specific concerns for organ toxicity. While recipients of HCT have a limited time during which they are at risk for this complication, recipients of SOT have a lifelong requirement for immunosuppression, so approaches that limit compromising or help restore immune surveillance are of high interest. Furthermore, while EBV-positive and EBV-negative PTLDs are not intrinsically resistant to chemotherapy, the poor tolerance of chemotherapy in the post-transplant setting makes it essential to minimize potential treatment-related toxicities and explore alternative treatment algorithms. Therefore, reduced-toxicity approaches such as single-agent CD20 monoclonal antibodies or bortezomib, reduced dosing of standard chemotherapeutic agents, and non-chemotherapy-based approaches such as cytotoxic T cells have all been explored. Here, we review the chemotherapy and non-chemotherapy treatment landscape for PTLD.
| S-EPMC8415721 | biostudies-literature
Project description:Background and objectivesPost-transplant lymphoproliferative disorders arising after kidney transplantation portend an increased risk of morbidity and mortality. Retransplantation of patients who had developed post-transplant lymphoproliferative disorder remains questionable owing to the potential risks of recurrence when immunosuppression is reintroduced. Here, we investigated the feasibility of kidney retransplantation after the development of post-transplant lymphoproliferative disorder.Design, setting, participants, & measurementsWe reviewed the data from all patients who underwent kidney retransplantation after post-transplant lymphoproliferative disorder in all adult kidney transplantation centers in France between 1998 and 2015.ResultsWe identified a total of 52 patients with kidney transplants who underwent 55 retransplantations after post-transplant lymphoproliferative disorder. The delay from post-transplant lymphoproliferative disorder to retransplantation was 100±44 months (28-224); 98% of patients were Epstein-Barr virus seropositive at the time of retransplantation. Induction therapy for retransplantation was used in 48 patients (i.e., 17 [31%] patients received thymoglobulin, and 31 [57%] patients received IL-2 receptor antagonists). Six patients were also treated with rituximab, and 53% of the patients received an antiviral drug. The association of calcineurin inhibitors, mycophenolate mofetil, and steroids was the most common maintenance immunosuppression regimen. Nine patients were switched from a calcineurin inhibitor to a mammalian target of rapamycin inhibitor. One patient developed post-transplant lymphoproliferative disorder recurrence at 24 months after retransplantation, whereas post-transplant lymphoproliferative disorder did not recur in 51 patients.ConclusionsThe recurrence of post-transplant lymphoproliferative disorder among patients who underwent retransplantation in France is a rare event.
| S-EPMC5628715 | biostudies-literature
Project description:BackgroundThe 2008 World Health Organization (WHO) classification distinguishes three entities among the large granular lymphocytic leukemia (LGL leukemia): T-cell LGL leukemia (T-LGL leukemia), aggressive natural killer (NK) cell leukemia, and chronic NK lymphoproliferative disorders (LPD), the later considered as a provisional entity. Only a few and small cohorts of chronic NK LPD have been published.Patients and methodsWe report here clinicobiological features collected retrospectively from 70 cases of chronic NK LPD, and compared with those of T-LGL leukemia.ResultsThere were no statistical differences between chronic NK LPD and T-LGL leukemia concerning median age [61 years (range 23-82 years)], organomegaly (26%), associated autoimmune diseases (24%), and associated hematological malignancies (11%). Patients with chronic NK LPD were significantly less symptomatic (49% versus 18%, P < 0.001) and the association with rheumatoid arthritis was more rarely observed (7% versus 17%, P = 0.03). The neutropenia (<0.5 × 10(9)/l) was less severe in chronic NK LPD (33% versus 61%, P < 0.001) without difference in the rate of recurrent infections. STAT3 mutation was detected in 12% of the cohort, which is lower than the frequency observed in T-LGL leukemia. Thirty-seven percent of the patients required specific therapy. Good results were obtained with cyclophosphamide. Overall and complete response rates were, respectively, 69% and 56%. Overall survival was 94% at 5 years.ConclusionThis study suggests very high similarities between chronic NK LPD and T-LGL leukemias. Since chronic NK LPD is still a provisional entity, our findings should be helpful when considering further revisions of the WHO classification.
| S-EPMC4176455 | biostudies-literature
Project description:BackgroundPost-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication following lung transplant. We studied incidence and risk factors for PTLD in adult lung transplant recipients (LTRs) using the International Society for Heart and Lung Transplantation Registry.MethodsThe International Society for Heart and Lung Transplantation Registry was used to identify adult, first-time, single and bilateral LTRs with at least 1 year of follow-up between 2006 and 2016. Kaplan-Meier method was used to describe the timing and distribution of PTLD. Univariable and multivariable Cox proportional hazards regression models were used to examine clinical characteristics associated with PTLD.ResultsOf 19,309 LTRs in the analysis cohort, we identified 454 cases of PTLD. Cumulative incidence of PTLD was 1.1% (95% CI = 1.0%-1.3%) at 1 year and 4.1% (95% CI = 3.6%-4.6%) at 10 years. Of the PTLD cases, 47.4% occurred within the first year following lung transplantation. In the multivariable model, independent risk factors for PTLD included age, Epstein-Barr virus serostatus, restrictive lung diseases, and induction. Risk of PTLD during the first year after transplant increased with increasing age in patients between 45 and 62 years at time of transplantation; the inverse was true for ages <45 years or >62 years. Finally, receiving a donor organ with human leukocyte antigen types A1 and A24 was associated with an increased risk of PTLD, whereas the recipient human leukocyte antigen type DR11 was associated with a decreased risk.ConclusionsOur study indicates that PTLD is a relatively rare complication among adult LTRs. We identified clinical characteristics that are associated with an increased risk of PTLD.
| S-EPMC7530100 | biostudies-literature
Project description:Post-transplant lymphoproliferative disease (PTLD) is a well-recognized complication after transplant. This study aimed to develop and validate a risk score to predict PTLD among solid organ transplant (SOT) recipients. Poisson regression identified predictors of PTLD with the best fitting model selected for the risk score. The derivation cohort consisted of 2546 SOT recipients transpanted at Rigshospitalet, Copenhagen between 2004 and 2019; 57 developed PTLD. Predictors of PTLD were high-risk pre-transplant Epstein-Barr Virus (EBV), IgG donor/recipient serostatus, and current positive plasma EBV DNA, abnormal hemoglobin and C-reactive protein levels. Individuals in the high-risk group had almost 7 times higher incidence of PTLD (incidence rate ratio (IRR) 6.75; 95% CI: 4.00-11.41) compared to the low-risk group. In the validation cohort of 1611 SOT recipients from the University Hospital of Zürich, 24 developed PTLD. A similar 7 times higher risk of PTLD was observed in the high-risk group compared to the low-risk group (IRR 7.17, 95% CI: 3.05-16.82). The discriminatory ability was also similar in derivation (Harrell's C-statistic of 0.82 95% CI (0.76-0.88) and validation (0.82, 95% CI:0.72-0.92) cohorts. The risk score had a good discriminatory ability in both cohorts and helped to identify patients with higher risk of developing PTLD.
| S-EPMC9265532 | biostudies-literature
Project description:Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening neoplasms after organ transplantation. Because of their rarity and multiple grades of malignancy, the incidence, outcomes, and clinicopathological features affecting patient survival after liver transplantation (LT) remain unclear. We reviewed 1954 LTs in 1849 recipients (1990-2020), including 886 pediatric (<18 years of age) and 963 adult recipients. The following clinicopathological factors were studied: age, sex, liver etiologies, malignancy grades, Epstein-Barr virus status, performance status (PS), Ann Arbor stage, international prognostic index, and histopathological diagnosis. Of 1849 recipients, 79 PTLD lesions (4.3%) were identified in 70 patients (3.8%). After excluding 3 autopsy cases incidentally found, 67 (45 pediatric [5.1%] and 22 adult [2.3%]) patients were finally enrolled. Comorbid PTLDs significantly worsened recipient survival compared with non-complicated cases (P < 0.001). The 3-year, 5-year, and 10-year overall survival rates after PTLD diagnosis were 74%, 66%, and 58%, respectively. The incidence of PTLDs after LT (LT-PTLDs) was significantly higher (P < 0.001) with earlier onset (P = 0.002) in children, whereas patient survival was significantly worse in adults (P = 0.002). Univariate and multivariate analyses identified the following 3 prognostic factors: age at PTLD diagnosis ≥18 years (hazard ratio [HR], 11.2; 95% confidence interval [CI], 2.63-47.4; P = 0.001), PS ≥2 at diagnosis (HR, 6.77; 95% CI, 1.56-29.3; P = 0.01), and monomorphic type (HR, 6.78; 95% CI, 1.40-32.9; P = 0.02). A prognostic index, the "LT-PTLD score," that consists of these 3 factors effectively stratified patient survival and progression-free survival (P = 0.003 and <0.001, respectively). In conclusion, comorbid PTLDs significantly worsened patient survival after LT. Age ≥18 years and PS ≥2 at PTLD diagnosis, and monomorphic type are independent prognostic factors, and the LT-PTLD score that consists of these 3 factors may distinguish high-risk cases and guide adequate interventions.
| S-EPMC8453854 | biostudies-literature
Project description:Post-transplant lymphoproliferative disorders (PTLD) are a major complication of solid organ transplantation and represent a cause of severe morbidity and mortality among transplanted patients. Apart from EBV infection, knowledge of the pathogenesis of monoclonal PTLD is limited. Powerful analysis techniques, such as whole genomic DNA profiling (arrayCGH), can improve our understanding of PTLD pathogenesis. Toward this aim, we obtained the whole genome profiling using the Affymetrix GeneChip Human Mapping 10k 2.0 from 20 cases of PTLD and we compared them with those assessed in 25 cases of DLBCL from immunocompetent patients, as a control group. Recurrent lesions were detected among all the samples. Chromosome 18q, 7q, 3q and 12 were the most common gains in DLBCL of immunocompetent hosts. Chromosomes 5p and 11p were commonly gained in PTLD-DLBCL. The latter had frequent losses of 6q, 17p, 1p, and 9p. Chromosome 12p was the most frequent target of deletions among PTLD-DLBCL. The LOH pattern was characterized by involvement of chromosomes 13q and 17p in DLBCL and 10, 1q, 9p and 11q among PTLD-DLBCL. Interestingly, LOH did not always match the DNA loss. In particular, chromosome 10 seemes to be targeted by uniparental disomy in PTLD. Small deletions and gains, involving both known (BCL2 and PAX5) and unknown genes (ZDHHC14), have been identified. Our data suggest that PTLD share, at a lower frequency, common genetic aberrations with DLBCL from immunocompetent patients. The demonstration of 9p13 amplification indicates the importance of PAX5 in PTLD. The combination of DNA copy number and LOH assessment lead to the hypothesis that uniparental disomy may be a potential mechanism in B-cell lymphomagenesis. Twenty specimens of monoclonal B-cell PTLD, collected from 20 solid organ transplant recipients. Keywords: Genomic DNA on Affymetrix 10K SNP array
2007-06-15 | GSE8123 | GEO
Project description:Epstein-Barr virus (EBV) infection is correlated with several lymphoproliferative disorders, including Hodgkin disease, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and post-transplant lymphoproliferative disorder (PTLD). The oncogenic EBV is present in 80% of PTLD. EBV infection influences immune response and has a causative role in the oncogenic transformation of lymphocytes. The development of PTLD is the consequence of an imbalance between immunosurveillance and immunosuppression. Different approaches have been proposed to treat this disorder, including suppression of the EBV viral load, reduction of immune suppression, and malignant clone destruction. In some cases, upfront chemotherapy offers better and durable clinical responses. In this work, we elucidate the clinicopathological and molecular-genetic characteristics of PTLD to clarify the biological differences of EBV(+) and EBV(-) PTLD. Gene expression profiling, next-generation sequencing, and microRNA profiles have recently provided many data that explore PTLD pathogenic mechanisms and identify potential therapeutic targets. This article aims to explore new insights into clinical behavior and pathogenesis of EBV(-)/(+) PTLD with the hope to support future therapeutic studies.
| S-EPMC7225286 | biostudies-literature