Search Results (56)

Individuals with immunosuppressive conditions are at a higher risk of developing malignancies than those in the general population. Immunosuppression weakens tumor immunity, hinders the detection of pro-oncogenic cells, and activates oncogenic viruses. Malignancies arising in immunosuppressed patients tend to be aggressive, have a high incidence of virus-associated cancers, and are reversible in some cases. Notably, immunosuppressive agents influence the frequency and type of malignancies, as well as their clinicopathological features. Organ transplant recipients receive long-term immunosuppressants to prevent acute rejection. Post-transplant malignancies vary depending on the type of drug administered before the onset of these diseases. Patients with rheumatoid arthritis (RA) are treated with long-term immunosuppressive medications, such as methotrexate (MTX). MTX is widely recognized as being associated with a specific type of lymphoproliferative disorder (LPD), known as MTX-associated LPD. Our recent report indicated that the clinicopathological features of rheumatoid arthritis-associated lymphoproliferative disorder (RA-LPD) also vary based on the other anti-RA agents used, such as tacrolimus and tumor necrosis factor inhibitors. Therefore, the clinicopathological characteristics of post-transplant LPD and RA-LPD evolve alongside the changes in the immunosuppressants/immunomodulators administered. Understanding the various characteristics and time trends of immunosuppressive neoplasms, particularly LPDs, in relation to different immunosuppressant/immunomodulator medications is highly valuable in clinical practice. Full article

Background: Post-transplant lymphoproliferative disorder (PTLD) encompasses an uncommon but wide spectrum of clinical conditions resulting from abnormal lymphoproliferation in patients receiving chronic immunosuppression following organ transplantation. Undoubtedly, reduced immune surveillance of the Epstein–Barr Virus (EBV) is highly implicated in disease pathogenesis. The incidence of PTLD varies significantly depending upon the organ transplanted, along with the age and EBV serostatus of the transplant recipient. Some programs advocate the use of routine surveillance for EBV in peripheral blood. In the case of liver transplantation, the incidence, clinical features, and outcomes in adult transplant recipients are poorly described. Methods: We performed a single centre retrospective study of 1409 individual liver transplant recipients from 20 June 1988 until 31 December 2024, with a view to describing incidence, clinical and histopathologic features, the impact of EBV, and patient outcomes. Results: There was a 2.0% incidence of PTLD (28 patients). The onset of PTLD was a late clinical event, with a median time of 11.4 (IQR 3.4–6.2) years from transplantation to diagnosis. Most cases were monomorphic PTLD of the diffuse large B cell lymphoma (DLBCL) histologic subtype (85.2%), and the bowel was the most involved organ. EBV was detectable within the tumour in only 52% and within peripheral blood in only 61.5%. Whilst the presence of EBV did not appear to influence the outcome, those patients who were EBV naive at time of transplant, and received an EBV-positive graft, developed PTLD at a significantly earlier post-transplant stage (0.9 years, IQR 0.3–5.8, vs. 11.1 years, IQR 5.5–1.43, p = 0.02). The type of immunosuppression used did not influence the outcome. In addition, 50% of the patients with PTLD died during the study period, at a median of 0.6 (IQR 0.2–2.6) years from disease diagnosis. Conclusions: PTLD remains uncommon in the adult liver transplant population and is usually a late clinical event, with EBV detectable in peripheral blood in only 61.5% of cases. Whilst advocated in some units, routine screening for EBV in peripheral blood is unlikely to be of clinical utility in an adult liver transplant cohort. Full article

Post-transplant lymphoproliferative disorders (PTLD) represent a life-threatening complication following solid organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in patients with relapsed or refractory (R/R) disease, where therapeutic options are limited and prognosis is poor. Among emerging strategies, adoptive cellular immunotherapy—specifically Epstein–Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)—significantly improved outcomes in this challenging patient population. EBV-CTLs restore virus-specific immunity and induce sustained remissions with minimal toxicity, even in heavily pretreated individuals. The most promising cellular product to date is tabelecleucel, an off-the-shelf, allogeneic EBV-specific T-cell therapy, which is currently the only cellular therapy approved by the European Medicines Agency (EMA) for the treatment of R/R EBV-positive PTLD following SOT or allo-HSCT. This review aims to provide an overview of PTLD treatment with a specific focus on adoptive cellular immunotherapy. We highlight the most robust clinical outcomes reported with EBV-CTLs, particularly those achieved with tabelecleucel, and explore emerging cellular approaches such as CAR T-cell therapy, which may further broaden therapeutic strategies in the near future. Full article

Background/Objectives: The risk of post-transplantation lymphoproliferative disorder (PTLD) varies according to the type of transplanted organ. To investigate the factors contributing to PTLD development and treatment outcomes, we established a multicenter registry that included patients diagnosed with PTLD within a population of 13,263 kidney, liver, and lung transplant recipients (KTRs, LTRs, and LngTRs, respectively), observed in a period between 2000 and 2023. Methods: The chi-squared test was used to analyze differences in group composition. Univariate and multivariate Cox regression were applied to determine the impact of factors upon PTLD onset and patient survival. Results: Our registry included 58 out of 9432 KTRs, 40 out of 3500 LTRs, and 5 out of 331 LngTRs. The median time to PTLD onset was significantly longer among KTRs (117 months post-transplant) than among LTRs (49 months, p < 0.001) and LngTRs (5 months, p < 0.001). LTRs treated with tacrolimus developed PTLD later compared to LTRs treated with cyclosporin (p = 0.042). In multivariate analysis, older age at first transplantation correlated with earlier disease development in SOTRs (HR = 1.03, p = 0.006) and KTRs (HR = 1.04, p = 0.003). Older age at first transplantation was also associated with worse survival among KTRs (p = 0.045). Conclusions: We identified clear differences in the factors affecting PTLD onset and survival between KTRs and LTRs. Organ-specific analyses are needed to improve our understanding of PTLD risk factors, treatment choices, and clinical outcomes. Full article

Background and Clinical Significance: Post-transplant lymphoproliferative disorder (PTLD) is a severe complication of solid organ transplantation, often associated with prolonged immunosuppression. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype. Managing PTLD requires a balance between reducing immunosuppression and preventing graft rejection. Case Presentation: A 41-year-old female kidney transplant recipient developed PTLD eight years post-transplant, presenting with a right submandibular mass. Biopsy confirmed CD20-positive DLBCL. Initial treatment involved reducing immunosuppression and rituximab monotherapy, which failed to prevent disease progression. The patient underwent six cycles of R-CHOP chemotherapy, achieving complete metabolic remission. Relapse occurred twice, with disease progression in the cervical nodes and tonsils. Salvage therapies, including polatuzumab vedotin and rituximab, achieved remission. During a subsequent relapse, loncastuximab tesirine induced metabolic resolution. Compromised renal function limited treatment options and a second renal transplant was delayed, reducing the risk of PTLD recurrence. Conclusions: This case underscores the challenges of managing PTLD in transplant recipients, especially in relapsed/refractory cases. Single-agent rituximab was insufficient, but combination chemotherapy and novel agents like loncastuximab tesirine were effective. Balancing oncologic control and graft preservation remains critical. This case highlights the need for individualized approaches and novel therapies in managing PTLD while addressing the complexities of immunosuppression and organ preservation. Full article

CD3⁺ CD8⁺ CD57⁺ mono-, oligo-, and poly-clonal expansions, both idiopathic and clinically related diseases, including as autoimmunity, viral infections, post-transplant, and hematologic malignancies, can cause T large granular lymphocyte (T-LGL) lymphoproliferative disorders. It is yet unknown if this variability is a result of a dynamic process of cytotoxic T cell responses to exoantigens and autoantigens. The major aim of this review is to gather evidence from the literature in order to further highlight the possible pathogenetic mechanism that may underly the above clinical entities. Major research findings include the following: (i) pronounced skewing of the TRBV repertoire; (ii) existence of more than one immunodominant clonotype; (iii) persistent clonotypes in different timepoints albeit with fluctuating frequencies (clonal drift); and (iv) shared (‘public’) clonotypes between cases and the public databases, further suggesting a limited number of antigens implicated in pathogenesis of T-LGL cases. However, there is no clear distinction between polyclonal, oligoclonal, and monoclonal T-LGL lymphoproliferative conditions; rather, the progression from a polyclonal cytotoxic response to the emergence of T-LGL leukemia is slow. In the ontogeny and evolution of T-LGL leukemia, repertoire limits, public clonotypes, and clonal drift all clearly show selection by limited (perhaps shared) antigens. Full article

Epstein–Barr virus (EBV) is strongly associated with the development of post-transplant lymphoproliferative disorder (PTLD) in pediatric liver transplant recipients. PTLD is one of the most common malignancies following liver transplantation and is associated with significant morbidity and mortality. Factors such as EBV–serostatus mismatch and prolonged or high levels of immunosuppression impact a patient’s risk of developing PTLD. While pre-transplant EBV serological screening and post-transplant monitoring of EBV-DNA levels are strongly recommended, universal guidelines for its prevention and management are lacking. Due to a lack of robust prospective studies, current clinical practices vary widely. The treatment of PTLD typically involves reducing immunosuppression and using targeted therapies such as rituximab, or chemotherapy for refractory cases. This review aims to address our current understanding of EBV’s relationship with PTLD, evaluate the available treatment modalities, and highlight evolving strategies for using EBV as a biomarker for PTLD screening and prevention. Full article

Post-transplant lymphoproliferative disorder (PTLD) is the most common malignancy in adults who receive solid organ transplantation (SOT), apart from skin cancer. It is a serious and potentially fatal complication of chronic immunosuppression (ISI) in SOT recipients. This report describes a 20-year (2001–2021) clinicopathological experience with 59 PTLD patients at an urban center. The median time from transplant to PTLD was 8.5 years and the most common types of transplants were kidney (41%) and liver (31%). Epstein–Barr encoding region (EBER) was positive in 51% tumors, and 50% patients had Epstein–Barr virus (EBV) viremia at diagnosis. Overall survival (OS) at 1 year and 5 years was 78% and 64%, respectively. OS was significantly (p < 0.05) shorter in males (hazard ratio [HR] 3.7), certain organ transplants (lung HR 10.4; liver HR 3.9 relative to kidney), PTLD diagnosed within 12 months of transplant (HR 4.1), multi-organ involvement at diagnosis (HR 7.1), vitamin D deficiency at diagnosis (HR 4.5), and low serum albumin level at diagnosis (HR 3.6). Our study highlights the prognostic factors of PTLD and corroborates improved PTLD outcomes in the past 20 years. Full article

Monitoring immune function in post-transplant patients is crucial to reduce the risk of viral infections (e.g., cytomegalovirus [CMV] or Epstein–Barr virus [EBV]), which can lead to serious complications such as post-transplant lymphoproliferative disorder (PTLD). Recently, Torque Teno virus (TTV) has attracted interest as a marker of immune function. Thus, we studied the kinetics of common post-transplant viral infections (TTV, EBV, CMV, human herpesvirus-6 [HHV-6], and adenovirus [AdV]) and their association with clinical parameters in 23 HSCT recipients who developed PTLD (PTLD-HSCT) and 25 post-HSCT patients without PTLD (Non-PTLD-HSCT) at three different timepoints: at the time of the transplant (T0), 3 months (T1), and 6 months (T2) post-HSCT. Additionally, 25 healthy donors (HD) were used as the control. EBV, CMV, HHV-6, or AdV infections were found in a few samples, while TTV was found in all of our samples. The highest TTV levels (4.61 [T0], 6.24 [T1] and 6.70 [T2] log₁₀ copies/mL) were seen in PTLD-HSCT patients compared to Non-PTLD-HSCT (3.39 [T0], 4.86 [T1], and 3.75 [T2] log₁₀ copies/mL) and HD (2.25 log₁₀ copies/mL) at all timepoints. Higher TTV levels were also seen in patients with a destructive type of PTLD and in surviving PTLD-HSCT patients compared to deceased ones. TTV kinetics in PTLD patients post-HSCT showed that TTV levels increase with the fall in the host immunocompetence and that by monitoring TTV kinetics, the immune status of the patient can be monitored. Full article

Lymphocryptoviruses (LCVs) are ubiquitous gamma-herpesviruses that establish life-long infections in both humans and non-human primates (NHPs). In immunocompromised hosts, LCV infections are commonly associated with B cell disorders and malignancies such as lymphoma. In this study, we evaluated simian LCV-encoded small microRNAs (miRNAs) present in lymphoblastoid cell lines (LCLs) derived from a Mauritian cynomolgus macaque (Macaca fascicularis) with cyLCV-associated post-transplant lymphoproliferative disease (PTLD) as well as the viral miRNAs expressed in a baboon (Papio hamadryas) LCL that harbors CeHV12. Via sequence comparisons, we further predicted viral miRNAs encoded by LCVs that infect two additional NHP species: stump-tailed macaques (Macaca arctoides) and bonobos (Pan paniscus). Together, these species represent two arms of the primate phylogeny: Hominoids (Pan) and Old-World monkeys (Macaca, Papio). Through our analysis, we defined sequences for >95 viral miRNAs encoded by these four NHP LCVs. Our study provides the most comprehensive annotation of NHP LCV miRNAs to date, yielding a resource for developing sequence-specific reagents to detect these molecules. Importantly, we further demonstrate that cyLCV miRNAs can be detected in circulation in vivo and have biomarker potential for LCV-related PTLD. Full article

The Herpesviridae include the Epstein–Barr Virus (EBV) and the Kaposi Sarcoma-associated Herpesvirus (KSHV), both of which are oncogenic gamma-herpesviruses. These viruses manipulate host cellular mechanisms, including through ubiquitin-mediated pathways, to promote viral replication and oncogenesis. Ubiquitin, a regulatory protein which tags substrates for degradation or alters their function, is manipulated by both EBV and KSHV to facilitate viral persistence and cancer development. EBV infects approximately 90% of the global population and is implicated in malignancies including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), post-transplant lymphoproliferative disorder (PTLD), and nasopharyngeal carcinoma. EBV latency proteins, notably LMP1 and EBNA3C, use ubiquitin-mediated mechanisms to inhibit apoptosis, promote cell proliferation, and interfere with DNA repair, contributing to tumorigenesis. EBV’s lytic proteins, including BZLF1 and BPLF1, further disrupt cellular processes to favor oncogenesis. Similarly, KSHV, a causative agent of Kaposi’s Sarcoma and lymphoproliferative disorders, has a latency-associated nuclear antigen (LANA) and other latency proteins that manipulate ubiquitin pathways to degrade tumor suppressors, stabilize oncogenic proteins, and evade immune responses. KSHV’s lytic cycle proteins, such as RTA and Orf64, also use ubiquitin-mediated strategies to impair immune functions and promote oncogenesis. This review explores the ubiquitin-mediated interactions of EBV and KSHV proteins, elucidating their roles in viral oncogenesis. Understanding these mechanisms offers insights into the similarities between the viruses, as well as provoking thought about potential therapeutic targets for herpesvirus-associated cancers. Full article

Introduction: Deoxyguanosine Kinase (DGUOK) deficiency is a very rare disorder characterized by liver dysfunction, neurological manifestations, and metabolic disorders secondary to severely reduced mitochondrial DNA content. These patients develop early-onset liver failure, and their liver transplantation (LT) indication remains debatable due to the possibility of neurological involvement. Case Report: We present the case of a 6-month-old female diagnosed with DGUOK deficiency who developed liver failure. At 9 months, she underwent a living-related LT with an initial favorable evolution under immunosuppression therapy with tacrolimus. Four months after LT, she presented two prolonged bacterial and Rotavirus enteritis episodes. She developed classical post-transplant complications (severe renal tubular acidosis type IV, secondary to the high tacrolimus level, and post-transplant lymphoproliferative disease) during these episodes. Her condition deteriorated progressively, with reversible hypotonia and significant weight loss. However, the neurological evaluation did not reveal any signs suggestive of the progression of the underlying disease. A few months later, her clinical features and laboratory parameters improved considerably. Conclusions: This case highlights the unpredictable evolution of children with LT for liver failure due to DGUOK deficiency. Full article

The acquisition or reactivation of Epstein–Barr virus (EBV) after allogeneic Hematopoietic Stem Cell Transplant (HSCT) can be associated with complications including the development of post-transplant lymphoproliferative disorder (PTLD), which is associated with significant morbidity and mortality. A number of risk factors for PTLD have been defined, including T-cell depletion, and approaches to monitoring EBV, especially in high-risk patients, with the use of preemptive therapy upon viral activation have been described. Newer therapies for the preemption or treatment of PTLD, such as EBV-specific cytotoxic T-cells, hold promise. Further studies to help define risks, diagnosis, and treatment of EBV-related complications are needed in this at-risk population. Full article

Epstein–Barr virus-related post-transplantation lymphoproliferative disorder (EBV-PTLD) is a serious complication following hematopoietic stem cell transplantation (HSCT). A pre-emptive strategy using rituximab, which aims to manage patients early at the time of EBV reactivation to avoid PTLD, has been recommended by the most recent ECIL-6 guidelines in 2016. However, there is still a great heterogeneity of viral-load monitoring protocols, targeted patient populations, and pre-emptive treatment characteristics between centers, making precise EBV monitoring recommendations difficult. We conducted a literature review from the most recent publications between 1 January 2015 and 1 August 2023, to summarize the emerging data on EBV-PTLD prevention strategies in HSCT recipients, including the EBV-DNA threshold and use of rituximab. We also present the results of a survey of current practices carried out in 12 of the main HSCT centers across Canada. We confirm that pre-emptive rituximab remains an efficient strategy for EBV-PTLD prevention. However, there is an urgent need to perform prospective, randomized, multicentric trials with larger numbers of patients reflecting current practices to determine the best clinical conduct with regards to rituximab dosing, timing of treatment, and criteria to initiate treatments. Longer follow-ups will also be necessary to assess patients’ long-term outcomes. Full article

Post-transplant lymphoproliferative disease is a rare disorder with an annual incidence of 0.5% to 3.7%. Development of this disorder carries with it a poor prognosis. In this report, we describe a rare case of post-transplant primary cutaneous T-cell lymphoma (PT-CTCL) mycosis fungoides stage IIB in a patient following kidney transplantation, as well as a review of PT-CTCL reported in the literature. The treatment following diagnosis included bexarotene, cyclosporine, and prednisone. Currently, the patient is free from disease. This information aims to add to the knowledge of the prevalence and management of PT-CTCL. Full article