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1.
J Clin Exp Hematop ; 61(3): 120-125, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34511544

RESUMO

Post-transplant lymphoproliferative disorder (PTLD) and other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are iatrogenic lymphoproliferative disorders (LPD) that develop in association with immunosuppressive treatment in the setting of organ transplantation and autoimmune disease, respectively. Each has a spectrum of pathologies ranging from lymphoid hyperplasia to lymphoma. To clarify the characteristics of the diffuse large B-cell lymphoma (DLBCL) subtype in a cohort of 25 patients with PTLD or OIIA-LPD from our institute, we selected 13 with a histological subtype of DLBCL, including 2 cases of PTLD and 11 of OIIA-LPD. The median patient age at diagnosis was 70 years, with a female predominance. Both PTLD cases developed after kidney transplant. Of the patients with OIIA-LPD, 10 had rheumatoid arthritis, 1 had mixed connective tissue disease, and 8 were treated using methotrexate. Both of the PTLD patients and 6 of the OIIA-LPD patients had extranodal manifestations. All patients except for one were classified as having the non-germinal center B-cell (non-GCB) subtype according to the Hans algorithm. Tissue samples from 8 patients were positive for CD30 and 8 were positive for Epstein-Barr virus (EBV)-encoded small RNA. Seven patients had MYC-positive tissue samples, but none had MYC translocation. Our study suggests that extranodal manifestations and the non-GCB subtype are common, that EBV is associated with the DLBCL subtype of PTLD and OIIA-LPD, and that anti-CD30 therapy is applicable. In addition, our patients with the DLBCL subtype of PTLD and OIIA-LPD exhibited MYC overexpression without MYC translocation, suggesting an alternative mechanism of MYC upregulation.


Assuntos
Regulação da Expressão Gênica , Genes myc , Doença Iatrogênica , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/etiologia , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Idoso , Idoso de 80 Anos ou mais , Suscetibilidade a Doenças , Infecções por Vírus Epstein-Barr/complicações , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos
2.
Transpl Infect Dis ; 23(5): e13719, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34453768

RESUMO

BACKGROUND: The use of antithymocyte globulin (ATG) in allogeneic hematopoietic cell transplant (HCT) is associated with an increased risk of Epstein-Barr virus (EBV) reactivation and post-transplant lymphoproliferative disorders (PTLD). The dynamics and outcomes of EBV-DNAemia are not well described in this population. METHODS: We retrospectively assessed the kinetics of EBV-DNAemia after ATG conditioning of HCT recipients. Receiver operating characteristic (ROC) curves were used to assess EBV-DNAemia to predict EBV-PTLD in this group. RESULTS: A total of 174/405 (43%) consecutive HCT recipients from two centers met inclusion criteria of ATG conditioned, non-B-cell lymphoma patients. Of these with EBV-DNA measured using standardized IU/ml, 78.6% (92/117) developed EBV-DNAemia: 62% spontaneously resolved; 19% cleared after preemptive rituximab, and 13% developed EBV-PTLD. ROC curve analysis using maximum pre-EBV-PTLD EBV-DNAemia, demonstrated an AUC of 0.912 with EBV-DNAemia of 9782 IU/ml, associated with 82.6% sensitivity and 94.4% specificity for development of EBV-PTLD. Median time for EBV-DNAemia to increase from initial detection to >1000 IU/ml was 7 days; to >10 000 IU/ml, 12 days; and to >100 000 IU/ml, 18 days. Median EBV-DNAemia level prior to administration of rituximab was significantly lower in patients with successful preemptive treatment, compared with those who developed EBV-PTLD (3.41 log10  IU/ml [3.30-3.67] vs. 4.34 log10  IU/ml [3.85-5.13], p = .002; i.e., 2628 IU/ml vs. 21 965 IU/ml, respectively). CONCLUSIONS: EBV-DNAemia >10 000 IU/ml was the strongest predictor of the development of EBV-PTLD, and progression to this level was rapid in ATG-conditioned HCT recipients. This information may guide EBV-PTLD management strategies in these high-risk patients.


Assuntos
Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Transtornos Linfoproliferativos , Soro Antilinfocitário/uso terapêutico , DNA Viral , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4/genética , Humanos , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/etiologia , Estudos Retrospectivos
3.
BMJ Case Rep ; 14(8)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400429

RESUMO

A 45-year-old woman presented to us in March 2019 with complaints of fever and right lower quadrant abdominal pain for 1 month. She had undergone renal transplantation in 2017 for end-stage renal disease and developed four episodes of urinary tract infection in the next 16 months post transplantation, which were treated based on culture reports. She was subsequently kept on long-term prophylaxis with trimethoprim and sulfamethoxazole. Her present laboratory parameters showed a normal blood picture and elevated creatinine. Urine culture grew Escherichia coli Non-contrast CT of the abdomen-pelvis revealed an endo-exophytic hyperdense mass in the graft kidney showing local infiltration and associated few regional lymph nodes. PET-CT revealed the soft-tissue mass and regional lymph nodes to be hypermetabolic, raising the possibility of lymphoma. However, biopsy showed features of malakoplakia. She was subsequently initiated on long-term antibiotic therapy and her immunosuppression decreased.


Assuntos
Transplante de Rim , Transtornos Linfoproliferativos , Malacoplasia , Infecções Urinárias , Feminino , Humanos , Transplante de Rim/efeitos adversos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Malacoplasia/diagnóstico , Malacoplasia/etiologia , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
4.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072296

RESUMO

Diacylglycerol kinases are intracellular enzymes that control the balance between the secondary messengers diacylglycerol and phosphatidic acid. DGKα and DGKζ are the prominent isoforms that restrain the intensity of T cell receptor signalling by metabolizing PLCγ generated diacylglycerol. Thus, their activity must be tightly controlled to grant cellular homeostasis and refine immune responses. DGKα is specifically inhibited by strong T cell activating signals to allow for full diacylglycerol signalling which mediates T cell response. In X-linked lymphoproliferative disease 1, deficiency of the adaptor protein SAP results in altered T cell receptor signalling, due in part to persistent DGKα activity. This activity constrains diacylglycerol levels, attenuating downstream pathways such as PKCθ and Ras/MAPK and decreasing T cell restimulation induced cell death. This is a form of apoptosis triggered by prolonged T cell activation that is indeed defective in CD8+ cells of X-linked lymphoproliferative disease type 1 patients. Accordingly, inhibition or downregulation of DGKα activity restores in vitro a correct diacylglycerol dependent signal transduction, cytokines production and restimulation induced apoptosis. In animal disease models, DGKα inhibitors limit CD8+ expansion and immune-mediated tissue damage, suggesting the possibility of using inhibitors of diacylglycerol kinase as a new therapeutic approach.


Assuntos
Diacilglicerol Quinase/genética , Diacilglicerol Quinase/metabolismo , Suscetibilidade a Doenças , Genes Ligados ao Cromossomo X , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/metabolismo , Animais , Biomarcadores , Diacilglicerol Quinase/química , Ativação Enzimática , Estudos de Associação Genética/métodos , Loci Gênicos , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Transtornos Linfoproliferativos/diagnóstico , Ligação Proteica , Transdução de Sinais , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/metabolismo , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismo
5.
Am J Transplant ; 21(10): 3465-3471, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33942495

RESUMO

Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).


Assuntos
Infecções por Vírus Epstein-Barr , Linfoma não Hodgkin , Transtornos Linfoproliferativos , Adenina/análogos & derivados , Sistema Nervoso Central , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Herpesvirus Humano 4 , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/etiologia , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/etiologia , Piperidinas , Linfócitos T
7.
Front Immunol ; 12: 654167, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995370

RESUMO

In immunocompromised patients, EBV may elicit B-cell transformation and proliferation. A 5-year-old microcephalic boy was admitted with fever and non-malignant polymorphic T-cell lymphoproliferative disease associated with EBV. A presumptive diagnosis of primary immunodeficiency with inability to control EBV was made and next-generation sequencing led to the identification of a novel ZBTB24 mutation (ICF2-syndrome). This case shows that susceptibility to EBV seems to be particular of ICF-2 as it has not been described in the other types of ICF. It is mandatory to raise the hypothesis of an underlying PID in case of severe EBV infection.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/etiologia , Linfócitos T/imunologia , Linfócitos T/patologia , Biomarcadores , Biópsia , Pré-Escolar , Suscetibilidade a Doenças , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4 , Humanos , Masculino , Avaliação de Sintomas , Linfócitos T/metabolismo , Tomografia Computadorizada por Raios X
8.
Ann Hematol ; 100(8): 2043-2050, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33973053

RESUMO

Post-transplant lymphoproliferative disorders (PTLD) exclusively affecting the central nervous system-primary CNS-PTLD (pCNS-PTLD)-are rare. There is no standard therapy, and previous case series have included heterogeneous treatment approaches. We performed a retrospective, multi-centre analysis of 14 patients with pCNS-PTLD after solid organ transplantation (SOT) treated in the prospective German PTLD registry with reduction of immunosuppression (RI), whole-brain radiotherapy (WBRT), and concurrent systemic rituximab between 2001 and 2018. Twelve of fourteen patients were kidney transplant recipients and median age at diagnosis was 65 years. Thirteen of fourteen cases (93%) were monomorphic PTLD of the diffuse large B-cell lymphoma type, and 12/13 were EBV-associated. The median dose of WBRT administered was 40 Gy with a median fraction of 2 Gy. The median number of administered doses of rituximab (375 mg/m2) IV was four. All ten patients evaluated responded to treatment (100%). Median OS was 2.5 years with a 2-year Kaplan-Meier estimate of 63% (95% confidence interval 30-83%) without any recorded relapses after a median follow-up of 2.6 years. Seven of fourteen patients (50%) suffered grade III/IV infections under therapy (fatal in two cases, 14%). During follow-up, imaging demonstrated grey matter changes interpreted as radiation toxicity in 7/10 evaluated patients (70%). The combination of RI, WBRT, and rituximab was an effective yet toxic treatment of pCNS-PTLD in this series of 14 patients. Future treatment approaches in pCNS-PTLD should take into account the significant risk of infections as well as radiation-induced neurotoxicity.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Doenças do Sistema Nervoso Central/etiologia , Imunossupressores/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Transplante de Órgãos/efeitos adversos , Rituximab/uso terapêutico , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/efeitos da radiação , Doenças do Sistema Nervoso Central/epidemiologia , Doenças do Sistema Nervoso Central/radioterapia , Doenças do Sistema Nervoso Central/terapia , Feminino , Alemanha/epidemiologia , Humanos , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/radioterapia , Transtornos Linfoproliferativos/terapia , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Rituximab/efeitos adversos
9.
Curr Gastroenterol Rep ; 23(7): 9, 2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-33963950

RESUMO

PURPOSE OF THE REVIEW: Primary GI lymphomas of B cell origin are a diverse group of lymphomas. In this article, we provide an overview of the diagnosis, pathologic and molecular features, and management of these varied lymphomas. RECENT FINDINGS: The most common primary GI lymphomas are diffuse large B cell lymphoma (DLBCL) and marginal zone lymphomas (MZL), but follicular lymphomas (FL), mantle cell lymphomas (MCL), post-transplant lymphoproliferative disorders (PTLD), and Burkitt lymphoma of the GI tract also occur. Many features of these lymphomas are similar to their nodal counterparts, but certain clinical and biological aspects are unique. Diagnostic and treatment strategies for these lymphomas continue to evolve over time. There are ongoing discoveries about the unique pathophysiology, molecular characteristics, and complications of primary B cell GI lymphomas that are already leading to improvements in management of this histologically diverse set of lymphomas.


Assuntos
Neoplasias Gastrointestinais , Linfoma de Células B , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/fisiopatologia , Neoplasias Gastrointestinais/terapia , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Linfoma de Células B/fisiopatologia , Linfoma de Células B/terapia , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Linfoma Folicular/fisiopatologia , Linfoma Folicular/terapia , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/fisiopatologia , Transtornos Linfoproliferativos/terapia
11.
Bone Marrow Transplant ; 56(9): 2118-2124, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33864020

RESUMO

Published data describing the efficacy and safety of autologous stem-cell transplantation (autoSCT) in post-transplant lymphoproliferative disorders (PTLD) is limited to case reports. This is a retrospective analysis of 21 patients reported to the EBMT registry who received an autoSCT for PTLD post solid organ transplant (SOT). Median age at autoSCT was 47 (range: 22-71) years. The commonest SOTs were kidney (48%) and liver (24%). Commonest histologies included DLBCL-type PTLD (14/21) and plasmacytoma-like PTLD (3/21). Patients received a median of two lines of therapy (range: 1-4) pre-autoSCT. ECOG performance status pre-autoSCT was 0 in 14% and 1 in 86%. Remission status pre-autoSCT was CR 47% and PR 38%. BEAM conditioning was used in 57% and high-dose melphalan in 10%. The median follow-up post-autoSCT was 64 months for alive patients. 3-year PFS was 62% [95% confidence interval (CI) 44-87%] and 3-year OS was 61% [95% CI:43-86]. There were 12 deaths, including four related to autoSCT. 100-day non-relapse-mortality (NRM) was 14% and 1-year NRM was 24%. This study suggests that autoSCT, although feasible and with potential therapeutic activity, is associated with a high NRM, primarily driven by infectious toxicity. A multi-disciplinary approach, expert microbiological input and stringent patient selection are required to optimise outcomes.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Transtornos Linfoproliferativos , Transplante de Órgãos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/terapia , Recidiva Local de Neoplasia , Transplante de Órgãos/efeitos adversos , Estudos Retrospectivos , Transplante de Células-Tronco , Transplante Autólogo
12.
Acta Oncol ; 60(6): 771-778, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33793378

RESUMO

Background: Treatment with antithymocyte globulin (ATG) is a well-recognized risk factor for the development of post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation, but it is unknown how its use affects overall survival after PTLD.Methods: A total of 114 patients with PTLD and available data on immunosuppressive regimen were included from a nation-wide case series of solid organ transplant recipients in Sweden. Prior use of ATG was correlated to clinical features, PTLD subtype, and survival.Results: A total of 47 (41%) patients had received ATG prior to the diagnosis of PTLD. The ATG-treated patients were more likely to be recipients of hearts or lungs, and less likely of kidneys (p < 0.01). They had experienced more acute rejections (p = 0.02). The PTLDs arose earlier, median 2.0 vs. 6.6 years post-transplant (p = 0.002) and were more often situated in the allograft (32% vs. 7%, p < 0.001) in patients with prior ATG vs. no ATG treatment. The PTLDs in the ATG group were more often Epstein-Barr virus-positive (80% vs. 40%, p < 0.001). There were more polymorphic PTLDs (17% vs. 1.5%, p = 0.004) and less T-cell PTLDs (4% vs. 19%, p = 0.02) in the ATG group than in the no ATG group. Diffuse large B-cell lymphoma was equally common in patients with and without prior ATG therapy, but the non-germinal center subtype was more frequent in the ATG group (p = 0.001). In an adjusted Cox proportional hazards regression model, prior ATG treatment and better performance status were associated with superior overall survival, whereas older age, T-cell subtype of PTLD, presence of B symptoms, and elevated lactate dehydrogenase were associated with inferior overall survival. Patients receiving ATG solely as rejection therapy had superior overall survival compared with those receiving ATG as induction therapy or both (p = 0.03).Conclusions: ATG therapy, especially rejection therapy, prior to PTLD development is an independent prognostic factor for superior overall survival after PTLD diagnosis.


Assuntos
Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , Idoso , Soro Antilinfocitário/uso terapêutico , Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4 , Humanos , Imunossupressores/efeitos adversos , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/etiologia , Estudos Retrospectivos
13.
Rinsho Ketsueki ; 62(3): 170-175, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33828009

RESUMO

Post-transplant lymphoproliferative disorder (PTLD) usually develops with systemic symptoms, such as fever, generalized lymphadenopathy, and elevation in the lactate dehydrogenase level. Here, we present the case of a 65-year-old female patient with PTLD localized to the colon; the patient only had mild diarrhea without systemic symptoms. She had myelodysplastic syndrome and was treated with cord blood transplantation (CBT). She had a past medical history of sigmoid colon cancer treated with colonosectomy and adjuvant chemotherapy. After CBT, she achieved complete remission and was discharged after 60 days. Further, 79 days after CBT, she presented with abdominal pain. Computed tomography scan revealed adhesive ileus. The abdominal pain was resolved in 1 day with conservative treatment, however, mild diarrhea persisted. Therefore, we performed colonoscopy and found multiple ulcerative lesions in the upper colon. A pathological examination revealed PTLD. Furthermore, elevation of EBV-DNA in the blood was also confirmed. There was no detectable lesion on positron emission tomography-computed tomography (PET-CT) outside the colon; thus, we diagnosed PTLD localized into the colon that was successfully treated with rituximab. Our present experience suggests that it might be important to perform endoscopy and monitoring of EBV-DNA for early detection of PTLD, especially localized in the gastrointestinal tract.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , Idoso , Colo , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Diarreia/etiologia , Diarreia/terapia , Detecção Precoce de Câncer , Infecções por Vírus Epstein-Barr/complicações , Feminino , Humanos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/terapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
14.
Zhonghua Bing Li Xue Za Zhi ; 50(5): 465-469, 2021 May 08.
Artigo em Chinês | MEDLINE | ID: mdl-33915652

RESUMO

Objective: To investigate the clinicpathological characteristics of post-transplant lymphoproliferative disorders (PTLD) in transplanted lung, and to improve its diagnosis and treatment. Methods: The clinicopathological characteristics of PTLD in three transplanted lungs were evaluated at Wuxi People's Hospital Affiliated to Nanjing Medical University from 2014 to 2019. HE, immunohistochemical staining and in situ hybridization were performed. The relevant literature of PTLD was reviewed. Results: All three patients had chronic obstructive pulmonary disease (COPD) before lung transplantation. After receiving both lung transplants, they were all treated with anti-rejection drugs tacrolimus or mycophenolate mofetil, and combined with antiviral and/or rituximab. The time from transplantation to diagnosis of PTLD was four years, seven months, and five months, respectively. Two patients died one month and five months after initial diagnosis, and one patient was alive with no disease after one year. Histologically, all cases were monomorphic B-cell PTLD (diffuse large B-cell lymphoma, unspecified), and the tumor cells were positive for Epstein-Barr virus by in situ hybridization; one of the late-onset patients had herpes simplex virus infection. Conclusions: PTLD in the post-transplant lung tissue shows unique morphology and clinical characteristics, and is closely related to Epstein-Barr virus infection. Patients who receive lung transplantation due to COPD are more susceptible to develop PTLD, while late-onset ones occur more commonly in the hilum of lungs, and the prognosis is relatively poor.


Assuntos
Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , Herpesvirus Humano 4 , Humanos , Pulmão , Transtornos Linfoproliferativos/etiologia , Rituximab
15.
Liver Transpl ; 27(8): 1165-1180, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33655645

RESUMO

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.


Assuntos
Infecções por Vírus Epstein-Barr , Transplante de Fígado , Transtornos Linfoproliferativos , Adolescente , Adulto , Criança , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4 , Humanos , Transplante de Fígado/efeitos adversos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/etiologia , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de Risco
16.
Br J Haematol ; 193(6): 1178-1184, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33764500

RESUMO

Primary central nervous system (CNS) post-transplant lymphoproliferative disorder (PTLD) in childhood is rare. Twenty-five patients were retrieved from nine European Intergroup for Childhood Non-Hodgkin's Lymphoma and/or international Berlin-Frankfurt-Münster Study Group members. Types of allografts included kidney (n = 11), liver (n = 4), heart (n = 5), bowel (n = 1) and haematopoietic stem cells (n = 4). Eighteen were male, 16 ≥ 10 years old, 21 had monomorphic disease and 24 solid intracranial tumour masses. Four-year event-free and overall survival rates were 50% ± 10% and 74% ± 9% respectively. This report represents the largest paediatric series of CNS PTLD reported to date, showing favourable survival odds following systemic and intrathecal chemotherapy and rituximab administration.


Assuntos
Neoplasias Encefálicas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transtornos Linfoproliferativos , Transplante de Órgãos/efeitos adversos , Rituximab/administração & dosagem , Adolescente , Adulto , Aloenxertos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Injeções Espinhais , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/mortalidade , Masculino , Taxa de Sobrevida
17.
Clin Transplant ; 35(6): e14286, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33715217

RESUMO

Immunoglobulin is built by a pair of identical heavy and a pair of identical light chains. Light chains are produced in excess compared to heavy chains. Free light chains (FLCs) are those which are not combined with heavy chains. Currently, numerous assays are available for the measurement of serum FLCs (sFLCs). These assays cannot be used interchangeably, and renal function should be taken into account in interpreting test results. Levels of kappa and lambda sFLCs are usually used to diagnose and monitor plasma cell dyscrasias. However, the clinical relevance of sFLCs is being investigated in patients with a variety of diseases, including patients after transplantation. There are contradictory results regarding the usefulness of sFLCs in the prediction of post-transplant lymphoproliferative disorder (PTLD). However, it seems that sFLCs may be helpful in the prediction of early-onset PTLD. Some studies have shown that low levels of sFLCs are associated with a higher risk of infection in patients after transplantation. This review summarizes and highlights recent advances in the utility of sFLCs in the prediction of PTLD and infection, and inflammation assessment in patients after solid organ transplantation. Moreover, the influence of immunosuppressive treatment on sFLCs levels is described briefly.


Assuntos
Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , Transplante de Órgãos , Humanos , Cadeias Leves de Imunoglobulina , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Transplante de Órgãos/efeitos adversos , Transplantados
18.
Int J Hematol ; 114(1): 53-64, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33765256

RESUMO

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication of transplantation. In addition to reactivation of Epstein-Barr virus in immunocompromised patients, impaired tumor immunity is suggested to be a risk factor for PTLD. However, it remains unclear whether immune suppressive tumor-infiltrating lymphocytes (TILs) correlate with the occurrence or prognosis of PTLD. We analyzed TILs in 26 patients with PTLD to elucidate the clinicopathological significance of the expression of PD-1 and FoxP3, which are associated with exhausted T-cells and regulatory T-cells (Tregs), respectively. Numbers of PD-1+ TILs in the PTLD specimens were significantly higher in patients who developed PTLD early after transplantation (P = 0.0040), while numbers of FoxP3+ TILs were not (P = 0.184). There was no difference in overall response rate regardless of the expression of PD-1 or FoxP3. FoxP3high patients tended to have a shorter time to progression compared with FoxP3low patients, especially in the case of FoxP3high patients with diffuse large B-cell lymphoma-subtype PTLD (P = 0.011), while PD-1high patients did not. These results suggest that T-cell exhaustion may be mainly associated with PTLD development, while immune suppression by Tregs may be dominant in enhanced progression of PTLD following disease occurrence.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfócitos do Interstício Tumoral/patologia , Transtornos Linfoproliferativos/etiologia , Transplante de Órgãos/efeitos adversos , Receptor de Morte Celular Programada 1/análise , Adulto , Idoso , Feminino , Fatores de Transcrição Forkhead/análise , Humanos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
19.
Transplant Cell Ther ; 27(3): 261.e1-261.e7, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33781531

RESUMO

Central nervous system (CNS) involvement in Epstein-Barr virus-related post-transplant lymphoproliferative disorders (EBV-PTLDs) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poorly defined. We analyzed the incidence, clinical and pathological characteristics, and impact on outcomes of EBV-PTLDs with CNS involvement (CNS-PTLDs) in 1009 consecutive adult patients undergoing allo-HSCT at a single-center institution. Four hundred eighty-two patients received matched sibling donor (MSD) transplants, 388 umbilical cord blood transplants (UCBTs), 56 matched unrelated donor (MUD) transplants, and 83 haploidentical transplants. We detected 25 cases of biopsy-proven EBV-PTLDs. Of these, nine patients (36%) had CNS-PTLDs: six after UCBT (67%), one after MSD transplantation (11%), one after MUD transplantation (11%), and one after haploidentical transplantation (11%). The 5-year cumulative incidence risk of CNS-PTLDs was 0.9%. Median time from transplant to CNS-PTLDs was 187 days, and all patients had neurological symptoms at diagnosis. Six out of the nine cases (67%) occurred with systemic involvement, and three cases (33%) had isolated CNS involvement. The most frequent histological subtype was monomorphic EBV-PTLD, and laboratory characteristics were similar to EBV-PTLDs without CNS involvement. We observed statistical differences in the rate of positive EBV DNA detection in plasma between isolated CNS-PTLDs (detection in one out of three, 33%) and the rest of the EBV-PTLDs (100%) (P = .01). Treatment strategies included chemotherapy, radiotherapy, and T cell therapy. However, seven out of nine patients died due to progression of the CNS-PTLDs at a median time of 17 days (range, 8 to 163) from diagnosis. The 5-years overall survival in patients who developed CNS-PTLDs was 22% (95% confidence interval [CI], 7% to 75%) and 5-year treatment-related mortality was 78% (95% CI, 51% to 100%), with no statistically significant differences between CNS-PTLDs and the rest of the EBV-PTLDs. In conclusion, despite advances in EBV monitoring and treatment strategies, CNS-PTLDs remain an uncommon but serious complication after allo-HSCT, with very poor prognosis.


Assuntos
Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Transtornos Linfoproliferativos , Adulto , Sistema Nervoso Central , Infecções por Vírus Epstein-Barr/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4 , Humanos , Transtornos Linfoproliferativos/etiologia , Transplante Homólogo
20.
Int J Hematol ; 114(1): 136-140, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33675520

RESUMO

Here, we describe the case of a male patient with Epstein-Barr virus post-transplantation lymphoproliferative disorder (EBV-PTLD), which developed 18 months after a haploidentical hematopoietic stem cell transplantation (haplo-HSCT) and the administration of post-transplant cyclophosphamide (PTCy). Of note, no anti-thymoglobulin was used in the entire clinical course. Prior to the onset of EBV-PTLD, the patient had pulmonary chronic graft-versus-host disease and was treated with prednisolone and tacrolimus. After stopping immunosuppressive therapy, he was diagnosed with EBV-positive infectious mononucleosis PTLD, and EBV-associated hemophagocytic syndrome; therefore, dexamethasone and rituximab monotherapies were administered. After four courses of rituximab, EBV-DNA was no longer detected in the peripheral blood, and the patient's laboratory data improved. Overall, this study highlights the need to predict the risk factors associated with the development of EBV-PTLD in transplanted patients after haplo-HSCT with PTCy.


Assuntos
Ciclofosfamida/efeitos adversos , Infecções por Vírus Epstein-Barr/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Adulto , Ciclofosfamida/uso terapêutico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imunossupressores/uso terapêutico , Transtornos Linfoproliferativos/tratamento farmacológico , Masculino
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