Extranodal posttransplant plasmacytic hyperplasia with subsequent posttransplant plasmacytic malignancy: six-year interval case report and review of the literature.

PubMed

Dunphy, Cherie H; Galambos, Csaba; Polski, Jacek M; Evans, H Lance; Gardner, Laura J; Grosso, Leonard E; Montone, Kathleen T

2002-03-01

Posttransplant lymphoproliferative disorders (PTLDs) represent a morphologic, immunophenotypic, and genotypic spectrum of disease. Most recently, Knowles et al divided PTLDs into 3 distinct categories: (1) plasmacytic hyperplasia, (2) polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma, and (3) immunoblastic lymphoma and multiple myeloma. Although one form of PTLD may progress to another form, only 1 previous case has been reported in which multiple myeloma developed 14 months after an original diagnosis of plasmacytic hyperplasia. The type of solid organ transplant was not specified in that case. We report a post--cardiac transplant plasmacytic hyperplasia developing 7 years posttransplant. Six years subsequent to the plasmacytic hyperplasia, the patient developed a posttransplant plasmacytic malignancy, supported by morphology, flow cytometric immunophenotyping, and genotypic studies. Since we have no data to support disseminated bony disease or an abnormal serum protein, we have not used the term "multiple myeloma" for this case.

Lowered Immune Cell Function in Liver Recipients Recovered From Posttransplant Lymphoproliferative Disease Who Developed Graft Tolerance.

PubMed

Chung, Patrick Ho Yu; Chan, See Ching; Chan, Kwong Leung; Chan, Yuk Sing; Kwok, Janette Siu Yin; Lo, Chung Mau

2016-03-01

Tolerance after treatment and recovery from posttransplant lymphoproliferative disease (PTLD) have been described but little is known about the immunology. The objective of this study is to evaluate the immunity of pediatric recipients who recovered from PTLD. Pediatric recipients who recovered from PTLD after liver transplant and twice the number of recipients who never had PTLD were recruited. Their immune statuses were measured by ImmuKnow (measurement of adenosine 5-triphospate level produced CD4+ T helper cells), and the results were divided into 3 groups, "low" (≤225 ng/mL), "moderate" (226 to 524 ng/mL), and "high" (≥525 ng/mL). The results of both groups were compared and analyzed. Nine PTLD recipients and 20 non-PTLD recipients were recruited. There were no significant differences in terms of sex and age between the 2 groups. The majority of PTLD recipients (88.9%) had "low" immune status responses, and none of them had "high" responses. For non-PTLD recipients, more than half (55%) had "moderate" immune status responses. The median value of adenosine 5-triphospate levels was significantly lower in the PTLD group (119 ng/mL vs 380.5 ng/mL P = 0.014), and their trough immunosuppressant level was also lower (3.8 μg/L vs 7.7 μg/L; P = 0.004). None of the patients in either group had abnormal liver enzymes (aspartate aminotransferase/alanine aminotransferase) to suggest graft rejection. Patients who recovered from PTLD have a lower CD4 T-cell activity compared with those who have not suffered from PTLD. Under careful monitoring, their immunosuppressant levels can be kept at low levels to prevent recurrence of PTLD.

Risk factors for post-transplant lymphoproliferative disorder after Thymoglobulin-conditioned hematopoietic cell transplantation.

PubMed

Kalra, Amit; Roessner, Cameron; Jupp, Jennifer; Williamson, Tyler; Tellier, Raymond; Chaudhry, Ahsan; Khan, Faisal; Taparia, Minakshi; Jimenez-Zepeda, Victor H; Stewart, Douglas A; Daly, Andrew; Storek, Jan

2018-01-01

Epstein-Barr virus (EBV)-induced post-transplant lymphoproliferative disorder (PTLD) occurs frequently when rabbit antithymocyte globulin (ATG) is used in hematopoietic cell transplant (HCT) conditioning. We retrospectively studied 554 patients undergoing ATG-conditioned myeloablative HCT. Strategies used to minimize mortality due to PTLD were either therapy of biopsy-diagnosed PTLD in the absence of EBV DNAemia monitoring (n = 266) or prompt therapy of presumed PTLD (based on clinical/radiologic signs and high EBV DNAemia, in the setting of weekly EBV DNAemia monitoring) (n = 199). Both strategies resulted in similar mortality due to PTLD (0.7% vs 1% at 2 years, P = .43) and similar overall survival (63% vs 67% at 2 years, P = .23) even though there was a trend toward higher PTLD incidence with the prompt therapy. Donor positive with recipient negative EBV (D+R-) serostatus was a risk factor for developing PTLD. Older patient age, HLA-mismatched donor, and graft-versus-host disease were not associated with increased risk of PTLD. In summary, in ATG-conditioned HCT, D+R- serostatus, but not older age, mismatched donor or GVHD is a risk factor for developing PTLD. EBV DNAemia monitoring may be a weak risk factor for developing/diagnosing PTLD; the monitoring coupled with prompt therapy does not improve survival. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

HLA class I associations with EBV+ post-transplant lymphoproliferative disorder.

PubMed

Jones, Kimberley; Wockner, Leesa; Thornton, Alycia; Gottlieb, David; Ritchie, David S; Seymour, John F; Kumarasinghe, Gayathri; Gandhi, Maher K

2015-03-01

Epstein-Barr virus (EBV) is frequently associated with post-transplant lymphoproliferative disorders (EBV(+) PTLD). In these cases, impaired Epstein-Barr virus (EBV)-specific CD8(+) T-cell immunity is strongly implicated and antigen presentation within the malignant B-cell is intact. Interestingly, several studies have reported HLA class I alleles with protective or susceptibility associations. However, results are conflicting, likely influenced by methodology including inconsistent use of multiple hypothesis testing. By contrast, HLA class I associations have been repeatedly reported for classical Hodgkin Lymphoma (cHL), in which EBV is also implicated in a proportion of cases. In contrast to EBV(+) PTLD which expresses the immunodominant EBV latency III EBNA3A/B/C proteins, EBV(+) cHL is restricted to the subdominant EBNA1/LMP1/LMP2 proteins. Herein, we report a study of HLA class I associations in EBV(+) PTLD, with 263 patients with lymphoma (cHL or PTLD) evaluated. Two Australian population cohorts, n = 23,736 and n = 891 were used for comparison. Contrary to previous reports, no HLA class I associations with EBV(+) PTLD were found, whereas for cHL known HLA class I associations were confirmed, with HLA-A*02 homozygous individuals having the lowest odds of developing EBV(+) cHL. Our results suggest that HLA class I does not influence susceptibility to the viral latency III expressing lymphoma, EBV(+) PTLD. Further studies are required for definitive confirmation. Copyright © 2015. Published by Elsevier B.V.

The Role of Antiviral Prophylaxis for the Prevention of Epstein-Barr Virus-Associated Posttransplant Lymphoproliferative Disease in Solid Organ Transplant Recipients: A Systematic Review.

PubMed

AlDabbagh, M A; Gitman, M R; Kumar, D; Humar, A; Rotstein, C; Husain, S

2017-03-01

The role of antiviral prophylaxis for the prevention of posttransplant lymphoproliferative disease (PTLD) remains controversial for solid organ transplantation (SOT) recipients who are seronegative for Epstein-Barr virus (EBV) but who received organs from seropositive donors. We performed a systematic review and meta-analysis to address this issue. Two independent assessors extracted data from studies after determining patient eligibility and completing quality assessments. Overall, 31 studies were identified and included in the quantitative synthesis. Nine studies were included in the direct comparisons (total 2366 participants), and 22 were included in the indirect analysis. There was no significant difference in the rate of EBV-associated PTLD in SOT recipients among those who received prophylaxis (acyclovir, valacyclovir, ganciclovir, valganciclovir) compared with those who did not receive prophylaxis (nine studies; risk ratio 0.95, 95% confidence interval 0.58-1.54). No significant differences were noted across all types of organ transplants, age groups, or antiviral use as prophylaxis or preemptive therapy. There was no significant heterogeneity in the effect of antiviral prophylaxis on the incidence of PTLD. In conclusion, the use of antiviral prophylaxis in high-risk EBV-naive patients has no effect on the incidence of PTLD in SOT recipients. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

[Post-transplant lymphoproliferative disorder: a clinicopathologic study of 15 cases].

PubMed

Chen, Ding-bao; Wang, Ying; Song, Qiu-jing; Shen, Dan-hua

2012-09-01

To study the clinical and histopathologic features, diagnosis, pathogenesis and therapy of post-transplant lymphoproliferative disorders (PTLD). The clinical and pathologic features of 15 cases of PTLD were retrospectively analyzed by light microscopy, immunohistochemistry and in-situ hybridization, according to the updated 2008 WHO classification of tumors of hematopoietic and lymphoid tissues. Amongst the 15 cases studied, 14 cases had received allogenic hematopoietic stem cell transplantation (AHSCT) and 1 case had received renal transplantation. There were altogether 12 males and 3 females. The male-to-female ratio was 4:1. The mean age was 30.4 years and the median age was 31 years (range from 9 to 60 years). PTLD developed 1.5 to 132 months after transplantation (median 13.0 months). The mean age of the 14 patients with AHSCT was 28.3 years (range from 9 to 45 years) and PTLD developed 1.5 to 19 months after transplantation (mean 4.5 months). Major clinical presentation included fever and lymphadenopathy. Twelve cases involved mainly lymph nodes and the remaining 3 cases involved tonsils, stomach and small intestine, respectively. The histologic types in 4 cases represented early lesions, including plasmacytic hyperplasia (n = 1) and infectious mononucleosis-like PTLD (n = 3). Seven cases were polymorphic PTLD, with 4 cases containing a predominance of large cells. Graft-versus-host disease was also seen in the case of small intestinal involvement. Four cases were monomorphic PTLD, 3 of which were diffuse large B-cell lymphoma, 1 was plasmablastic lymphoma and 1 was a mixture of monomorphic and polymorphic PTLD. Foci of necrosis were seen in 5 cases. The proliferating index of Ki-67 was high. The positive rate of EBV-encoded RNA in AHSCT was 92.9%. The duration of PTLD onset was shorter in EBV-positive cases (range from 1.5 to 7 months) than EBV-negative cases (range from 19 and 132 months). Some cases were treated by reduction of immunosuppression, antiviral

Cerebral Vasculitis in X-linked Lymphoproliferative Disease Cured by Matched Unrelated Cord Blood Transplant.

PubMed

Gray, Paul E; O'Brien, Tracey A; Wagle, Mayura; Tangye, Stuart G; Palendira, Umaimainthan; Roscioli, Tony; Choo, Sharon; Sutton, Rosemary; Ziegler, John B; Frith, Katie

2015-10-01

Vasculitis occurs rarely in association with X-linked lymphoproliferative disease (XLP). There are four published cases of non-EBV XLP-associated cerebral vasculitis reported, none of whom have survived without major cognitive impairment. A 9-year old boy initially presented aged 5 years with a restrictive joint disease. He subsequently developed dysgammaglobulinemia, episodic severe pneumonitis, aplastic anaemia, gastritis and cerebral vasculitis. A diagnosis of XLP was made, based on flow cytometric analysis and the identification of a novel mutation in SH2D1A, c.96G>C. No peripheral blood lymphocyte clonal proliferation was identified and he was EBV negative, although human herpes virus-7 (HHV7) was detected repeatedly in his cerebrospinal fluid. He underwent a reduced intensity unrelated umbilical cord blood transplant, but failed to engraft. A second 5/6 matched cord gave 100 % donor engraftment. Complications included BK virus-associated haemorrhagic cystitis, a possible NK-cell mediated immune reconstitution syndrome and post-transplant anti-glomerular basement membrane disease, the latter treated with cyclophosphamide and rituximab. At +450 days post-transplant he is in remission from his vasculitis and anti-glomerular basement membrane disease, and HHV-7 has remained undetectable. This is the second published description of joint disease in XLP, and only the fourth case of non-EBV associated cerebral vasculitis in XLP, as well as being the first to be successfully treated for this manifestation. This case raises specific questions about vasculitis in XLP, in particular the potential relevance of HHV-7 to the pathogenesis.

Partial Least Squares Based Gene Expression Analysis in EBV- Positive and EBV-Negative Posttransplant Lymphoproliferative Disorders.

PubMed

Wu, Sa; Zhang, Xin; Li, Zhi-Ming; Shi, Yan-Xia; Huang, Jia-Jia; Xia, Yi; Yang, Hang; Jiang, Wen-Qi

2013-01-01

Post-transplant lymphoproliferative disorder (PTLD) is a common complication of therapeutic immunosuppression after organ transplantation. Gene expression profile facilitates the identification of biological difference between Epstein-Barr virus (EBV) positive and negative PTLDs. Previous studies mainly implemented variance/regression analysis without considering unaccounted array specific factors. The aim of this study is to investigate the gene expression difference between EBV positive and negative PTLDs through partial least squares (PLS) based analysis. With a microarray data set from the Gene Expression Omnibus database, we performed PLS based analysis. We acquired 1188 differentially expressed genes. Pathway and Gene Ontology enrichment analysis identified significantly over-representation of dysregulated genes in immune response and cancer related biological processes. Network analysis identified three hub genes with degrees higher than 15, including CREBBP, ATXN1, and PML. Proteins encoded by CREBBP and PML have been reported to be interact with EBV before. Our findings shed light on expression distinction of EBV positive and negative PTLDs with the hope to offer theoretical support for future therapeutic study.

Posttransplant Lymphoproliferative Disorder After Clinical Islet Transplantation: Report of the First Two Cases.

PubMed

Peters, A; Olateju, T; Deschenes, J; Shankarnarayan, S H; Chua, N; Shapiro, A M J; Senior, P

2017-09-01

We report the first two cases of posttransplant lymphoproliferative disorder (PTLD) in recipients of islet transplants worldwide. First, a 44-year-old recipient of three islet infusions developed PTLD 80 months after his initial transplantation, presenting with abdominal pain and diffuse terminal ileum thickening on imaging. He was treated with surgical excision, reduction of immunosuppression, and rituximab. Seven months later, he developed central nervous system PTLD, presenting with vertigo and diplopia; immunosuppression was discontinued, resulting in graft loss, and he was given high-dose methotrexate and underwent consolidative autologous stem cell transplantation. He remains in remission 37 months after the initial diagnosis. Second, a 58-year-old female recipient of two islet infusions developed PTLD 24 months after initial islet infusion, presenting with pancytopenia secondary to extensive bone marrow involvement. Immunosuppression was discontinued, resulting in graft loss, and she received rituximab and chemotherapy, achieving complete remission. Both patients were monomorphic B cell PTLD subtype by histology and negative for Epstein-Barr virus in tissue or blood. These cases document the first occurrences of this rare complication in islet transplantation, likely secondary to prolonged, intensive immunosuppression, and highlight the varying clinical manifestations of PTLD. Further studies are needed to determine incidence rate and risk factors in islet transplantation. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

B-cell posttransplant lymphoproliferative disorder isolated to the central nervous system is Epstein-Barr virus positive and lacks p53 and Myc expression by immunohistochemistry.

PubMed

Sundin, Andrew; Grzywacz, Bartosz J; Yohe, Sophia; Linden, Michael A; Courville, Elizabeth L

2017-03-01

In this retrospective study from one institution, we performed a clinicopathological study of a cohort of patients with posttransplant lymphoproliferative disorder (PTLD) confined to the central nervous system. We also identified a comparison cohort of patients with de novo primary diffuse large B-cell lymphoma of the central nervous system. We performed a detailed morphologic review, evaluated Epstein-Barr virus (EBV) by in situ hybridization, and interpreted a panel of immunohistochemical stains in a subset of cases including Hans classification markers (CD10, BCL6, MUM1), p53, CD30, Myc, and BCL2. All 17 of the posttransplant and none of 11 de novo cases were EBV positive (P < .005). Morphologic patterns identified in the PTLD cases were monomorphic diffuse large B-cell lymphoma pattern (10 patients) and "T-cell-rich" pattern (7 patients). The monomorphic posttransplant cases were more likely to be Myc negative (P = .015) and CD30 positive (P < .005) than the de novo cases, and showed a similarly low rate of p53 positivity by immunohistochemistry. No prognostic factors for overall survival were identified. Central nervous system PTLD is EBV positive, typically lacks p53 and Myc expression by immunohistochemistry, and can present with numerous background T lymphocytes. Copyright © 2016 Elsevier Inc. All rights reserved.

Epstein-barr virus DNAemia monitoring for the management of post-transplant lymphoproliferative disorder.

PubMed

Kalra, Amit; Roessner, Cameron; Jupp, Jennifer; Williamson, Tyler; Tellier, Raymond; Chaudhry, Ahsan; Khan, Faisal; Taparia, Minakshi; Jimenez-Zepeda, Victor H; Stewart, Douglas A; Daly, Andrew; Storek, Jan

2018-05-01

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation (HCT). Epstein-Barr virus (EBV) reactivation (detectable DNAemia) predisposes to the development of PTLD. We retrospectively studied 306 patients monitored for EBV DNAemia after Thymoglobulin-conditioned HCT to determine the utility of the monitoring in the management of PTLD. DNAemia was monitored weekly for ≥12 weeks post-transplantation. Reactivation was detected in 82% of patients. PTLD occurred in 14% of the total patients (17% of patients with reactivation). PTLD was treated with rituximab only when and if the diagnosis was established. This allowed us to evaluate potential DNAemia thresholds for pre-emptive therapy. We suggest 100,000-500,000 IU per mL whole blood as this would result in unnecessary rituximab administration to only 4-20% of patients and near zero mortality due to PTLD. After starting rituximab (for diagnosed PTLD), sustained regression of PTLD occurred in 25/25 (100%) patients in whom DNAemia became undetectable. PTLD progressed or relapsed in 12/17 (71%) patients in whom DNAemia was persistently detectable. In conclusion, for pre-emptive therapy of PTLD, we suggest threshold DNAemia of 100,000-500,000 IU/mL. Persistently detectable DNAemia after PTLD treatment with rituximab appears to have 71% positive predictive value and 100% negative predictive value for PTLD progression/relapse. Copyright © 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Analysis of immunoglobulin heavy and light chain variable genes in post-transplant lymphoproliferative disorders.

PubMed

Capello, Daniela; Cerri, Michaela; Muti, Giuliana; Lucioni, Marco; Oreste, Pierluigi; Gloghini, Annunziata; Berra, Eva; Deambrogi, Clara; Franceschetti, Silvia; Rossi, Davide; Alabiso, Oscar; Morra, Enrica; Rambaldi, Alessandro; Carbone, Antonino; Paulli, Marco; Gaidano, Gianluca

2006-12-01

Post-transplant lymphoproliferative disorders (PTLD) derive from antigen-experienced B-cells and represent a major complication of solid organ transplantation. We characterized usage, mutation frequency and mutation pattern of immunoglobulin variable (IGV) gene rearrangements in 50 PTLD (polymorphic PTLD, n=10; diffuse large B-cell lymphoma, n=35; and Burkitt/Burkitt-like lymphoma, n=5). Among PTLD yielding clonal IGV amplimers, a functional IGV heavy chain (IGHV) rearrangement was found in 40/50 (80.0%) cases, whereas a potentially functional IGV light chain rearrangement was identified in 36/46 (78.3%) PTLD. By combining IGHV and IGV light chain rearrangements, 10/50 (20.0%) PTLD carried crippling mutations, precluding expression of a functional B-cell receptor (BCR). Immunohistochemistry showed detectable expression of IG light chains in only 18/43 (41.9%) PTLD. Failure to detect a functional IGV rearrangement associated with lack of IGV expression. Our data suggest that a large fraction of PTLD arise from germinal centre (GC)-experienced B-cells that display impaired BCR. Since a functional BCR is required for normal B-cell survival during GC transit, PTLD development may implicate rescue from apoptosis and expansion of B-cells that have failed the GC reaction. The high frequency of IGV loci inactivation appears to be a peculiar feature of PTLD among immunodeficiency-associated lymphoproliferations.

Survival Analyses and Prognosis of Plasma Cell Myeloma and Plasmacytoma-Like Post-Transplant Lymphoproliferative Disorders

PubMed Central

Rosenberg, Aaron S.; Ruthazer, Robin; Paulus, Jessica K.; Kent, David M.; Evens, Andrew M.; Klein, Andreas K.

2016-01-01

Background Multiple myeloma/plasmacytoma-like post-transplant lymphoproliferative disorder (PTLD-MM) is a rare complication of solid organ transplant. Case series have shown variable outcomes and survival data in the modern era are lacking. Methods A cohort of 212 PTLD-MM patients was identified in the Scientific Registry of Transplant Recipients between 1999-2011. Overall survival (OS) was estimated using the Kaplan-Meier method and the effects of treatment and patient characteristics on OS evaluated with Cox proportional hazards models. OS in 185 PTLD-MM patients was compared with 4048 matched controls with multiple myeloma (SEER-MM) derived from SEER. Results Men comprised 71% of patients; extramedullary disease was noted in 58%. Novel therapeutic agents were used in 19% of patients (more commonly 2007-2011 versus 1999-2006 (P=0.01)), reduced immunosuppression in 55%, and chemotherapy in 32%. Median OS was 2.4 years, and improved in the later time period (aHR 0.64, P=0.05). Advanced age, creatinine>2, Caucasian race and use of OKT3 were associated with inferior OS in multivariable analysis. OS of PTLD-MM is significantly inferior to SEER-MM patients (aHR 1.6, p<0.001). Improvements in OS over time differed between PTLD-MM and SEER-MM. Median OS of patients diagnosed 2000-2005 was shorter for PTLD-MM than SEER-MM patients (18 vs 47 months P<0.001). There was no difference among those diagnosed 2006-2010 (44 mo vs median not reached P=0.5) (interaction P=0.08). Conclusions Age at diagnosis, elevated creatinine, Caucasian race and OKT3 were associated with inferior survival in patients with PTLD-MM. Survival of PTLD-MM is inferior to SEER-MM, though significant improvements in survival have been documented. PMID:27771291

Serial detection of Epstein-Barr virus DNA in sera and peripheral blood leukocyte samples of pediatric renal allograft recipients with persistent mononucleosis-like symptoms defines patients at risk to develop post-transplant lymphoproliferative disease.

PubMed

Campe, Hartmut; Jaeger, Gundula; Abou-Ajram, Claudia; Nitschko, Hans; Griebel, Martin; Montoya, Carmen; Klare, Bernd; Koszinowski, Ulrich

2003-02-01

We tested blood samples of 25 pediatric renal transplant recipients for Epstein-Barr virus (EBV) DNA load by quantitative polymerase chain reaction (PCR). Eleven of these transplant recipients showed clinical persistent mononucleosis-like symptoms years after transplantation (Tx). A quantitation of EBV DNA by PCR in peripheral blood lymphocyte (PBL) and serum samples revealed variable EBV DNA titers. The majority of EBV PCR results in samples of the 14 asymptomatic transplant recipients was repeatedly below detection limit. In contrast, patients with mononucleosis-like symptoms showed persistent EBV genome titers over a period of 6 months, ranging from 75 to 18 750 copies/10 000 PBL and from 680 to 335 000 copies/mL serum, respectively. One child suffering from this mononucleosis-like condition developed an EBV-associated Burkitt-like lymphoma 29 months after Tx. Whereas clinical and histological investigations did not indicate a post-transplant lymphoproliferative disorder (PTLD) until tumor detection, EBV titers in PBL and serum had been high for at least 8 months. We propose that pediatric transplant recipients who show both, recurrent mononucleosis-like symptoms and a sustained high EBV genome load, are at increased risk for severe EBV-related post-transplant complications.

Decreasing incidence of symptomatic Epstein-Barr virus disease and posttransplant lymphoproliferative disorder in pediatric liver transplant recipients: report of the studies of pediatric liver transplantation experience.

PubMed

Narkewicz, Michael R; Green, Michael; Dunn, Stephen; Millis, Michael; McDiarmid, Susan; Mazariegos, George; Anand, Ravinder; Yin, Wanrong

2013-07-01

Posttransplant lymphoproliferative disorder (PTLD) causes significant morbidity and mortality in pediatric recipients of liver transplantation (LT). Describe the incidence of PTLD and symptomatic Epstein-Barr virus (SEBV) disease in a large multicenter cohort of children who underwent LT with a focus on the risk factors and changes in incidence over time. SEBV and PTLD were prospectively determined in 2283 subjects who had undergone LT for the first time with at least 1 year of follow-up in the Studies of Pediatric Liver Transplantation database. SEBV was defined with specific criteria, and PTLD required tissue confirmation. The incidence of SEBV and PTLD was determined with a Kaplan-Meier analysis. Univariate and multivariate modeling of risk factors was performed with standard methods. SEBV occurred in 199 patients; 174 (87.4%) were EBV-negative at LT. Seventy-five patients developed PTLD, and 64 (85.3%) of these patients were EBV-negative at LT. Among the 2048 patients with at least 2 years of follow-up, 8.3% developed SEBV by the second year after LT, and 2.8% developed PTLD. There were lower rates of SEBV (5.9% versus 11.3%, P < 0.001) and PTLD (1.7% versus 4.2%, P = 0.001) in 2002-2007 versus 1995-2001. In 2002-2007, tacrolimus and cyclosporine trough blood levels in the first year after LT were significantly lower, and fewer children were receiving steroids. Biliary atresia, and recipient EBV status were correlated. In a multivariate analysis, era of LT, recipient EBV status, and frequent rejection episodes were associated with SEBV and PTLD. The incidence of SEBV and PTLD is decreasing in pediatric LT recipients concomitantly with a reduction in immunosuppression. Younger recipients and those with multiple rejections remain at higher risk for SEBV and PTLD. © 2013 American Association for the Study of Liver Diseases.

Preliminary experience on the use of PET/CT in the management of pediatric post-transplant lymphoproliferative disorder.

PubMed

Guerra-García, Pilar; Hirsch, Steffen; Levine, Daniel S; Taj, Mary M

2017-12-01

Post-transplant lymphoproliferative disorder (PTLD) is a well-known complication following prolonged immunosuppression. Contrary to other lymphomas, there is no standardized imaging approach to assess PTLD either at staging or for response to therapy. Positron emission tomography/computed tomography (PET/CT) is an imaging modality that has proven to be useful in lymphoma. However, there is still limited data concerning its use in pediatric PTLD. Our study evaluates the use of PET/CT in pediatric PTLD at our institution. To assess the role of PET/CT in pediatric PTLD, we reviewed the pediatric patients with PTLD who had undergone PET/CT at our institution between 2000 and 2016. Nine patients were identified. Six had PET/CT at diagnosis. All lesions seen on CT were identified with PET/CT. Fourteen PET/CTs were done during treatment. Eight PET/CTs were negative, including three where CT showed areas of uncertain significance. In these cases, PET/CT helped us to stop treatment and the patients remain in remission after a long follow-up (mean 74.3 months; range 12.4-180.9 months). PET/CT revealed additional disease in two cases, therefore treatment was intensified. Six biopsies and close follow-up was done to confirm PET/CT results. In one case, PET/CT did not identify central nervous system involvement demonstrated on magnetic resonance imaging. PET/CT may have an important role in the staging and follow-up of pediatric PTLD. In our cohort, PET/CT was helpful in staging and assessing treatment response and in clarifying equivocal findings on other imaging modalities. © 2017 Wiley Periodicals, Inc.

Current preventive strategies and management of Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplantation in Europe. Results of the ESGICH Questionnaire-based Cross-sectional Survey.

PubMed

San-Juan, R; Manuel, O; Hirsch, H H; Fernández-Ruiz, M; López-Medrano, F; Comoli, P; Caillard, S; Grossi, P; Aguado, J M

2015-06-01

There is limited clinical evidence on the utility of the monitoring of Epstein-Barr virus (EBV) DNAemia in the pre-emptive management of post-transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients. We investigated current preventive measures against EBV-related PTLD through a web-based questionnaire sent to 669 SOT programmes in 35 European countries. This study was performed on behalf of the ESGICH study group from the European Society of Clinical Microbiology and Infectious Diseases. A total of 71 SOT programmes from 15 European countries participated in the study. EBV serostatus of the recipient is routinely obtained in 69/71 centres (97%) and 64 (90%) have access to EBV DNAemia assays. EBV monitoring is routinely used in 85.9% of the programmes and 77.4% reported performing pre-emptive treatment for patients with significant EBV DNAemia levels. Pre-emptive treatment for EBV DNAemia included reduction of immunosuppression in 50.9%, switch to mammalian target of rapamycin inhibitors in 30.9%, and use of rituximab in 14.5% of programmes. Imaging by whole-body 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) is used in 60.9% of centres to rule out PTLD and complemented computer tomography is used in 50%. In 10.9% of centres, FDG-PET is included in the first-line diagnostic workup in patients with high-risk EBV DNAemia. Despite the lack of definitive evidence, EBV load measurements are frequently used in Europe to guide diagnostic workup and pre-emptive reduction of immunosuppression. We need prospective and controlled studies to define the impact of EBV monitoring in reducing the risk of PTLD in SOT recipients. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Identification of lymphoproliferative disease virus in wild turkeys (Meleagris gallopavo) in the United States

USDA-ARS?s Scientific Manuscript database

Viral-associated lymphoproliferative neoplasia in domestic poultry is caused by infection with a herpesvirus (Marek’s disease virus) or three species of retroviruses [Reticuloendotheliosis virus (REV), Avian leukosis/sarcoma virus, lymphoproliferative disease virus (LPDV)]. Previously, retroviral n...

[Lymphoproliferative disease in patients with autoimmune and inflammatory diseases: significance of antigenic stimulation and inflammatory processes].

PubMed

Tvarůzková, Zuzana; Pavlová, Sárka; Doubek, Michael; Mayer, Jirí; Pospísilová, Sárka

2011-01-01

Evidence has been growing that the pathogenesis of lymphoproliferative disease involves immune processes deregulation. It is believed that antigens or immunological elements can trigger transformation of normal lymphocyte polyclonal population into monoclonal neoplastic disorder--lymphoproliferative disease. Extensive studies point to the link between malignant lymphoma development and autoimmune or inflammatory diseases--namely rheumatoid arthritis, Sjörgen's syndrome, coeliac disease, systemic lupus erythematosus or thyroiditis. Increased risk of lymphoproliferative disease development was also proved for some infections. These infections involve both viral (e.g. Epstein-Barr virus, HIV or hepatitis C virus) and bacterial agents (e.g. Helicobacter pylori, Borrelia burgdorferi). Besides various lymphomas, the links to autoimmune/inflammatory diseases have also been described in chronic lymphocytic leukaemia. Regarding clinical medicine, it is necessary to distinguish patients with autoimmune, inflammatory and infectious diseases who are at the increased risk of tumour development. New approaches must be found to lower this risk. Also, the relationship between autoimmune/inflammatory disease therapy and lymphoma development should be clarified. Although lymphomas associated with autoimmune and inflammatory diseases represent only a small proportion of all lymphomas, any new findings regarding these diseases can cast light on lymphoma pathogenesis as a whole.

Post-Transplant Lymphoproliferative Disorder (PTLD) Manifesting in the Oral Cavity of a 13-Year-Old Liver Transplant Recipient (LTx).

PubMed

Krasuska-Sławińska, Ewa; Minko-Chojnowska, Izabela; Pawłowska, Joanna; Dembowska-Bagińska, Bożenna; Pronicki, Maciej; Olczak-Kowalczyk, Dorota

2015-08-18

BACKGROUND Post-transplant lymphoproliferative disorder (PTLD) is a potential complication of solid organ or bone marrow transplants. The main PTLD risk factors are: the Epstein-Barr virus (EBV), transplant type, and use of immunosuppressants. It mainly consists of an uncontrolled growth of lymphocytes in transplant recipients under chronic immunosuppressive therapy. About 85% of PTLDs are EBV-containing B-cell proliferations; 14% are T-cell proliferations, of which only 40% contain EBV; and the remaining 1% is NK-cell or plasmocyte proliferations. PTLD may present various clinical manifestations, from non-specific mononucleosis-like syndrome to graft or other organ damage resulting from pathologic lymphocyte infiltration. PTLD may manifest in the oral cavity. CASE REPORT The objective of this study was to present the case of a 13-year-old female living-donor liver transplant recipient, resulting from biliary cirrhosis caused by congenital biliary atresia, with exophytic fibrous lesions on buccal mucosa and tongue. Exophytic and hyperplastic lesion of oral mucosa were removed and histopathological examination revealed polymorphic PTLD. The patient underwent 6 cycles of CHOP chemotherapy and all the oral lesions regressed completely. CONCLUSIONS All oral pathological lesions in organ transplant recipients need to be surgically removed and histopathologically examined because they present an increased risk of neoplastic transformations such as PTLD.

Identification of lymphoproliferative disease virus in wild turkeys (Meleagris gallopavo) in the southeastern United States

USDA-ARS?s Scientific Manuscript database

The eight cases described herein represent the first reports of lymphoproliferative disease virus (LPDV) infection in wild turkeys and the first identification of LPDV in North America. Systemic lymphoproliferative disease was presumably the cause of morbidity and mortality in five of the eight turk...

Pearls and pitfalls: Autoimmune lymphoproliferative syndrome and autoimmune lymphoproliferative syndrome-like disease.

PubMed

Bartels, Anne K; Banks, Taylor A; Bay, Jeannie L

2017-07-01

A case of autoimmune lymphoproliferative syndrome (ALPS) was presented, followed by a discussion of the clinical characteristics, pathophysiology, diagnosis, and management of this disease. Clinical pearls and pitfalls are emphasized for the use of the practicing allergist and the fellow in-training. The diagnosis of ALPS was guided by published criteria. A careful history and workup were needed to exclude other possible etiologies for the patient's symptoms and physical findings. ALPS often carries significant morbidity and is best managed through a multidisciplinary approach.

Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease

PubMed Central

Vickers, Mark A; Wilkie, Gwen M; Robinson, Nicolas; Rivera, Nadja; Haque, Tanzina; Crawford, Dorothy H; Barry, Jacqueline; Fraser, Neil; Turner, David M; Robertson, Victoria; Dyer, Phil; Flanagan, Peter; Newlands, Helen R; Campbell, John; Turner, Marc L

2014-01-01

Epstein-Barr virus (EBV) is associated with several malignancies, including post-transplant lymphoproliferative disorder (PTLD). Conventional treatments for PTLD are often successful, but risk organ rejection and cause significant side effects. EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from peripheral blood lymphocytes provide an alternative treatment modality with few side effects, but autologous CTLs are difficult to use in clinical practice. Here we report the establishment and operation of a bank of EBV-specific CTLs derived from 25 blood donors with human leucocyte antigen (HLA) types found at high frequency in European populations. Since licensure, there have been enquiries about 37 patients, who shared a median of three class I and two class II HLA types with these donors. Cells have been infused into ten patients with lymphoproliferative disease, eight of whom achieved complete remission. Neither patient with refractory disease was matched for HLA class II. Both cases of EBV-associated non-haematopoietic sarcoma receiving cells failed to achieve complete remission. Thirteen patients died before any cells could be issued, emphasizing that the bank should be contacted before patients become pre-terminal. Thus, this third party donor-derived EBV-specific CTL cell bank can supply most patients with appropriately matched cells and most recipients have good outcomes. PMID:25066775

Interleukin 28B gene polymorphisms and Epstein-Barr virus-associated lymphoproliferative diseases.

PubMed

Akay, Ela; Patel, Mauli; Conibear, Tim; Chaggar, Turren; Haque, Tanzina

2014-01-01

Single-nucleotide polymorphisms (SNPs) near the interleukin (IL) 28B gene encoding a type III interferon (IFN-λ) are the most important genetic predictors of treatment response to hepatitis C virus (HCV). This retrospective study was undertaken to determine any association between IL28B SNPs and the development of viraemia in Epstein-Barr virus (EBV)-driven acute infectious mononucleosis (IM) and post-transplant lymphoproliferative disease (PTLD). Genomic DNA extracted from plasma from 45 EBV seropositive controls and 46 acute IM, 23 non-PTLD (transplant) and 21 PTLD patients was tested by PCR for 2 SNPs within IL28B. EBV DNA levels were tested in IM and PTLD samples by a real-time quantitative PCR. No significant differences were seen in SNP frequencies at rs12979860 and rs8099917 in IM and PTLD patients compared to EBV seropositive controls and transplant patients. EBV DNA levels were lower in IM and PTLD patients with CC (a favourable genotype in HCV) at rs12979860 compared to non-CC genotypes (p = 0.055). Acute IM patients with CC had significantly lower levels of EBV DNA in plasma compared to those with non-CC genotypes (p = 0.011). Genotype CC may influence anti-viral responses of IFN-λ, thereby allowing better control of EBV viraemia during lymphoproliferation, particularly in IM.

Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease.

PubMed

Vickers, Mark A; Wilkie, Gwen M; Robinson, Nicolas; Rivera, Nadja; Haque, Tanzina; Crawford, Dorothy H; Barry, Jacqueline; Fraser, Neil; Turner, David M; Robertson, Victoria; Dyer, Phil; Flanagan, Peter; Newlands, Helen R; Campbell, John; Turner, Marc L

2014-11-01

Epstein-Barr virus (EBV) is associated with several malignancies, including post-transplant lymphoproliferative disorder (PTLD). Conventional treatments for PTLD are often successful, but risk organ rejection and cause significant side effects. EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from peripheral blood lymphocytes provide an alternative treatment modality with few side effects, but autologous CTLs are difficult to use in clinical practice. Here we report the establishment and operation of a bank of EBV-specific CTLs derived from 25 blood donors with human leucocyte antigen (HLA) types found at high frequency in European populations. Since licensure, there have been enquiries about 37 patients, who shared a median of three class I and two class II HLA types with these donors. Cells have been infused into ten patients with lymphoproliferative disease, eight of whom achieved complete remission. Neither patient with refractory disease was matched for HLA class II. Both cases of EBV-associated non-haematopoietic sarcoma receiving cells failed to achieve complete remission. Thirteen patients died before any cells could be issued, emphasizing that the bank should be contacted before patients become pre-terminal. Thus, this third party donor-derived EBV-specific CTL cell bank can supply most patients with appropriately matched cells and most recipients have good outcomes. © 2014 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

Posttransplant Lymphoproliferative Disorder of the Thorax: CT and FDG-PET Features in a Single Tertiary Referral Center.

PubMed

Yoon, Ga Young; Kim, Mi Young; Huh, Joo Rryung; Jo, Kyung-Wook; Shim, Tae Sun

2015-08-01

To investigate the chest computed tomography (CT) and F-18 fluoro-2-deoxy-D-glucose positron emission tomographic (FDG-PET) findings of posttransplant lymphoproliferative disorder (PTLD) in the thorax.From November 2004 to February 2013, the cases of 12 adult patients (3 female and 9 male, age range 34-68, and median age 46 years) with proven PTLD were retrospectively reviewed. The transplanted organs included the kidney (5/12), liver (4/12), heart (1/12), combined kidney and pancreas (1/12), and hematopoietic stem cell (1/12). We investigated the relationship of the Epstein-Barr virus (EBV) to the patients' long-term follow-up, and evaluated the characteristics of the lesions on the chest CT and FDG-PET. The lesions were classified into 2 patterns: that of lymph node and lung involvement.The interval between the transplantation and the onset of PTLD was 2 to 128 months (median, 49). Positive EBV-encoded RNA in the pathologic specimens was found in 10 patients (83.3%). Eight patients were positive for EBV PCR in their blood, and 3 patients showed seroconversion without antiviral therapy. The responses to treatment were complete in 7 cases (58.3%), partial remission in 4 cases (33.3%), and undetermined in 1 case (8.3%). The more common chest CT patterns showed lymph node involvement (10/12) rather than lung involvement (3/12). The median maximum-standardized uptake value on the FDG-PET scans was 7.7 (range, 2.7-25.5).In patients with PTLD involving the thorax, lymphadenopathy was the more common manifestation on the chest CT rather than lung involvement. The lesions showed hypermetabolism on FDG-PET.

Imaging manifestations of autoimmune disease-associated lymphoproliferative disorders of the lung.

PubMed

Lee, Geewon; Lee, Ho Yun; Lee, Kyung Soo; Lee, Kyung Jong; Cha, Hoon-Suk; Han, Joungho; Chung, Man Pyo

2013-10-01

Lymphoproliferative disorders (LPDs) may involve intrathoracic organs in patients with autoimmune disease, but little is known about the radiologic manifestations of autoimmune disease-associated LPDs (ALPDs) of the lungs. The purpose of our work was to identify the radiologic characteristics of pulmonary involvement in ALPDs. A comprehensive search for PubMed database was conducted with the combination of MeSH words. All articles which had original images or description on radiologic findings were included in this analysis. Also, CT images of eight patients with biopsy-proven lymphoproliferative disorder observed from our institution were added. Overall, 44 cases of ALPD were identified, and consisted of 24 cases of bronchus-associated lymphoid tissue lymphoma (BALToma), eight cases of non-Hodgkin's lymphoma (NHL), six cases of lymphoid interstitial pneumonia (LIP), two cases of nodular lymphoid hyperplasia, two cases of unclassified lymphoproliferative disorder, and one case each of lymphomatoid granulomatosis and hyperblastic BALT. Multiple nodules (n = 14, 32 %) and single mass (n = 8, 18 %) were the predominant radiologic manifestations. The imaging findings conformed to previously described findings of BALToma, NHL, or LIP. Data suggest that BALToma, NHL, and LIP are the predominant ALPDs of the lung, and ALPD generally shared common radiologic features with sporadic LPDs. Familiarity with ALPDs and their imaging findings may enable radiologists or clinicians to include the disease as a potential differential diagnosis and thus, to prompt early biopsy followed by appropriate treatment.

A Rare Presentation of Isolated CNS Posttransplantation Lymphoproliferative Disorder

PubMed Central

Smith, Casey; Streicher, Andrew; Magnuson, Allison; Newman, Susan; Bertoli, Robert

2017-01-01

Posttransplantation lymphoproliferative disorder (PTLD) is a recognized and extremely morbid complication of solid organ transplantation, but central nervous system involvement, particularly in isolation, is rare. There are no standardized treatment strategies for PTLD, though commonly used strategies include reduction of immunosuppression, chemotherapy, rituximab, radiation, and surgery. We present a case of an unusual morphologic variant of primary central nervous system PTLD with successful response to rituximab and cranial radiation. A 69-year-old Asian male, who underwent postrenal transplant nine years earlier, presented with a one-month history of new onset seizure activity. His evaluation revealed multiple brain lesions on magnetic resonance imaging (MRI), as well as serologic and cerebrospinal fluid studies which were positive for Epstein-Barr Virus (EBV) infection. Ultimately, he underwent craniotomy with tissue biopsy with the final pathology report showing posttransplant lymphoproliferative disorder, polymorphic type. The patient was managed with reduction in immunosuppression, rituximab therapy, and cranial radiation treatments. He had demonstrated marked improvement in his neurologic function and was ultimately discharged to inpatient rehabilitation facility. PMID:28116196

A Rare Presentation of Isolated CNS Posttransplantation Lymphoproliferative Disorder.

PubMed

Morris, Jaime; Smith, Casey; Streicher, Andrew; Magnuson, Allison; Newman, Susan; Bertoli, Robert

2017-01-01

Posttransplantation lymphoproliferative disorder (PTLD) is a recognized and extremely morbid complication of solid organ transplantation, but central nervous system involvement, particularly in isolation, is rare. There are no standardized treatment strategies for PTLD, though commonly used strategies include reduction of immunosuppression, chemotherapy, rituximab, radiation, and surgery. We present a case of an unusual morphologic variant of primary central nervous system PTLD with successful response to rituximab and cranial radiation. A 69-year-old Asian male, who underwent postrenal transplant nine years earlier, presented with a one-month history of new onset seizure activity. His evaluation revealed multiple brain lesions on magnetic resonance imaging (MRI), as well as serologic and cerebrospinal fluid studies which were positive for Epstein-Barr Virus (EBV) infection. Ultimately, he underwent craniotomy with tissue biopsy with the final pathology report showing posttransplant lymphoproliferative disorder, polymorphic type. The patient was managed with reduction in immunosuppression, rituximab therapy, and cranial radiation treatments. He had demonstrated marked improvement in his neurologic function and was ultimately discharged to inpatient rehabilitation facility.

Posttransplant hypertension: multipathogenic disease process.

PubMed

Barbari, Antoine

2013-04-01

Arterial hypertension is prevalent among kidney transplant recipients. The multifactorial pathogenesis involves the interaction of the donor and the recipient's genetic backgrounds with several environmental parameters that may precede or follow the transplant procedure (eg, the nature of the renal disease, the duration of the chronic kidney disease phase and maintenance dialytic therapy, the commonly associated cardiovascular disease with atherosclerosis and arteriosclerosis, the renal mass at implantation, the immunosuppressive regimen used, life of the graft, and de novo medical and surgical complications that may occur after a transplant). Among calcineurin inhibitors, tacrolimus seems to have a better cardiovascular profile. Steroid-free protocols and calcineurin inhibitor-free regimens seem to be associated with better blood pressure control. Posttransplant hypertension is a major amplifier of the chronic kidney disease-cardiovascular disease continuum. Despite the adverse effects of hypertension on graft and patient survival, blood pressure control remains poor because of the high cardiovascular risk profile of the donor-recipient pair. Although the optimal blood pressure level remains unknown, it is recommended to maintain the blood pressure at < 130/80 mm Hg and < 125/75 mm Hg in the absence or presence of proteinuria.

Epstein–Barr virus-positive T/NK-cell lymphoproliferative disorders

PubMed Central

Cai, Qingqing; Chen, Kailin; Young, Ken H

2015-01-01

Epstein–Barr virus, a ubiquitous human herpesvirus, can induce both lytic and latent infections that result in a variety of human diseases, including lymphoproliferative disorders. The oncogenic potential of Epstein–Barr virus is related to its ability to infect and transform B lymphocytes into continuously proliferating lymphoblastoid cells. However, Epstein–Barr virus has also been implicated in the development of T/natural killer cell lymphoproliferative diseases. Epstein–Barr virus encodes a series of products that mimic several growth, transcription and anti-apoptotic factors, thus usurping control of pathways that regulate diverse homeostatic cellular functions and the microenvironment. However, the exact mechanism by which Epstein–Barr virus promotes oncogenesis and inflammatory lesion development remains unclear. Epstein–Barr virus-associated T/natural killer cell lymphoproliferative diseases often have overlapping clinical symptoms as well as histologic and immunophenotypic features because both lymphoid cell types derive from a common precursor. Accurate classification of Epstein–Barr virus-associated T/natural killer cell lymphoproliferative diseases is a prerequisite for appropriate clinical management. Currently, the treatment of most T/natural killer cell lymphoproliferative diseases is less than satisfactory. Novel and targeted therapies are strongly required to satisfy clinical demands. This review describes our current knowledge of the genetics, oncogenesis, biology, diagnosis and treatment of Epstein–Barr virus-associated T/natural killer cell lymphoproliferative diseases. PMID:25613730

Systemic Epstein-Barr Virus-positive T-Cell Lymphoproliferative Disease of Childhood With Good Response to Steroid Therapy.

PubMed

Kim, Do-Hoon; Kim, Myungshin; Kim, Yonggoo; Han, Kyungja; Han, Eunhee; Lee, Jae Wook; Chung, Nack-Gyun; Cho, Bin

2017-11-01

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease of childhood is a rare disease and has a very fulminant clinical course with high mortality. A 21-month-old female patient was referred to our hospital with a 1 week history of fever and was subsequently diagnosed with systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood. After starting treatment with dexamethasone, she showed early defervescence and improvement of laboratory parameters, and has remained disease-free after stopping steroid treatment, although longer follow-up is necessary. Our report underscores the possibility that this disease entity may be heterogenous in terms of prognosis.

Posttransplant Immune Activation

PubMed Central

Bamoulid, Jamal; Crepin, Thomas; Rebibou, Jean-Michel; Courivaud, Cecile; Saas, Philippe

2017-01-01

Cardiovascular disease is a major cause of morbidity, disability, and mortality in kidney transplant patients. Cumulative reports indicate that the excessive risk of cardiovascular events is not entirely explained by the increased prevalence of traditional cardiovascular risk factors. Atherosclerosis is a chronic inflammatory disease, and it has been postulated that posttransplant immune disturbances may explain the gap between the predicted and observed risks of cardiovascular events. Although concordant data suggest that innate immunity contributes to the posttransplant accelerated atherosclerosis, only few arguments plead for a role of adaptive immunity. We report and discuss here consistent data demonstrating that CD8+ T cell activation is a frequent posttransplant immune feature that may have pro-atherogenic effects. Expansion of exhausted/activated CD8+ T cells in kidney transplant recipients is stimulated by several factors including cytomegalovirus infections, lymphodepletive therapy (e.g., antithymocyte globulins), chronic allogeneic stimulation, and a past history of renal insufficiency. This is observed in the setting of decreased thymic activity, a process also found in elderly individuals and reflecting accelerated immune senescence. PMID:29113470

CD4+ memory T cells retain surface expression of CD31 independently of thymic function in patients with lymphoproliferative disorders following autologous hematopoietic stem-cell transplantation.

PubMed

Batorov, Egor V; Tikhonova, Marina A; Kryuchkova, Irina V; Sergeevicheva, Vera V; Sizikova, Svetlana A; Ushakova, Galina Y; Batorova, Dariya S; Gilevich, Andrey V; Ostanin, Alexander A; Shevela, Ekaterina Y; Chernykh, Elena R

2017-07-01

High-dose chemotherapy with autologous hematopoietic stem-cell transplantation (AHSCT) causes severe and long-lasting immunodeficiency in patients with lymphoproliferative disorders. The thymus begins to restore the T-cell repertoire approximately from the sixth month post-transplant. We assessed the dynamics of post-transplant recovery of CD4 + CD45RA + CD31 + T cells, "recent thymic emigrants" (RTEs), and a poorly described subtype of CD4 + CD45RA - CD31 + T cells in 90 patients with lymphoproliferative disorders following high-dose chemotherapy with AHSCT. Relative and absolute counts of CD4 + CD31 + naïve and memory T cells were evaluated before AHSCT, at the day of engraftment, and 6- and 12-month post-transplant. The pre-transplant count of CD4 + CD45RA + CD31 + T cells was lower than in healthy controls, and did not reach donors' values during the 12-month period. The pre-transplant number of CD4 + CD45RA - CD31 + T cells was higher than in healthy controls and was restored rapidly following AHSCT. Post-transplant mediastinal radiotherapy reduced counts of RTEs and elongated recovery period. Non-thymic tissue irradiation did not reduce this subset. The obtained data indicate that homeostatic proliferation may decrease the significance of CD31 expression on CD4 + CD45RA + T cells as a marker of RTEs, and suggest that evaluation of RTEs recovery by flow cytometry requires an accurate gating strategy to exclude CD31 + memory T cells.

Prospective Epstein-Barr virus-related post-transplant lymphoproliferative disorder prevention program in pediatric allogeneic hematopoietic stem cell transplant: virological monitoring and first-line treatment.

PubMed

Chiereghin, A; Prete, A; Belotti, T; Gibertoni, D; Piccirilli, G; Gabrielli, L; Pession, A; Lazzarotto, T

2016-02-01

In 28 pediatric allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, we aimed to evaluate: (i) the impact of routine Epstein-Barr virus (EBV) DNA monitoring on the development of EBV-related post-transplant lymphoproliferative disorder (EBV-PTLD); (ii) the incidence of EBV infection and the potential risk factors; and (iii) the suitability of whole blood (WB) as clinical specimen to monitor the risk of patients to develop EBV-PTLD. Quantitative real-time polymerase chain reaction assay was performed on WB samples for all patients. EBV DNA quantification also in peripheral blood mononuclear cells (PBMCs) samples was adopted for the patients at higher risk of developing EBV-PTLD (≥ 10,000 copies/mL WB). High EBV DNAemia levels were observed in 37.5% of the actively infected recipients (57.1%). Severe aplastic anemia, matched-unrelated donor transplant, the reduced-intensity conditioning regimen and, to a lesser extent, the in vivo T-cell depletion with anti-thymocyte immunoglobulin were associated with high viral load. A significant correlation between EBV DNA levels in WB and PBMC samples was obtained (r = 0.755, P < 0.001). A similar kinetics of EBV DNA in the 2 blood compartments was observed. Clinically, both specimen types appeared to be equally informative to assess the risk of patients to develop PTLD. On the basis of EBV DNAemia levels, in 3 patients (10.7%) immunosuppressive therapy was reduced and 1 patient (3.5%) received early treatment for probable EBV disease. No patients developed EBV-PTLD. WB proved to be a suitable clinical specimen to monitor EBV DNA load after allo-HSCT for the management of EBV infection and PTLD prevention. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Posttransplant lymphoproliferative disorder in a kidney-pancreas transplanted recipient: simultaneous development of clonal lymphoid B-cell proliferation of host and donor origin.

PubMed

Heyny-von Haussen, Roland; Klingel, Karin; Riegel, Werner; Kandolf, Reinhard; Mall, Gerhard

2006-07-01

Posttransplant lymphoproliferative disorders (PTLDs) are lymphoid proliferations or lymphomas that develop as a consequence of immunosuppression after solid organ or bone marrow transplantation and are mostly associated with an Epstein-Barr virus infection. The morphologic categories include different types of benign and malignant lymphoid proliferations. The majority of PTLDs is of B-cell origin with clonal rearrangements of the immunoglobulin genes. The PTLDs in solid organ transplants are reported to be either of host or of donor origin. Donor-related PTLDs frequently involve the allograft. We report a case of a 52-year-old woman recipient who developed simultaneously PTLDs in several organs 5 month after receiving a sex-mismatched renal and pancreas allograft. Immunosuppression regimen comprised antithymocyte globulin, tacrolimus, mycophenolate mofetil, and steroids. Pathologic features appeared as polymorphic PTLDs in the renal allograft, liver, and central nervous system (CNS). Molecular genetic studies revealed different clonal immunoglobulin heavy chain gene rearrangements in all 3 organs as determined by polymerase chain reaction (PCR). Epstein-Barr virus were detected by nested PCR and in situ hybridization in all 3 tumors. The PTLDs in liver and CNS were of host origin whereas the allograft kidney PTLD was found to originate from the male donor as shown by the simultaneous detection of female and male sex chromosomes by PCR and fluorescence in situ hybridization. The recipient died in consequence of the CNS involvement, after intracerebral hemorrhage with uncal and tonsillar herniation.

Posttransplant Immune Activation: Innocent Bystander or Insidious Culprit of Posttransplant Accelerated Atherosclerosis.

PubMed

Ducloux, Didier; Bamoulid, Jamal; Crepin, Thomas; Rebibou, Jean-Michel; Courivaud, Cecile; Saas, Philippe

2017-09-01

Cardiovascular disease is a major cause of morbidity, disability, and mortality in kidney transplant patients. Cumulative reports indicate that the excessive risk of cardiovascular events is not entirely explained by the increased prevalence of traditional cardiovascular risk factors. Atherosclerosis is a chronic inflammatory disease, and it has been postulated that posttransplant immune disturbances may explain the gap between the predicted and observed risks of cardiovascular events. Although concordant data suggest that innate immunity contributes to the posttransplant accelerated atherosclerosis, only few arguments plead for a role of adaptive immunity. We report and discuss here consistent data demonstrating that CD8 + T cell activation is a frequent posttransplant immune feature that may have pro-atherogenic effects. Expansion of exhausted/activated CD8 + T cells in kidney transplant recipients is stimulated by several factors including cytomegalovirus infections, lymphodepletive therapy (e.g., antithymocyte globulins), chronic allogeneic stimulation, and a past history of renal insufficiency. This is observed in the setting of decreased thymic activity, a process also found in elderly individuals and reflecting accelerated immune senescence.

Avian oncogenesis induced by lymphoproliferative disease virus: a neglected or emerging retroviral pathogen?

USDA-ARS?s Scientific Manuscript database

Lymphoproliferative disease virus (LPDV) is an exogenous oncogenic retrovirus that induces lymphoid tumors in some galliform species of birds. Historically, outbreaks of LPDV have been reported from Europe and Israel. Although the virus has previously never been detected in North America, herein we ...

Epstein-Barr virus: general factors, virus-related diseases and measurement of viral load after transplant

PubMed Central

Gequelin, Luciana Cristina Fagundes; Riediger, Irina N.; Nakatani, Sueli M.; Biondo, Alexander W.; Bonfim, Carmem M.

2011-01-01

The Epstein-Barr virus is responsible for infectious mononucleosis syndrome and is also closely associated to several types of cancer. The main complication involving Epstein-Barr virus infection, both in recipients of hematopoietic stem cells and solid organs, is post-transplant lymphoproliferative disease. The importance of this disease has increased interest in the development of laboratory tools to improve post-transplant monitoring and to detect the disease before clinical evolution. Viral load analysis for Epstein-Barr virus through real-time polymerase chain reaction is, at present, the best tool to measure viral load. However, there is not a consensus on which sample type is the best for the test and what is its predictive value for therapeutic interventions. PMID:23049344

Successful bone marrow transplantation in a boy with X-linked lymphoproliferative syndrome and acute severe infectious mononucleosis.

PubMed

Pracher, E; Panzer-Grümayer, E R; Zoubek, A; Peters, C; Gadner, H

1994-05-01

We report a 5.9-year-old boy with X-linked lymphoproliferative syndrome (XLP) who presented with acute severe infectious mononucleosis. Clinical symptoms rapidly improved after chemotherapy with etoposide. Allogeneic bone marrow transplantation (BMT) was performed after conditioning with etoposide, busulfan and cyclophosphamide. After successful hematopoietic recovery we were able to demonstrate seroconversion from an impaired antibody response to Epstein-Barr virus (EBV) to a normal antibody-producing state in an immunocompetent child. The only post-transplant complication was mild acute graft-versus-host disease (GVHD). Three years after BMT, the boy is healthy and shows no signs of immunodeficiency. This is the first report on successful allogeneic BMT in the severe course of acute infectious mononucleosis in a patient with XLP. We speculate that the application of etoposide contributed to the positive outcome in this patient.

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease.

PubMed

Nabhani, Schafiq; Ginzel, Sebastian; Miskin, Hagit; Revel-Vilk, Shoshana; Harlev, Dan; Fleckenstein, Bernhard; Hönscheid, Andrea; Oommen, Prasad T; Kuhlen, Michaela; Thiele, Ralf; Laws, Hans-Jürgen; Borkhardt, Arndt; Stepensky, Polina; Fischer, Ute

2015-09-01

Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20-30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease. Copyright© Ferrata Storti

Genetics Home Reference: X-linked lymphoproliferative disease

MedlinePlus

... infects most humans. In some people it causes infectious mononucleosis (commonly known as "mono"). Normally, after initial infection, ... severe susceptibility to EBV infection severe susceptibility to infectious mononucleosis X-linked lymphoproliferative syndrome XLP Related Information How ...

Comprehensive molecular diagnosis of Epstein-Barr virus-associated lymphoproliferative diseases using next-generation sequencing.

PubMed

Ono, Shintaro; Nakayama, Manabu; Kanegane, Hirokazu; Hoshino, Akihiro; Shimodera, Saeko; Shibata, Hirofumi; Fujino, Hisanori; Fujino, Takahiro; Yunomae, Yuta; Okano, Tsubasa; Yamashita, Motoi; Yasumi, Takahiro; Izawa, Kazushi; Takagi, Masatoshi; Imai, Kohsuke; Zhang, Kejian; Marsh, Rebecca; Picard, Capucine; Latour, Sylvain; Ohara, Osamu; Morio, Tomohiro

2018-05-18

Epstein-Barr virus (EBV) is associated with several life-threatening diseases, such as lymphoproliferative disease (LPD), particularly in immunocompromised hosts. Some categories of primary immunodeficiency diseases (PIDs) including X-linked lymphoproliferative syndrome (XLP), are characterized by susceptibility and vulnerability to EBV infection. The number of genetically defined PIDs is rapidly increasing, and clinical genetic testing plays an important role in establishing a definitive diagnosis. Whole-exome sequencing is performed for diagnosing rare genetic diseases, but is both expensive and time-consuming. Low-cost, high-throughput gene analysis systems are thus necessary. We developed a comprehensive molecular diagnostic method using a two-step tailed polymerase chain reaction (PCR) and a next-generation sequencing (NGS) platform to detect mutations in 23 candidate genes responsible for XLP or XLP-like diseases. Samples from 19 patients suspected of having EBV-associated LPD were used in this comprehensive molecular diagnosis. Causative gene mutations (involving PRF1 and SH2D1A) were detected in two of the 19 patients studied. This comprehensive diagnosis method effectively detected mutations in all coding exons of 23 genes with sufficient read numbers for each amplicon. This comprehensive molecular diagnostic method using PCR and NGS provides a rapid, accurate, low-cost diagnosis for patients with XLP or XLP-like diseases.

Persistent Epstein-Barr viral load in Epstein-Barr viral naïve pediatric heart transplant recipients: Risk of late-onset post-transplant lymphoproliferative disease.

PubMed

Das, Bibhuti; Morrow, Robert; Huang, Rong; Fixler, David

2016-12-24

To examine the risk of late-onset post-transplant lymphoproliferative disorder (PTLD) in the presence of persisting high Epstein-Barr virus (EBV) in EBV naïve pediatric heart transplant (HT) recipients. A retrospective review of the medical records of the 145 pediatric HT recipients who had serial EBV viral load monitoring at our center was performed. We defined EBV naive patients whose EBV serology either IgM or IgG in the blood were negative at the time of HT and excluded passive transmission from mother to child in subjects less than 6 mo of age. PTLD was diagnosed in 8 out of 145 patients (5.5%); 6/91 (6.5%) in those who were EBV seropositive and 2/54 (3.7%) in the EBV naïve group at the time of HT ( P = 0.71). We found 32/145 (22%) patients with persistently high EBV load during continuing follow-up; 20/91 (22%) in EBV seropositive group vs 12/54 (22%) in EBV naïve group ( P = 0.97). There was no significant association between pre-HT serostatus and EBV load after transplant ( P > 0.05). In the EBV seropositive group, PTLD was diagnosed in 15% (3/20) of patients with high EBV vs 4.2% (3/71) of patients with low or undetectable EBV load ( P = 0.14) whereas in EBV naïve patients 8.3% (1/12) of those with high EBV load and 2.3% (1/42) with low or undetectable EBV load ( P = 0.41). There was a highly significant association between occurrence of PTLD in those with high EBV load and duration of follow up (4.3 ± 3.9 years) after HT by Cochran-Armitage test for the entire cohort ( P = 0.005). At least one episode of acute rejection occurred in 72% (23/32) of patients with high EBV vs 36% (41/113) patients with low or undetectable EBV after HT ( P < 0.05). There is an association between persistently high EBV load during post-HT follow up and the occurrence of late-onset PTLD in pediatric HT recipients irrespective of serostatus at the time of transplant. The occurrence of allograft rejection increased in patients with high EBV load presumably due to reduction in

Tacrolimus/Everolimus vs. Tacrolimus/MMF in Pediatric Heart Transplant Recipients Using the MATE Score

ClinicalTrials.gov

2018-03-05

Pediatric Heart Transplantation; Immunosuppression; Chronic Kidney Diseases; Cardiac Allograft Vasculopathy; Heart Transplant Failure and Rejection; Post-transplant Lymphoproliferative Disorder; Heart Transplant Infection

Epstein-Barr viral load before a liver transplant in children with chronic liver disease.

PubMed

Shakibazad, Nader; Honar, Naser; Dehghani, Seyed Mohsen; Alborzi, Abdolvahab

2014-12-01

Many children with chronic liver disease require a liver transplant. These patients are prone to various infections, including Epstein-Barr virus infection. This study sought to measure the Epstein-Barr viral load by polymerase chain reaction before a liver transplant. This cross-sectional study was done at the Shiraz University of Medical Sciences, Shiraz, Iran, in 2011. All patients were aged younger than 18 years with chronic liver disease and were candidates for a liver transplant at the Shiraz Nemazee Hospital Organ Transplant Center. They had been investigated regarding their demographic characteristics, underlying disease, laboratory findings, and Epstein-Barr viral load by real-time TaqMan polymerase chain reaction. Ninety-eight patients were studied and the mean age was 6.5 ± 5.9 years. Cryptogenic cirrhosis was the most-prevalent reason for liver transplant, and the death rate before a transplant was 15%. Among the study subjects, 6 had measurable Epstein-Barr viral load by polymerase chain reaction before the transplant, and 4 of them had considerably higher Epstein-Barr viral loads (more than 1000 copies/mL). With respect to the close prevalence of posttransplant lymphoproliferative disease (6%) and the high Epstein-Barr viral load in the patients before a transplant (4%), high pretransplant Epstein-Barr viral load can be considered a risk factor for posttransplant lymphoproliferative disorder.

Association of Pretransplant Skin Cancer With Posttransplant Malignancy, Graft Failure and Death in Kidney Transplant Recipients.

PubMed

Kang, Woosun; Sampaio, Marcelo Santos; Huang, Edmund; Bunnapradist, Suphamai

2017-06-01

Posttransplant malignancy (PTM) is one of the leading causes of late death in kidney recipients. Those with a cancer history may be more prone to develop a recurrent or a new cancer. We studied the association between pretransplant skin cancer, PTM, death, and graft failure. Primary adult kidney recipients transplanted between 2005 and 2013 were included. Malignancy information was obtained from Organ Procurement Kidney Transplant Network/United Network for Organ Sharing registration and follow-up forms. Posttransplant malignancy was classified into skin cancer, solid tumor, and posttransplant lymphoproliferative disorder (PTLD). Competing risk and survival analysis with adjustment for confounders were used to calculate risk for PTM, death and graft failure in recipients with pretransplant skin cancer compared with those without cancer. Risk was reported in hazard ratios (HR) with 95% confidence interval (CI). The cohort included 1671 recipients with and 102 961 without pretransplant skin malignancy. The 5-year cumulative incidence of PTM in patients with and without a pretransplant skin cancer history was 31.6% and 7.4%, respectively (P < 0.001). Recipients with pretransplant skin cancer had increased risk of PTM (sub-HR [SHR], 2.60; 95% CI, 2.27-2.98), and posttransplant skin cancer (SHR, 2.92; 95% CI, 2.52-3.39), PTLD (SHR, 1.93; 95% CI, 1.01-3.66), solid tumor (SHR, 1.44; 95% CI, 1.04-1.99), death (HR, 1.20; 95% CI, 1.07-1.34), and graft failure (HR, 1.17; 95% CI, 1.05-1.30) when compared with those without pretransplant malignancy. Pretransplant skin cancer was associated with an increased risk of posttransplant skin cancer, PTLD, solid organ cancer, death and graft failure.

Autoimmune lymphoproliferative syndrome: more than a FAScinating disease

PubMed Central

Bride, Karen; Teachey, David

2017-01-01

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited syndrome characterized by abnormal lymphocyte survival caused by failure of apoptotic mechanisms to maintain lymphocyte homeostasis. This failure leads to the clinical manifestations of non-infectious and non-malignant lymphadenopathy, splenomegaly, and autoimmune pathology, most commonly, autoimmune cytopenias. Since ALPS was first characterized in the early 1990s, insights in disease biology have improved both diagnosis and management of this syndrome. Sirolimus is the best-studied and most effective corticosteroid-sparing therapy for ALPS and should be considered first-line for patients in need of chronic treatment. This review highlights practical clinical considerations for the diagnosis and management of ALPS. Further studies could reveal new proteins and regulatory pathways that are critical for lymphocyte activation and apoptosis. PMID:29123652

Early Detection of Epstein-Barr Virus Related Disease.

ClinicalTrials.gov

2018-05-22

Post-transplant Lymphoproliferative Disorder; Mononucleosis; Epstein-Barr Virus Infections; Epstein-Barr Virus Related Malignancy; Epstein-Barr Viraemia; Epstein-Barr Virus-Related Hodgkin Lymphoma; Epstein-Barr Virus-Related Non-Hodgkin Lymphoma; Hemophagocytic Lymphohistiocytoses; Hemophagocytosis

Systematic Epstein-Barr virus-positive T-cell lymphoproliferative disease presenting as a persistent fever and cough: a case report.

PubMed

Ameli, Fereshteh; Ghafourian, Firouzeh; Masir, Noraidah

2014-08-27

Systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is an extremely rare disorder and classically arises following primary acute or chronic active Epstein-Barr virus infection. It is characterized by clonal proliferation of Epstein-Barr virus-infected T-cells with an activated cytotoxic phenotype. This disease has a rapid clinical course and is more frequent in Asia and South America, with relatively few cases being reported in Western countries. The clinical and pathological features of the disease overlap with other conditions including infectious mononucleosis, chronic active Epstein-Barr virus infection, hemophagocytic lymphohistiocytosis and natural killer cell malignancies. We describe the rare case of systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease in a 16-year-old Malay boy. He presented with a six-month history of fever and cough, with pulmonary and mediastinal lymphadenopathy and severe pancytopenia. Medium- to large-sized, CD8+ and Epstein-Barr virus-encoded RNA-positive atypical lymphoid cells were present in the bone marrow aspirate. He subsequently developed fatal virus-associated hemophagocytic syndrome and died due to sepsis and multiorgan failure. Although systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is a disorder which is rarely encountered in clinical practice, our case report underlines the importance of a comprehensive diagnostic approach in the management of this disease. A high level of awareness of the disease throughout the diagnosis process for young patients who present with systemic illness and hemophagocytic syndrome may be of great help for the clinical diagnosis of this disease.

Herpesvirus-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

PubMed

Wu, Meiqing; Huang, Fen; Jiang, Xinmiao; Fan, Zhiping; Zhou, Hongsheng; Liu, Can; Jiang, Qianli; Zhang, Yu; Zhao, Ke; Xuan, Li; Zhai, Xiao; Zhang, Fuhua; Yin, Changxin; Sun, Jing; Feng, Ru; Liu, Qifa

2013-01-01

Herpesvirus infections of the central nervous system (CNS) are associated with encephalitis/myelitis and lymphoproliferative diseases in immunocompromised individuals. As of now, data of herpesvirus-associated CNS diseases in transplant recipients is limited. Hence, in this prospective study, we investigated the incidence of herpesvirus-associated CNS diseases and explored the diagnosis of these diseases in 281 allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Herpesvirus-DNA and cerebrospinal fluid (CSF) cells were sampled from 58 recipients with herpesvirus-associated diseases or with unexplainable CNS manifestations. Results showed that 23 patients were diagnosed as herpesvirus-associated CNS diseases, including 15 Epstein-Barr virus (EBV)-associated diseases (4 encephalitis and 11 lymphoproliferative diseases), 5 herpes simplex virus type 1 encephalitis, 2 cytomegalovirus encephalitis/myelitis and 1 varicella zoster virus encephalitis. The median time of diseases onset was 65 (range 22-542) days post-transplantation. The 3-year cumulative incidence of herpesvirus-associated encephalitis/myelitis and post-transplant lymphoproliferative disorder (PTLD) was 6.3% ± 1.9% and 4.1% ± 1.2%, respectively. Of the evaluable cases, CSF cells mainly consisted of CD19(+)CD20(+) B cells (7/11) and had clonal rearrangement of immunoglobulin genes (3/11) in patients with CNS-PTLD. On the contrary, in patients with encephalitis/myelitis, CSF cells were comprised of different cell populations and none of the gene rearrangement was detected. Herpesvirus-associated CNS diseases are common in the early stages of allo-HSCT, wherein EBV is the most frequent causative virus. The immunophenotypic and clonal analysis of CSF cells might be helpful in the differential diagnosis between encephalitis and lymphoproliferative diseases.

Recipient But Not Donor Adiponectin Polymorphisms Are Associated With Early Posttransplant Hepatic Steatosis in Patients Transplanted for Non-Nonalcoholic Fatty Liver Disease Indications.

PubMed

John, Binu V; Aiken, Taylor; Garber, Ari; Thomas, Dawn; Lopez, Rocio; Patil, Deepa; Konjeti, Venkata Rajesh; Fung, John J; McCollough, Arthur J; Askar, Medhat

2018-06-01

De novo steatosis after liver transplant is common and can occur in up to one-third of patients who are transplanted for liver disease other than for nonalcoholic fatty liver disease. Genetic factors may influence posttransplant steatosis; in a posttransplant setting, donor or recipient genetic factors could also play roles. Genetic polymorphisms in the adiponectin gene have been associated with metabolic syndrome in the pretransplant setting. We aimed to assess the association between donor and recipient adiponectin polymorphisms and early posttransplant hepatic steatosis identified on liver biopsies. Clinical data were collected for 302 liver transplant patients who underwent protocol biopsies for hepatitis C. Of these, 111 patients had available biopsies and donor/recipient DNA. Patients with grade 1 steatosis or greater (35% of patients) were compared with patients without posttransplant steatosis with respect to clinical features and donor/recipient adiponectin polymorphism genotypes. Patients who developed posttransplant steatosis and those without steatosis were similar with respect to individual components of metabolic syndrome. The adiponectin polymorphisms rs1501299 G/G and rs17300539 G/G genotypes in recipients were associated with early posttransplant graft steatosis. We found no associations between graft steatosis and donor adiponectin polymorphisms. Genetic polymorphisms in the adiponectin gene of recipients (but not donors) are associated with early de novo posttransplant hepatic steatosis, independent of components of metabolic syndrome.

End-of-Treatment Positron Emission Tomography After Uniform First-Line Therapy of B-Cell Posttransplant Lymphoproliferative Disorder Identifies Patients at Low Risk of Relapse in the Prospective German PTLD Registry.

PubMed

Zimmermann, Heiner; Denecke, Timm; Dreyling, Martin H; Franzius, Christiane; Reinke, Petra; Subklewe, Marion; Amthauer, Holger; Kneba, Michael; Riess, Hanno; Trappe, Ralf U

2018-05-01

Fluorine-18 fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) is a recommended standard in the staging and response assessment of 18F-FDG-avid lymphoma. Posttransplant lymphoproliferative disorder (PTLD) can be detected by 18F-FDG-PET at diagnosis with high sensitivity and specificity. However, the role of response assessment by end-of-treatment (EOT) PET has only been addressed in small case series. We performed a retrospective, multicenter study of 37 patients with CD20-positive PTLD after solid organ transplantation treated with uniform, up-to-date, first-line protocols in the prospective German PTLD registry who had received EOT 18F-FDG-PET between 2006 and 2014. Median follow-up was 5.0 years. Any nonphysiological 18F-FDG uptake (Deauville score greater 2) was interpreted as PET-positive. By computed tomography (CT) final staging, 18 of 37 patients had a complete response, 18 had a partial response and 1 patient had stable disease. EOT PET was negative in 24 of 37 patients and positive in 13 of 37 patients. The positive predictive value of EOT PET for PTLD relapse was 38%, and the negative predictive value was 92%. Time to progression (TTP) and progression-free-survival were significantly longer in the PET negative group (P = 0.019 and P = 0.013). In the 18 patients in a partial response by CT staging, we noted highly significant differences in overall survival (P = 0.001), time to progression (P = 0.007), and progression-free survival (P < 0.001) by EOT PET. Even without baseline imaging, EOT PET in PTLD identifies patients at low risk of relapse and offers clinically relevant information, particularly in patients in a partial remission by CT staging.

Cutaneous lymphoproliferative disorder complicating infectious mononucleosis in an immunosuppressed patient.

PubMed

Owen, Cindy England; Callen, Jeffrey P; Bahrami, Soon

2011-01-01

Infectious mononucleosis is the syndrome produced by primary infection with Epstein-Barr virus during adolescence or early adulthood. In immunosuppressed individuals, depressed T-cell function allows the Epstein-Barr virus-driven B-cell proliferation to continue unabated, potentially leading to a lymphoproliferative disorder. A 15-year-old girl with a history of ulcerative colitis treated with 6-mercaptopurine and mesalamine presented with the acute onset of a rapidly enlarging, ulcerative nodule on her left lower eyelid 4 weeks following recovery from infectious mononucleosis. The biopsy revealed an Epstein-Barr virus-positive lymphoproliferative disorder. Systemic disease was absent. Following discontinuation of 6-mercaptopurine, the patient was treated with two courses of intravenous cyclophosphamide. The lesion resolved completely and she remains disease free at 14 months following diagnosis. We report a solitary cutaneous lesion of an immunosuppression-related lymphoproliferative disorder (IR-LPD) occurring as a complication of infectious mononucleosis, and review the pathogenesis and reported cases of Epstein-Barr virus-related immunosuppression-related lymphoproliferative disorder arising in the setting of inflammatory bowel disease. It is important for dermatologists and dermatopathologists to be aware of the occurrence of IR-LPD in patients being treated for inflammatory conditions, including inflammatory bowel disease. Given the role of primary infection with Epstein-Barr virus in the development of IR-LPD, consideration may be given to assessing Epstein-Barr virus status prior to initiating immunosuppressive therapy in young patients. © 2010 Wiley Periodicals, Inc.

Negative outcomes after liver transplantation in patients with alcoholic liver disease beyond the fifth post-transplant year.

PubMed

Grąt, Michał; Lewandowski, Zbigniew; Grąt, Karolina; Wronka, Karolina Maria; Krasnodębski, Maciej; Barski, Krzysztof; Zborowska, Hanna; Patkowski, Waldemar; Zieniewicz, Krzysztof; Krawczyk, Marek

2014-10-01

Although up to 50% of patients with alcoholic liver disease (ALD) resume alcohol consumption after liver transplantation (LT), numerous studies indicate that long-term results are not compromised. This study focused on evaluating the impact of ALD on outcomes up to and beyond the fifth year after LT. Among the 432 primary LT recipients included in this study, 97 underwent transplantation for ALD. Alcohol relapse rate at 10 yr was 33.5%, with younger recipient age being the only independent predictor (p = 0.019). Survival of patients with ALD (77.0%) was similar to those without (79.0%) up to the fifth post-transplant year (p = 0.655) but worse during the five subsequent years among the five-yr survivors (70.6% vs. 92.9%; p = 0.002). ALD was an independent risk factor for poorer survival beyond the fifth post-transplant year (p = 0.049), but not earlier (p = 0.717). Conversely, alcohol relapse increased the risk of death only during the first five post-transplant years (p = 0.039). There were no significant differences regarding graft failure incidence between ALD and non-ALD recipients up to the fifth post-transplant year (7.3% vs. 11.6%; p = 0.255) and beyond (12.9% vs. 5.0%; p = 0.126). In conclusion, pre-transplant diagnosis of ALD yields negative effects on post-transplant outcomes beyond the fifth post-transplant year, not attributable to recidivism. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Adult systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease: A case report.

PubMed

Wang, Youping; Liu, Xinyue; Chen, Yan

2015-09-01

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease (EBV + T-LPD) occurs mainly in Asia and South America and is extremely rare in adults. The disease is characterized by a clonal proliferation of EBV-infected T cells with a cytotoxic immunophenotype and is associated with a poor clinical outcome and can be life-threatening. The majority of the patients have evidence of systemic disease, often with lymph node, liver and spleen involvement. The present study describes a case of adult systemic EBV + T-LPD with high fever, systemic lymphadenopathy, hepatosplenomegaly, nose-pharynx neoplasm, pancytopenia, EB virus infection and proliferative bone marrow, with the aim of improving the understanding of the condition.

Two rare cases of Epstein-Barr virus-associated lymphoproliferative disorders in inflammatory bowel disease patients on thiopurines and other immunosuppressive medications.

PubMed

Subramaniam, K; Cherian, M; Jain, S; Latimer, M; Corbett, M; D'Rozario, J; Pavli, P

2013-12-01

The setting of chronic immunosuppression in inflammatory bowel disease (IBD) may promote the proliferation of Epstein-Barr virus-positive neoplastic clones. We report two rare cases of Epstein-Barr virus-associated lymphoproliferative disorder in IBD patients: one resembled lymphomatoid granulomatosis, and the other was a lymphoma resembling Hodgkin lymphoma. There are currently no guidelines for the prevention of lymphoproliferative disorder in IBD patients on immunosuppressive therapy. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome.

PubMed

Zhang, Xixi; Fan, Cunxian; Zhang, Haiwei; Zhao, Qun; Liu, Yongbo; Xu, Chengxian; Xie, Qun; Wu, Xiaoxia; Yu, Xianjun; Zhang, Jianke; Zhang, Haibing

2016-09-20

MLKL, a key component downstream of RIPK3, is suggested to be a terminal executor of necroptosis. Genetic studies have revealed that Ripk3 ablation rescues embryonic lethality in Fadd- or Caspase-8-deficient mice. Given that RIPK3 has also been implicated in non-necroptotic pathways including apoptosis and inflammatory signaling, it remains unclear whether the lethality in Fadd(-/-) mice is indeed caused by necropotosis. Here, we show that genetic deletion of Mlkl rescues the developmental defect in Fadd-deficient mice and that Fadd(-/-)Mlkl(-/-) mice are viable and fertile. Mlkl(-/-)Fadd(-/-) mice display significantly accelerated lymphoproliferative disease characterized by lymphadenopathy and splenomegaly when compared to Ripk3(-/-)Fadd(-/-) mice. Mlkl(-/-)Fadd(-/-) bone-marrow-derived macrophages and dendritic cells have impaired NLRP3 inflammasome activation associated with defects in ASC speck formation and NF-κB-dependent NLRP3 transcription. Our findings reveal that MLKL and FADD play critical roles in preventing lymphoproliferative disease and activating the NLRP3 inflammasome. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

EBV-Negative Monomorphic B-Cell Posttransplant Lymphoproliferative Disorder with Marked Morphologic Pleomorphism and Pathogenic Mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53.

PubMed

Bogusz, Agata M

2017-01-01

Posttransplant lymphoproliferative disorders (PTLDs) are a diverse group of lymphoid or plasmacytic proliferations frequently driven by Epstein-Barr virus (EBV). EBV-negative PTLDs appear to represent a distinct entity. This report describes an unusual case of a 33-year-old woman that developed a monomorphic EBV-negative PTLD consistent with diffuse large B-cell lymphoma (DLBCL) 13 years after heart-lung transplant. Histological examination revealed marked pleomorphism of the malignant cells including nodular areas reminiscent of classical Hodgkin lymphoma (cHL) with abundant large, bizarre Hodgkin-like cells. By immunostaining, the malignant cells were immunoreactive for CD45, CD20, CD79a, PAX5, BCL6, MUM1, and p53 and negative for CD15, CD30, latent membrane protein 1 (LMP1), and EBV-encoded RNA (EBER). Flow cytometry demonstrated lambda light chain restricted CD5 and CD10 negative B-cells. Fluorescence in situ hybridization studies (FISH) were negative for cMYC , BCL2, and BCL6 rearrangements but showed deletion of TP53 and monosomy of chromosome 17. Next-generation sequencing studies (NGS) revealed numerous genetic alterations including 6 pathogenic mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53 (x2) genes and 30 variants of unknown significance (VOUS) in ABL1, ASXL1, ATM, BCOR, BCORL1, BRNIP3, CDH2, CDKN2A, DNMT3A, ETV6, EZH2, FBXW7, KIT, NF1, RUNX1, SETPB1, SF1, SMC1A, STAG2, TET2, TP53, and U2AF2.

EBV-Negative Monomorphic B-Cell Posttransplant Lymphoproliferative Disorder with Marked Morphologic Pleomorphism and Pathogenic Mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53

PubMed Central

2017-01-01

Posttransplant lymphoproliferative disorders (PTLDs) are a diverse group of lymphoid or plasmacytic proliferations frequently driven by Epstein-Barr virus (EBV). EBV-negative PTLDs appear to represent a distinct entity. This report describes an unusual case of a 33-year-old woman that developed a monomorphic EBV-negative PTLD consistent with diffuse large B-cell lymphoma (DLBCL) 13 years after heart-lung transplant. Histological examination revealed marked pleomorphism of the malignant cells including nodular areas reminiscent of classical Hodgkin lymphoma (cHL) with abundant large, bizarre Hodgkin-like cells. By immunostaining, the malignant cells were immunoreactive for CD45, CD20, CD79a, PAX5, BCL6, MUM1, and p53 and negative for CD15, CD30, latent membrane protein 1 (LMP1), and EBV-encoded RNA (EBER). Flow cytometry demonstrated lambda light chain restricted CD5 and CD10 negative B-cells. Fluorescence in situ hybridization studies (FISH) were negative for cMYC, BCL2, and BCL6 rearrangements but showed deletion of TP53 and monosomy of chromosome 17. Next-generation sequencing studies (NGS) revealed numerous genetic alterations including 6 pathogenic mutations in ASXL1, BCOR, CDKN2A, NF1, and TP53(x2) genes and 30 variants of unknown significance (VOUS) in ABL1, ASXL1, ATM, BCOR, BCORL1, BRNIP3, CDH2, CDKN2A, DNMT3A, ETV6, EZH2, FBXW7, KIT, NF1, RUNX1, SETPB1, SF1, SMC1A, STAG2, TET2, TP53, and U2AF2. PMID:28487787

CD30-Positive T-Cell Lymphoproliferative Disease of the Oral Mucosa in Children: A Manifestation of Epstein-Barr Virus-Associated T-Lymphoproliferative Disorder.

PubMed

Hong, Mineui; Ko, Young Hyeh

2015-11-01

Eosinophilic ulcer of the oral mucosa (EUOM) is a very rare, benign, self-limiting ulcerative lesion of the oral cavity of unknown pathogenesis, and belongs to the same spectrum of CD30(+) T-cell lymphoproliferative disease (LPD) of the oral mucosa. The etiology and pathogenesis of the disease are unknown. We report two cases in children who were initially diagnosed with EUOM and CD30(+) T-cell LPD, respectively. However, retrospective analysis revealed that a majority of infiltrated atypical T cells were positive for Epstein-Barr virus (EBV). The present cases suggest that the pathogenesis and etiology of EUOM or CD30(+) T-cell LPD occurring in children are different from those in adults. EUOM or CD30(+) T-cell LPD in children is a manifestation of EBV-positive T-cell LPD, and should therefore be distinguished from the disease in adults.

Mapping the x-linked lymphoproliferative syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skare, J.C.; Milunsky, A.; Byron, K.S.

1987-04-01

The X-linked lymphoproliferative syndrome is triggered by Epstein-Barr virus infection and results in fatal mononucleosis, immunodeficiency, and lymphoproliferative disorders. This study shows that the mutation responsible for X-linked lymphoproliferative syndrome is genetically linked to a restriction fragment length polymorphism detected with the DXS42 probe (from Xq24-q27). The most likely recombination frequency between the loci is 4%, and the associated logarithm of the odds is 5.26. Haplotype analysis using flanking restriction fragment length polymorphism markers indicates that the locus for X-linked lymphoproliferative syndrome is distal to probe DXS42 but proximal to probe DXS99 (from Xq26-q27). It is now possible to predictmore » which members of a family with X-linked lymphoproliferative syndrome are carrier females and to diagnose the syndrome prenatally.« less

Successful treatment of lymphoproliferative disease complicating primary immunodeficiency/immunodysregulatory disorders with reduced-intensity allogeneic stem-cell transplantation.

PubMed

Cohen, Jonathan M; Sebire, Neil J; Harvey, Julia; Gaspar, H Bobby; Cathy, Cale; Jones, Alison; Rao, Kanchan; Cubitt, David; Amrolia, Persis J; Davies, E Graham; Veys, Paul

2007-09-15

Lymphoproliferative disease (LPD) is a recognized complication of primary immunodeficiency (PID) and immunodysregulatory syndromes. Historically, it has a very poor outcome. For patients surviving LPD, myeloablative hematopoietic stem cell transplantation (SCT) was the only cure for the underlying PID, with a high risk of developing posttransplantation complications, including recurrent lymphoproliferative disease. We describe 8 patients with a range of PID and immunodysregulatory syndromes complicated by LPD. After initial treatment of the LPD (including the use of anti-CD20 monoclonal antibody, rituximab, in 6 of the patients), all patients underwent reduced-intensity conditioning (RIC) SCT with prospective monitoring for Epstein-Barr virus (EBV) viremia. After transplantation, 3 patients received rituximab, and 3 patients received prophylactic EBV-specific cytotoxic T-lymphocytes. Only 1 patient developed recurrent LPD posttransplantation, which responded to rituximab. All patients who underwent transplantation survive free of LPD and are cured of their PID at a median follow-up of 4 years (range, 1-7 years). With careful monitoring and pre-emptive therapy, we advocate this RIC SCT approach to patients with PID who have pre-existing EBV-LPD.

Increased Risk of Post-Transplant Malignancy and Mortality in Transplant Tourists

PubMed Central

Chung, Mu-Chi; Wu, Ming-Ju; Chang, Chao-Hsiang; Muo, Chih-Hsin; Yu, Tung-Min; Ho, Hao-Chung; Shu, Kuo-Hsiung; Chung, Chi-Jung

2014-01-01

Abstract Information on post-transplant malignancy and mortality risk in kidney transplant tourists remains controversial and is an important concern. The present study aimed to evaluate the incidence of post-transplant malignancy and mortality risk between tourists and domestic transplant recipients using the claims data from Taiwan's universal health insurance. A retrospective study was performed on 2394 tourists and 1956 domestic recipients. Post-transplant malignancy and mortality were defined from the catastrophic illness patient registry by using the International Classification of Diseases, 9th Revision. Cox proportional hazard regression and Kaplan–Meier curves were used for the analyses. The incidence for post-transplant de novo malignancy in the tourist group was 1.8-fold higher than that of the domestic group (21.8 vs 12.1 per 1000 person-years). The overall cancer recurrence rate was approximately 11%. The top 3 post-transplant malignancies, in decreasing order, were urinary tract, kidney, and liver cancers, regardless of the recipient type. Compared with domestic recipients, there was significant higher mortality risk in transplant tourists (adjusted hazard ratio = 1.2, 95% confidence interval: 1.0–1.5). In addition, those with either pre-transplant or post-transplant malignancies were associated with increased mortality risk. We suggest that a sufficient waiting period for patients with pre-transplant malignancies should be better emphasized to eliminate recurrence, and transplant tourists should be discouraged because of the possibility of higher post-transplant de novo malignancy occurrence and mortality. PMID:25546686

Cutaneous EBV-related lymphoproliferative disorders.

PubMed

Gru, Alejandro A; Jaffe, Elaine S

2017-01-01

This article will focus on the cutaneous lymphoproliferative disorders associated with EBV, with an emphasis on the upcoming changes in the revised 4th Edition of the WHO classification of tumors of the hematopoietic system, many of which deal with cutaneous disorders derived from NK-cells or T-cells. Extranodal NK/T-cell lymphoma usually presents in the upper aerodigestive tract, but can involve the skin secondarily. EBV-associated T- and NK-cell lymphoproliferative disorders (LPD) in the pediatric age group include the systemic diseases, chronic active EBV infection (CAEBV) and systemic EBV+ T-cell lymphoma of childhood. Hydroa vacciniforme (HV)-like LPD is a primarily cutaneous form of CAEBV and encompasses the lesions previously referred to as HV and HV-like lymphoma (HVLL). All the T/NK-cell-EBV-associated diseases occur with higher frequency in Asians, and indigenous populations from Central and South America and Mexico. Among the B-cell EBV-associated LPD two major changes have been introduced in the WHO. The previously designated EBV-positive diffuse large B-cell lymphoma (EBV-DLBCL) of the elderly, has been changed to EBV-DLBCL with 'not otherwise specified' as a modifier (NOS). A new addition to the WHO system is the more recently identified EBV+ mucocutaneous ulcer, which involves skin and mucosal-associated sites. Copyright © 2017 Elsevier Inc. All rights reserved.

Favorable outcome of Epstein-Barr virus-associated B-cell lymphoproliferative disorder complicated by immunoglobulin G4-related disease treated with rituximab-based therapy: a case report.

PubMed

Ueda, Koki; Ikeda, Kazuhiko; Ogawa, Kazuei; Sukegawa, Masumi; Sano, Takahiro; Kimura, Satoshi; Suzuki, Osamu; Hashimoto, Yuko; Takeishi, Yasuchika

2016-08-24

After acute infection of Epstein-Barr virus, Epstein-Barr virus-infected B cells survive but usually do not show clonal proliferation. However, Epstein-Barr virus-infected B cells occasionally acquire a proliferative capacity that provokes clonal lymphoproliferative disorders. We herein present a case with Epstein-Barr virus-infected CD30+ B cell and immunoglobulin G4+ plasmacytoid cell proliferation in the lymph nodes, suggesting a pathological and clinical interaction between Epstein-Barr virus-associated B-cell lymphoproliferative disorders and immunoglobulin G4-related disease. Immunoglobulin G4-related disease has been recognized as a benign disease with proliferation of IgG4-related disease+ plasmacytoid cells. Several studies have recently reported the coexistence of immunoglobulin G4-related disease+ plasmacytoid cells with Epstein-Barr virus-infected B cells in lymph nodes in some immunoglobulin G4-related disease cases. However, the pathogenic role of the clonal proliferation of Epstein-Barr virus-infected B cells in immunoglobulin G4-related disease, as well as the treatments for patients with both Epstein-Barr virus-infected B cells and immunoglobulin G4-related disease, have never been discussed. A 50-year-old Japanese man was referred to us for persistent fatigue and lymphadenopathy. His blood examination showed elevated IgG4, and detected high levels of Epstein-Barr virus DNA. A lymph node biopsy revealed IgG4+ plasmacytoid cells and infiltration of large lymphoid cells, which were positive for CD20, CD30, Epstein-Barr virus-related late membrane protein 1, and Epstein-Barr virus-encoded RNA, and were negative for IgG4. Based on the diagnosis of both Epstein-Barr virus-associated B-cell lymphoproliferative disorder and IgG4-related disease, the patient received eight cycles of rituximab combined with cyclophosphamide and prednisolone, which resulted in the complete disappearance of lymphadenopathy. Moreover, his serum IgG4 level was significantly

Epstein-Barr Virus–Associated Lymphoproliferative Disorders: Review and Update on 2016 WHO Classification

PubMed Central

Kim, Hyun-Jung; Ko, Young Hyeh; Kim, Ji Eun; Lee, Seung-Sook; Lee, Hyekyung; Park, Gyeongsin; Paik, Jin Ho; Cha, Hee Jeong; Choi, Yoo-Duk; Han, Jae Ho; Huh, Jooryung

2017-01-01

Epstein-Barr virus (human herpesvirus-4) is very common virus that can be detected in more than 95% of the human population. Most people are asymptomatic and live their entire lives in a chronically infected state (IgG positive). However, in some populations, the Epstein-Barr virus (EBV) has been involved in the occurrence of a wide range of B-cell lymphoproliferative disorders (LPDs), including Burkitt lymphoma, classic Hodgkin’s lymphoma, and immune–deficiency associated LPDs (post-transplant and human immunodeficiency virus–associated LPDs). T-cell LPDs have been reported to be associated with EBV with a subset of peripheral T-cell lymphomas, angioimmunoblastic T-cell lymphomas, extranodal nasal natural killer/T-cell lymphomas, and other rare histotypes. This article reviews the current evidence covering EBV-associated LPDs based on the 2016 classification of the World Health Organization. These LPD entities often pose diagnostic challenges, both clinically and pathologically, so it is important to understand their unique pathophysiology for correct diagnoses and optimal management. PMID:28592786

Immune-mediated neuropathy with Epstein-Barr virus-positive T-cell lymphoproliferative disease.

PubMed

Hattori, Takaaki; Arai, Ayako; Yokota, Takanori; Imadome, Ken-Ichi; Tomimitsu, Hiroyuki; Miura, Osamu; Mizusawa, Hidehiro

2015-01-01

A 47-year-old man with Epstein-Barr virus (EBV)-positive T/NK- cell lymphoproliferative disease (EBV-T/NK-LPD) developed acute-onset weakness. A nerve conduction study showed a conduction block in both the proximal and most distal segments. Although the patient's neuropathy transiently responded to intravenous immunoglobulin, it was progressive for at least 25 days until the start of prednisolone (PSL) administration, after which it remarkably improved. The neuropathy further improved after allogeneic bone marrow transplantation (BMT). The present patient's clinical course is not consistent with that of typical Guillain-Barré syndrome. This case suggests that EBV-T/NK-LPD can cause progressive immune-mediated neuropathy as a result of chronic EBV antigen presentation and can be treated with PSL and BMT.

Epstein-Barr virus in inflammatory bowel disease: the spectrum of intestinal lymphoproliferative disorders.

PubMed

Nissen, Loes H C; Nagtegaal, Iris D; de Jong, Dirk J; Kievit, Wietske; Derikx, Lauranne A A P; Groenen, Patricia J T A; van Krieken, J Han J M; Hoentjen, Frank

2015-05-01

Inflammatory bowel disease (IBD) patients on thiopurine therapy are at increased risk of Epstein-Barr virus (EBV)-associated lymphomas. This virus is frequently detected in the intestinal mucosa of IBD patients and may cause a wide spectrum of lymphoproliferations similar to post-transplantation lymphoproliferative disorders (PTLDs). We aimed to assess whether histological aberrations aid in predicting EBV presence and to correlate histological assessment and EBV load with disease outcome in IBD. We included all IBD patients from our centre who underwent EBV testing of intestinal biopsies between January 2004 and October 2013. All biopsies were classified according to the WHO PTLD classification and the EBV load was scored per high-power field (HPF). Clinical data were collected from patient charts. Reported clinical outcomes included colectomy, need for chemotherapy and mortality. Our cohort included 58 patients: 28 were EBV-positive and 30 EBV-negative. An atypical infiltrate was seen more frequently in EBV-positive than in EBV-negative patients (57.1 versus 3.3%; p < 0.001). A high EBV load occurred more frequently in EBV-positive patients undergoing colectomy than in EBV-positive patients without colectomy (50.0 versus 10.0%; p = 0.048). Monomorphic lymphoproliferative disorders, including two overt lymphomas, were present in 10 patients. Reduction of immunosuppression resulted in histological normalization and loss of EBV expression in seven of eight non-lymphoma patients. The presence of atypical infiltrate in the intestinal mucosa of IBD patients warrants EBV testing. Reduction of immunosuppression is an effective strategy to achieve morphological normalization and loss of EBV. Lymphoproliferation related to IBD appears to have less aggressive clinical behaviour than PTLDs. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Bone marrow with diffuse tumor infiltration in patients with lymphoproliferative diseases: dynamic gadolinium-enhanced MR imaging.

PubMed

Rahmouni, Alain; Montazel, Jean-Luc; Divine, Marine; Lepage, Eric; Belhadj, Karim; Gaulard, Philippe; Bouanane, Mohamed; Golli, Mondher; Kobeiter, Hicham

2003-12-01

To evaluate gadolinium enhancement of bone marrow in patients with lymphoproliferative diseases and diffuse bone marrow involvement. Dynamic contrast material-enhanced magnetic resonance (MR) imaging of the thoracolumbar spine was performed in 42 patients with histologically proved diffuse bone marrow involvement and newly diagnosed myeloma (n = 31), non-Hodgkin lymphoma (n = 8), or Hodgkin disease (n = 3). The maximum percentage of enhancement (Emax), enhancement slope, and enhancement washout were determined from enhancement time curves (ETCs). A three-grade system for scoring bone marrow involvement was based on the percentage of neoplastic cells in bone marrow samples. Quantitative ETC values for the 42 patients were compared with ETC values for healthy subjects and with grades of bone marrow involvement by using mean t test comparisons. Receiver operating characteristic (ROC) analysis was conducted by comparing Emax values between patients with and those without bone marrow involvement. Baseline and follow-up MR imaging findings were compared in nine patients. Significant differences in Emax (P <.001), slope (P <.001), and washout (P =.005) were found between subjects with normal bone marrow and patients with diffuse bone marrow involvement. ROC analysis results showed Emax values to have a diagnostic accuracy of 99%. Emax, slope, and washout values increased with increasing bone marrow involvement grade. The mean Emax increased from 339% to 737%. Contrast enhancement decreased after treatment in all six patients who responded to treatment but not in two of three patients who did not respond to treatment. Dynamic contrast-enhanced MR images can demonstrate increased bone marrow enhancement in patients with lymphoproliferative diseases and marrow involvement.

[Systemic EBV+ T-cell lymphoproliferative disease of childhood].

PubMed

Lemaire, Anne-Sophie; Daussay, Dorothée; Bouchindhomme, Brigitte; Grardel, Nathalie; Botte, Astrid; Copin, Marie-Christine

2014-08-01

Systemic EBV+ T-cell lymphoproliferative disease of childhood is a recent entity described in the 2008 World Health Organisation tumours of haematopoietic system and lymphoid tissues as a clonal T-cell EBV+ systemic proliferation. It occurs after acute or chronic active EBV infection. We report the case of a caucasian, immunocompetent 12-year-old girl, with no particular history, who presented with hemophagocytic lymphohistiocytosis in the aftermath of an infectious mononucleosis. Main symptoms were multiple organ failure, hepatosplenomegaly and pancytopenia. Histopathology of peripheral lymph node and bone marrow revealed a T-cell, CD8+, EBV+ lymphoproliferation. An elevated viral load was detected in blood by PCR. The patient died within 3 weeks. Since most of the cases have been reported in Asia and South America, few cases still have been described in Europe. Unlike B-cell lymphoproliferation in immunocompromised individuals, T-cell EBV+ lymphoproliferation occurs in immunocompetent patients and seems to be the consequence of a proliferative disorder of EBV-infected T-cells, attributed to a cytotoxic T-cell response deficiency. These T-cell proliferations are more frequently immunoreactive for CD8 than CD4. A key feature of the diagnosis might be EBV viral load. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Hemagglutination and graft-versus-host disease in the severe combined immunodeficiency mouse lymphoproliferative disease model.

PubMed Central

Pirruccello, S. J.; Nakamine, H.; Beisel, K. W.; Kleveland, K. L.; Okano, M.; Taguchi, Y.; Davis, J. R.; Mahloch, M. L.; Purtilo, D. T.

1992-01-01

In the course of evaluating the severe combined immunodeficiency mouse-human peripheral blood lymphocyte (SCID-PBL) model of lymphoproliferative disease, we noted hemagglutination occurring in peripheral blood smears of mice with serum human immunoglobulin levels greater than 1.0 mg/ml. The hemagglutinating process was mediated by human anti-mouse red cell antibodies of the IgM class, peaked at five to seven weeks post-transfer of 5 to 7 x 10(7) human PBL and was generally self limiting. However, death resulted in some mice when serum immunoglobulin levels were greater than 3.0 mg/ml. The most severely affected mice had hemagglutination induced congestion of liver, lungs and spleen. Several mice also had lesions consistent with graft-versus-host disease (GVHD) including focal hepatic necrosis and destruction of mouse splenic hematopoietic elements. The lesions associated with hemagglutination and GVHD in SCID-PBL mice are distinct from those associated with EBV-induced lymphoproliferation. Recognition of these pathologic processes are required for a thorough understanding of the SCID-PBL model. Images Figure 1 Figure 3 Figure 4 PMID:1580330

Avian oncogenesis induced by lymphoproliferative disease virus: a neglected or emerging retroviral pathogen?

PubMed Central

Allison, Andrew B.; Keel, M. Kevin; Philips, Jamie E.; Cartoceti, Andrew N.; Munk, Brandon A.; Nemeth, Nicole M.; Welsh, Trista I.; Thomas, Jesse M.; Crum, James M.; Lichtenwalner, Anne B.; Fadly, Aly M.; Zavala, Guillermo; Holmes, Edward C.; Brown, Justin D.

2014-01-01

Lymphoproliferative disease virus (LPDV) is an exogenous oncogenic retrovirus that induces lymphoid tumors in some galliform species of birds. Historically, outbreaks of LPDV have been reported from Europe and Israel. Although the virus has previously never been detected in North America, herein we describe the widespread distribution, genetic diversity, pathogenesis, and evolution of LPDV in the United States. Characterization of the provirus genome of the index LPDV case from North America demonstrated an 88% nucleotide identity to the Israeli prototype strain. Although phylogenetic analysis indicated that the majority of viruses fell into a single North American lineage, a small subset of viruses from South Carolina were most closely related to the Israeli prototype. These results suggest that LPDV was transferred between continents to initiate outbreaks of disease. However, the direction (New World to Old World or vice versa), mechanism, and time frame of the transcontinental spread currently remain unknown. PMID:24503062

Epstein-Barr virus lymphoproliferative disease after hematopoietic stem cell transplant.

PubMed

Rouce, Rayne H; Louis, Chrystal U; Heslop, Helen E

2014-11-01

Epstein-Barr virus (EBV) reactivation can cause significant morbidity and mortality after allogeneic hematopoietic stem cell transplant. Delays in reconstitution of EBV-specific T lymphocyte activity can lead to life-threatening EBV lymphoproliferative disease (EBV-PTLD). This review highlights recent advances in the understanding of pathophysiology, risk factors, diagnosis, and management of EBV viremia and PTLD. During the past decade, early detection strategies, such as serial measurement of EBV-DNA load, have helped identify high-risk patients and diagnose early lymphoproliferation. The most significant advances have come in the form of innovative treatment options, including manipulation of the balance between outgrowing EBV-infected B cells and the EBV cytotoxic T lymphocyte response, and targeting infected B cells with monoclonal antibodies, chemotherapy, unmanipulated donor lymphocytes, and donor or more recently third-party EBV cytotoxic T lymphocytes. Defining criteria for preemptive therapy remains a challenge. EBV reactivation is a significant complication after stem cell transplant. Continued improvements in risk stratification and treatment options are required to improve the morbidity and mortality caused by EBV-associated diseases. Current approaches use rituximab to deplete B cells or adoptive transfer of EBV cytotoxic T lymphocyte to reconstitute immunity. The availability of rapid EBV-specific T cell products offers the possibility of improved outcomes.

Avian oncogenesis induced by lymphoproliferative disease virus: a neglected or emerging retroviral pathogen?

PubMed

Allison, Andrew B; Kevin Keel, M; Philips, Jamie E; Cartoceti, Andrew N; Munk, Brandon A; Nemeth, Nicole M; Welsh, Trista I; Thomas, Jesse M; Crum, James M; Lichtenwalner, Anne B; Fadly, Aly M; Zavala, Guillermo; Holmes, Edward C; Brown, Justin D

2014-02-01

Lymphoproliferative disease virus (LPDV) is an exogenous oncogenic retrovirus that induces lymphoid tumors in some galliform species of birds. Historically, outbreaks of LPDV have been reported from Europe and Israel. Although the virus has previously never been detected in North America, herein we describe the widespread distribution, genetic diversity, pathogenesis, and evolution of LPDV in the United States. Characterization of the provirus genome of the index LPDV case from North America demonstrated an 88% nucleotide identity to the Israeli prototype strain. Although phylogenetic analysis indicated that the majority of viruses fell into a single North American lineage, a small subset of viruses from South Carolina were most closely related to the Israeli prototype. These results suggest that LPDV was transferred between continents to initiate outbreaks of disease. However, the direction (New World to Old World or vice versa), mechanism, and time frame of the transcontinental spread currently remain unknown. © 2013 Published by Elsevier Inc.

Isolated post-transplantation lymphoproliferative disease involving the breast and axilla as peripheral T-cell lymphoma.

PubMed

Hwang, Ji-Young; Cha, Eun Suk; Lee, Jee Eun; Sung, Sun Hee

2013-01-01

Post-transplantation lymphoproliferative disorders (PTLDs) are a heterogeneous group of diseases that represent serious complications following immunosuppressive therapy for solid organ or hematopoietic-cell recipients. In contrast to B-cell PTLD, T-cell PTLD is less frequent and is not usually associated with Epstein Barr Virus infection. Moreover, to our knowledge, isolated T-cell PTLD involving the breast is extremely rare and this condition has never been reported previously in the literature. Herein, we report a rare case of isolated T-cell PTLD of the breast that occurred after a patient had been treated for allogeneic peripheral blood stem cell transplantation due to acute myeloblastic leukemia.

T-cell replete haploidentical donor transplantation using post-transplant CY: an emerging standard-of-care option for patients who lack an HLA-identical sibling donor.

PubMed

Bashey, A; Solomon, S R

2014-08-01

Availability of an HLA-identical sibling (MRD) or suitably matched unrelated donor (MUD) has historically been a limiting factor in the application of allogeneic hematopoietic transplantation. Although almost all patients have an HLA-haploidentical family donor, prior attempts at transplantation from such donors using T-cell replete grafts and conventional immunosuppression were associated with unacceptable rates of GVHD, and when stringent ex vivo T-cell depletion was used to control GVHD, rates of graft rejection and post-transplant infections were prohibitive. The recent approach to HLA-haploidentical donor transplantation developed in Baltimore that uses T-cell replete grafts and post-transplant CY (Haplo-post-HCT-CY) to control post-transplant allo-reactivity appears to have overcome many of the obstacles historically associated with haploidentical donor transplantation. In particular, TRM rates of <10% are usual and rapid reconstitution of immunity leads to a low rate of post-transplant infections and no post-tranplant lymphoproliferative disorders (PTLD), consistent with the hypothesis that post-transplant CY selectively depletes proliferating alloreactive T cells responsible for GVHD and graft rejection while preserving resting memory T cells essential for post-transplant immunologic recovery. In parallel trials using similar non-myeloablative conditioning regimens, Haplo-post-HCT-CY produced similar overall survival to double umbilical cord blood transplantation(DUCBT) in adult patients (62% vs 54%), with low rates of TRM (7% vs 24%), severe acute GVHD (0% vs 21%) and chronic GVHD (13% vs 25%). Furthermore, recent non-randomized comparisons adjusted for risk factors show that Haplo-post-HCT-CY achieve at least equivalent outcomes to conventional MRD and MUD transplants. Although most experience has been obtained using BM, emerging data suggest that a G-CSF mobilized PBSC graft can also safely be used for Haplo-post-HCT-CY. Haplo-post-HCT-CY also avoids the

Posttransplantation lymphoproliferative disease involving the pituitary gland.

PubMed

Meriden, Zina; Bullock, Grant C; Bagg, Adam; Bonatti, Hugo; Cousar, John B; Lopes, M Beatriz; Robbins, Mark K; Cathro, Helen P

2010-11-01

Posttransplantation lymphoproliferative disorders (PTLD) are heterogeneous lesions with variable morphology, immunophenotype, and molecular characteristics. Multiple distinct primary lesions can occur in PTLD, rarely with both B-cell and T-cell characteristics. Lesions can involve both grafted organs and other sites; however, PTLD involving the pituitary gland has not been previously reported. We describe a patient who developed Epstein-Barr virus-negative PTLD 13 years posttransplantation involving the terminal ileum and pituitary, which was simultaneously involved by a pituitary adenoma. Immunohistochemistry of the pituitary lesion showed expression of CD79a, CD3, and CD7 with clonal rearrangements of both T-cell receptor gamma chain (TRG@) and immunoglobulin heavy chain (IGH@) genes. The terminal ileal lesion was immunophenotypically and molecularly distinct. This is the first report of pituitary PTLD and illustrates the potentially complex nature of PTLD. Copyright © 2010 Elsevier Inc. All rights reserved.

Staged Hand-Assisted Bilateral Native Nephrectomy for Management of Posttransplant Polyuria in an Adult with Dent's Disease

PubMed Central

Montero, Rosa M.; Olsburgh, Jonathon

2015-01-01

Polyuria after kidney transplantation causes graft dysfunction and increased thrombotic risk. We present a case of a polyuric adult with Dent's disease who underwent staged bilateral native nephrectomies, the first operation before transplant and the second four months after transplant. This led to improved allograft function maintained during four years of follow-up. The retroperitoneal laparoscopic approach was well tolerated and allowed continuation of peritoneal dialysis before transplantation. A staged approach helps regulate fluid balance perioperatively and may be tailored to individual need according to posttransplant urine output. This novel approach should be considered for polyuric patients with tubular dysfunction including Dent's disease. PMID:25649339

CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA.

PubMed Central

Kawa-Ha, K; Ishihara, S; Ninomiya, T; Yumura-Yagi, K; Hara, J; Murayama, F; Tawa, A; Hirai, K

1989-01-01

Lymphoproliferative disease of granular lymphocytes (LDGL) is a heterogeneous disorder and the pathogenesis is likely to be complex. Some patients with chronic active EBV (CAEBV) infection also have LDGL. To investigate the relationship between EBV infection and the pathogenesis of LDGL, we conducted a survey for EBV DNA sequences by Southern blot analysis of DNA obtained from the peripheral blood of seven patients with LDGL, including one with CAEBV infection. Interestingly, EBV DNA was detected in the sample from the patient with CAEBV infection, and in the samples from four other patients with CD3-LDGL. Moreover, a single band for the joined termini of the EBV genome was demonstrated in two samples, suggesting a clonal disorder of those LDGL. These findings strongly suggest that EBV may play a pathogenic role in some cases of LDGL. Images PMID:2544630

CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA.

PubMed

Kawa-Ha, K; Ishihara, S; Ninomiya, T; Yumura-Yagi, K; Hara, J; Murayama, F; Tawa, A; Hirai, K

1989-07-01

Lymphoproliferative disease of granular lymphocytes (LDGL) is a heterogeneous disorder and the pathogenesis is likely to be complex. Some patients with chronic active EBV (CAEBV) infection also have LDGL. To investigate the relationship between EBV infection and the pathogenesis of LDGL, we conducted a survey for EBV DNA sequences by Southern blot analysis of DNA obtained from the peripheral blood of seven patients with LDGL, including one with CAEBV infection. Interestingly, EBV DNA was detected in the sample from the patient with CAEBV infection, and in the samples from four other patients with CD3-LDGL. Moreover, a single band for the joined termini of the EBV genome was demonstrated in two samples, suggesting a clonal disorder of those LDGL. These findings strongly suggest that EBV may play a pathogenic role in some cases of LDGL.

Autoimmune lymphoproliferative syndrome mimicking chronic active Epstein-Barr virus infection.

PubMed

Nomura, Keiko; Kanegane, Hirokazu; Otsubo, Keisuke; Wakiguchi, Hiroshi; Noda, Yukihiro; Kasahara, Yoshihito; Miyawaki, Toshio

2011-06-01

Chronic active Epstein-Barr virus infection (CAEBV) is defined as a systemic EBV-associated lymphoproliferative disease characterized by fever, lymphadenopathy, and splenomegaly in apparently immunocompetent persons. Recent studies have revealed that EBV infects T or natural killer cells in most patients with CAEBV; the etiology of CAEBV, however, remains unknown. Autoimmune lymphoproliferative disorder (ALPS) is an inherited disorder associated with defects in apoptosis, and clinically characterized by lymphadenopathy, splenomegaly, hypergammaglobulinemia, and autoimmune disease. ALPS is most often associated with mutations in the FAS gene, which is an apoptosis-signaling receptor important for homeostasis of the immune system. Based on the clinical similarity between ALPS and CAEBV with respect to lymphoproliferation, we have examined the possibility of the co-occurrence of ALPS in patients with a diagnosis of CAEBV. In this study, we have identified FAS gene mutations in three Japanese patients with lymphadenopathy, hepatosplenomegaly, and unusual EBV infection, who were diagnosed with CAEBV. These observations, which indicate that the clinical development of ALPS may be associated with EBV infection, alert us to a potential diagnostic pitfall of CAEBV.

Droplet Digital PCR for Minimal Residual Disease Detection in Mature Lymphoproliferative Disorders.

PubMed

Drandi, Daniela; Ferrero, Simone; Ladetto, Marco

2018-01-01

Minimal residual disease (MRD) detection has a powerful prognostic relevance for response evaluation and prediction of relapse in hematological malignancies. Real-time quantitative PCR (qPCR) has become the settled and standardized method for MRD assessment in lymphoid disorders. However, qPCR is a relative quantification approach, since it requires a reference standard curve. Droplet digital TM PCR (ddPCR TM ) allows a reliable absolute tumor burden quantification withdrawing the need for preparing, for each experiment, a tumor-specific standard curve. We have recently shown that ddPCR has a good concordance with qPCR and could be a feasible and reliable tool for MRD monitoring in mature lymphoproliferative disorders. In this chapter we describe the experimental workflow, from the detection of the clonal molecular marker to the MRD monitoring by ddPCR, in patients affected by multiple myeloma, mantle cell lymphoma and follicular lymphoma. However, standardization programs among different laboratories are needed in order to ensure the reliability and reproducibility of ddPCR-based MRD results.

Liver alone or simultaneous liver-kidney transplant? Pretransplant chronic kidney disease and post-transplant outcome - a retrospective study.

PubMed

Nagai, Shunji; Safwan, Mohamed; Collins, Kelly; Schilke, Randolph E; Rizzari, Michael; Moonka, Dilip; Brown, Kimberly; Patel, Anita; Yoshida, Atsushi; Abouljoud, Marwan

2018-05-02

The new Organ Procurement and Transplant Network/United Organ Sharing Network (OPTN/UNOS) simultaneous liver-kidney transplant (SLK) policy has been implemented. The aim of this study was to review liver transplant outcomes utilizing the new SLK policy. Liver transplant alone (LTA) and SLK patients between 2009 and 2015 were reviewed. Graft survival and post-transplant kidney function were investigated among LTA patients meeting the chronic kidney disease (CKD) criteria of the new policy (LTA-CKD group). To validate our findings, we reviewed and applied our analysis to the OPTN/UNOS registry. A total of 535 patients were eligible from our series. The LTA-CKD group (n = 27) showed worse 1-year graft survival, compared with the SLK group (n = 44), but not significant (81% vs. 93%, P = 0.15). The LTA-CKD group significantly increased a risk of post-transplant dialysis (odds ratio = 5.59 [95% CI = 1.27-24.7], P = 0.02 [Ref. normal kidney function]). Post-transplant dialysis was an independent risk factor for graft loss (hazard ratio = 7.25, 95% CI = 3.3-15.91, P < 0.001 [Ref. SLK]). In the validation analysis based on the OPTN/UNOS registry, the hazard of 1-year-graft loss in the LTA-CKD group (n = 751) was 34.8% higher than the SLK group (n = 2856) (hazard ratio = 1.348, 95% CI = 1.157-1.572, P < 0.001). Indicating SLK for patients who meet the CKD criteria may significantly improve transplant outcomes. © 2018 Steunstichting ESOT.

Activated phosphoinositide 3-kinase δ syndrome presenting with gut-associated T-cell lymphoproliferative disease.

PubMed

Teranishi, Hideto; Ishimura, Masataka; Koga, Yuuki; Eguchi, Katsuhide; Sonoda, Motoshi; Kobayashi, Tetsuko; Shiraishi, Satoru; Nakashima, Kentaro; Ikegami, Kouji; Aman, Murasaki; Yamamoto, Hidetaka; Takada, Hidetoshi; Ohga, Shouichi

2017-01-01

A 13-year-old boy was admitted to our hospital because of persistent diarrhea, abdominal pain, and bloody stools. The patient had experienced repeated hospitalizations for the treatment of respiratory infections since early childhood. Colonoscopic and pathological studies led to a diagnosis of gut-associated T-cell lymphoproliferative disease (T-cell LPD). Laboratory data showed T-lymphocytopenia (492/µl), increased serum IgG levels (1,984 mg/dl), and low serum antibody titers for specific pathogens. Combined immunodeficiency accompanied by T-LPD suggested the diagnosis of activated PI3Kδ syndrome (APDS). Genetic analyses identified a heterozygous mutation of the PIK3CD gene (c.1573 G to A p.Glu525Lys). Although prednisolone and cyclosporine therapy has controlled the T-cell LPD, this patient awaits allogeneic hematopoietic cell transplantation to achieve a complete cure of his APDS.

Lymphoproliferative lung disorders: a radiologic-pathologic overview. Part II: Neoplastic disorders.

PubMed

Restrepo, Carlos S; Carrillo, Jorge; Rosado de Christenson, Melissa; Ojeda Leon, Paulina; Lucia Rivera, Aura; Koss, Micheal N

2013-12-01

Lymphoproliferative pulmonary neoplasms can occur as primary pulmonary lymphomas or because of secondary pulmonary involvement. Neoplastic disorders may be difficult to differentiate from reactive pulmonary lymphoproliferative disorders, and immunohistochemical evaluation is often required to differentiate the 2 types of lesions. Neoplastic lymphoproliferative disorders are monoclonal lesions. Most affected patients present with systemic complaints, and imaging findings typically include nodules, masses, and lymphadenopathy. Primary pulmonary lymphomas are rare and account for less than 4% of the lymphomas that arise in extranodal sites. Secondary pulmonary lymphomas can affect the lung via hematogenous dissemination or by secondary involvement from tumor in adjacent or contiguous sites. Neoplastic lymphoproliferative lesions also include leukemia and plasma cell neoplasms. Posttransplantation lymphoproliferative disorders constitute a special type of lymphoid proliferation occurring in the setting of the chronic immunosuppression required for solid organ and bone marrow transplantation. Copyright © 2013 Elsevier Inc. All rights reserved.

EBV-Positive T/NK-Cell Lymphoproliferative Disease of Childhood

PubMed Central

Hong, Mineui; Yoo, Keon Hee; Koo, Hong Hoe; Kim, Seok Jin; Kim, Won Seog

2013-01-01

Background Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), EBV-positive systemic T-cell lymphoproliferative disease (STLPD) of childhood, and chronic active EBV (CAEBV) infection may develop after primary EBV infection. This study reviewed the clinicopathological spectrum of EBV-associated T- and natural killer (NK)-cell LPD, including STLPD and CAEBV infection, with an analysis of T-cell clonality. Methods Clinicopathological features of seven patients with EBV-associated HLH or STLPD and 12 patients with CAEBV infection were reviewed. Immunohistochemical staining and a T-cell receptor (TCR) gene rearrangement study were performed. Results STLPD and EBV-positive HLH showed significantly overlapping clinicopathological findings. One patient with STLPD and one patient with EBV-positive HLH demonstrated moderate to severe atypia of the infiltrating lymphocytes, whereas the remaining patients lacked significant atypia. Twelve patients had CAEBV infection, four of whom suffered mosquito-bite hypersensitivity, five showed NK lymphocytosis, and one suffered hydroa vacciniforme. Infiltrating lymphocytes were predominantly small and devoid of atypia. Hemophagocytic histiocytosis was found in seven of 11 patients. Monoclonality was detected in three (50%) of the six patients with successful TCR gene analysis. Conclusions EBV-positive HLH and STLPD share similar clinicopathological findings and may constitute a continuous spectrum of acute EBV-associated T- or NK-cell proliferative disorders. The distinction of EBV-positive T-cell LPD from EBV-positive HLH may be difficult during routine diagnoses because of the technical limitations of clonality assessment. PMID:23667373

EBV-Positive T/NK-Cell Lymphoproliferative Disease of Childhood.

PubMed

Hong, Mineui; Ko, Young Hyeh; Yoo, Keon Hee; Koo, Hong Hoe; Kim, Seok Jin; Kim, Won Seog; Park, Heejung

2013-04-01

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), EBV-positive systemic T-cell lymphoproliferative disease (STLPD) of childhood, and chronic active EBV (CAEBV) infection may develop after primary EBV infection. This study reviewed the clinicopathological spectrum of EBV-associated T- and natural killer (NK)-cell LPD, including STLPD and CAEBV infection, with an analysis of T-cell clonality. Clinicopathological features of seven patients with EBV-associated HLH or STLPD and 12 patients with CAEBV infection were reviewed. Immunohistochemical staining and a T-cell receptor (TCR) gene rearrangement study were performed. STLPD and EBV-positive HLH showed significantly overlapping clinicopathological findings. One patient with STLPD and one patient with EBV-positive HLH demonstrated moderate to severe atypia of the infiltrating lymphocytes, whereas the remaining patients lacked significant atypia. Twelve patients had CAEBV infection, four of whom suffered mosquito-bite hypersensitivity, five showed NK lymphocytosis, and one suffered hydroa vacciniforme. Infiltrating lymphocytes were predominantly small and devoid of atypia. Hemophagocytic histiocytosis was found in seven of 11 patients. Monoclonality was detected in three (50%) of the six patients with successful TCR gene analysis. EBV-positive HLH and STLPD share similar clinicopathological findings and may constitute a continuous spectrum of acute EBV-associated T- or NK-cell proliferative disorders. The distinction of EBV-positive T-cell LPD from EBV-positive HLH may be difficult during routine diagnoses because of the technical limitations of clonality assessment.

[Lymphocytic Clonal Expansion in Adult Patients with Epstein-Barr Virus-Associated Lymphoproliferative Disease].

PubMed

Zhong, Feng-Luan; Zhang, Hong-Yu; Zhang, Qian; Feng, Jia; Zhang, Wen-Li; Xu, Lei; Xu, Hai-Chan; Wen, Juan-Juan; Meng, Qing-Xiang

2017-12-01

To explore the lymphocytic clonal expansion in adult patients with Epstein-Barr virus-associated lymphoproliferative diseases (EBV+LPD), and to investigate the experimental methods for EBV+LPD cells so as to provide a more objective measure for the diagnosis, classification and prognosis in the early stage of this disease. Peripheral blood samples from 5 patients with EBV+LPD, 4 patients with adult infectious mononucleosis(IM) as negative control and 3 patients with acute NK-cell leukemia(ANKL) as positive control were collected. Prior to immunochemotherapy, viral loads and clonality were analysed by flow cytometry (FCM), T cell receptor gene rearrangement (TCR) was detected by real-time polymerase chain reaction (RT-PCR), and diversity of EB virus terminal repeat (EBV-TR) was detected by Southern blot. FCM showed only 1 case with clonal TCRVβ in 5 patients with EBV+LPD, TCR clonal expansion could be detected both in patients with IM(4 of 4) and 4 patients with EBV+LPD(4 of 5), Out of patients with EBV+LPD, 1 patient displayed a monoclonal band and 2 patients showed oligoclonal bands when detecting EBV-TR by southen blot. Detecting the diversity of EBV-TR by Southern blot may be the most objective way to reflex clonal transformation of EBV+LPD, which is of great benefit to the diagnosis, classification and prognosis in the early stage of this disease.

Predicting Post-transplant Recurrence of IgA Nephropathy: The Importance of Crescents

PubMed Central

Avasare, Rupali S.; Rosenstiel, Paul E.; Zaky, Ziad S.; Tsapepas, Demetra; Appel, Gerald B.; Markowitz, Glen S.; Bomback, Andrew S.; Canetta, Pietro A.

2017-01-01

Background Most studies assessing the predictors of recurrent IgA nephropathy in the renal allograft have focused on post-transplant features. Identifying high risk pre-transplant features of IgA nephropathy is useful for counseling patients and may help tailor immunosuppression post-transplant. Methods We investigated the pre-transplant clinical and biopsy features of 62 patients with IgAN who received transplants at Columbia University Medical Center from 2001 to 2012 and compared the characteristics and outcomes of patients with IgAN recurrence to those without recurrence. The primary outcome was time to recurrent IgAN. Secondary outcomes were a composite of doubling of creatinine or allograft failure, and recurrent IgAN as a cause of allograft dysfunction. Results Of the 62 patients, 14 had recurrent IgAN in the allograft. Mean time to recurrence was 2.75 years. Those with recurrent disease were younger at time of native kidney biopsy (29 years vs. 41 years, P < 0.0009). Black race and Hispanic ethnicity composed a higher proportion of the recurrent disease group. On multivariable analysis, significant predictors of recurrent IgAN included age at diagnosis (HR 0.911, 95% CI 0.85 to 0.98), burden of crescents on native biopsy (HR 1.21 per 10% increase in crescents, 95% CI 1.00 to 1.47), and allograft rejection (HR 3.59, 95% CI 1.10 to 11.7) Conclusions Features of native IgAN can help predict the risk of recurrent disease in the renal allograft. In particular, immunologically active disease represented by earlier age of onset and greater burden of crescents on native biopsy is more likely to recur post-transplant. PMID:28056461

Expression of CD43 in chronic lymphoproliferative leukemias.

PubMed

Sorigue, Marc; Juncà, Jordi; Sarrate, Edurne; Grau, Javier

2018-01-01

CD43 has been used on histological samples for the differential diagnosis of lymphoproliferative disorders but there is scarce data on its use by flow cytometry (FC). We set out to characterize the expression of CD43 by FC in B-cell lymphoproliferative disorders and to determine its possible role in the differential diagnosis of these malignancies. We analyzed the expression of CD43 in clonal B-cell lymphoproliferative disorders with exclusive peripheral blood and/or bone marrow involvement based on their Moreau chronic lymphocytic leukemia (CLL) score with particular emphasis on Moreau CLL score 3 (MS3) cases, which often present a diagnostic challenge. The cohort included 433 CLL (score 4-5), 34 MS3 and 166 lymphoproliferative disorders with lower scores. Generally, the higher the Moreau CLL score, the higher CD43-positivity (425/443 [96%] for CLL, 23/34 [67%] for MS3 and 18/166 [11%] for cases with lower scores). MS3 cases constituted 5.4% of all cases and were more frequently CD5, CD200, CD43-positive and had del(q13) than score 0-2 cases. Among MS3 cases, del(13q) cases were predominantly CD43-positive (12/13). The frequency of CD43-positivity increases sharply with the Moreau score. MS3 cases seem to include both CLL and non-CLL lymphoproliferative disorders and CD43 could aid in the differential diagnosis between the two. However, studies analyzing the correlation between CD43 expression and the underlying biologic changes of these cases are warranted. © 2017 International Clinical Cytometry Society. © 2017 International Clinical Cytometry Society.

The Impact of Donor Viral Replication at Transplant on Recipient Infections Posttransplant: A Prospective Study

PubMed Central

Verghese, Priya S.; Schmeling, David O.; Knight, Jennifer A.; Matas, Arthur J.; Balfour, Henry H.

2014-01-01

Background Organ donors are often implicated as the source of posttransplant recipient infection. We prospectively studied kidney and liver donor-recipient pairs to determine if donor viral replication of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and BK polyomavirus (BKV) at transplant was a risk factor for posttransplant recipient infection and disease. Methods Donors and recipients were studied for antibodies against CMV and EBV and for quantitative viral replication of CMV, EBV and BKV in oral washes, urine, and whole blood pretransplant. Recipient testing continued every 3 months posttransplant. Demographic and clinical data on infections and graft and subject outcomes were obtained. Results The 98 donor-recipient pairs included 15 liver and 83 kidney transplants (18 of whom were children). No donor had detectable CMV replication; therefore its impact on recipient CMV replication could not be analyzed. Donor EBV replication occurred in 22%, mostly in the oral wash and had no impact on posttransplant recipient EBV replication (p 0.9) or EBV viremia (p 0.6) in kidney or liver recipients. Donor BKV replication occurred in 17%, mostly in the urine and although not associated with posttransplant recipient urinary BKV replication in recipients, it was associated with BKV viremia (p 0.02), and a significantly shorter time to BKV viremia (p 0.01) in kidney recipients. Conclusion Donor replication of CMV or EBV did not impact posttransplant recipient viral replication in kidney/liver transplants. Donor urinary BKV replication is associated with recipient BKV viremia in kidney transplants. PMID:25148381

Using OCT to predict post-transplant renal function

NASA Astrophysics Data System (ADS)

Andrews, Peter M.; Chen, Yu; Wierwille, Jeremiah; Joh, Daniel; Alexandrov, Peter; Rogalsky, Derek; Moody, Patrick; Chen, Allen; Cooper, Matthew; Verbesey, Jennifer E.; Gong, Wei; Wang, Hsing-Wen

2013-03-01

The treatment of choice for patients with end-stage renal disease is kidney transplantation. However, acute tubular necrosis (ATN) induced by an ischemic insult (e.g., from prolonged ex vivo storage times, or non-heart beating cadavers) is a major factor limiting the availability of donor kidneys. In addition, ischemic induced ATN is a significant risk factor for eventual graft survival and can be difficult to discern from rejection. Currently, there are no rapid and reliable tests to determine ATN suffered by donor kidneys and whether or not donor kidneys might exhibit delayed graft function. OCT (optical coherence tomography) is a rapidly emerging imaging modality that can function as a type of "optical biopsy", providing cross-sectional images of tissue morphology in situ and in real-time. In a series of recent clinical trials, we evaluated the ability of OCT to image those features of the renal microstructure that are predictive of ATN. Specifically, we found that OCT could effectively image through the intact human renal capsule and determine the extent of acute tubular necrosis. We also found that Doppler based OCT (i.e., DOCT) revealed renal blood flow dynamics that is also reported to be a determiner of post-transplant renal function. This kind of information will allow transplant surgeons to make the most efficient use of available donor kidneys, eliminate the possible use of bad donor kidneys, provide a measure of expected post-transplant renal function, and allow better distinction between post-transplant immunological rejection and ischemic-induced acute renal failure.

Initial Steroid Sensitivity in Children with Steroid-Resistant Nephrotic Syndrome Predicts Post-Transplant Recurrence

PubMed Central

Ding, Wen Y.; Koziell, Ania; McCarthy, Hugh J.; Bierzynska, Agnieszka; Bhagavatula, Murali K.; Dudley, Jan A.; Inward, Carol D.; Coward, Richard J.; Tizard, Jane; Reid, Christopher; Antignac, Corinne; Boyer, Olivia

2014-01-01

Of children with idiopathic nephrotic syndrome, 10%–20% fail to respond to steroids or develop secondary steroid resistance (termed initial steroid sensitivity) and the majority progress to transplantation. Although 30%–50% of these patients suffer disease recurrence after transplantation, with poor long-term outcome, no reliable indicator of recurrence has yet been identified. Notably, the incidence of recurrence after transplantation appears reduced in patients with steroid-resistant nephrotic syndrome (SRNS) due to monogenic disorders. We reviewed 150 transplanted patients with SRNS to identify biomarkers that consistently predict outcome of SRNS after transplantation. In all, 25 children had genetic or familial SRNS and did not experience post-transplant recurrence. We reviewed phenotypic factors, including initial steroid sensitivity, donor type, age, ethnicity, time to ESRD, and time on dialysis, in the remaining 125 children. Of these patients, 57 (45.6%) developed post-transplant recurrence; 26 of 28 (92.9%) patients with initial steroid sensitivity recurred after transplantation, whereas only 26 of 86 (30.2%) patients resistant from the outset recurred (odds ratio, 30; 95% confidence interval, 6.62 to 135.86; P<0.001). We were unable to determine recurrence in two patients (one with initial steroid sensitivity), and nine patients did not receive initial steroids. Our data show that initial steroid sensitivity is highly predictive of post-transplant disease recurrence in this pediatric patient population. Because a pathogenic circulating permeability factor in nephrotic syndrome remains to be confirmed, we propose initial steroid sensitivity as a surrogate marker for post-transplant recurrence. PMID:24511128

Excess primary intestinal lymphoproliferative disorders in patients with inflammatory bowel disease.

PubMed

Sokol, Harry; Beaugerie, Laurent; Maynadié, Marc; Laharie, David; Dupas, Jean-Louis; Flourié, Bernard; Lerebours, Eric; Peyrin-Biroulet, Laurent; Allez, Matthieu; Simon, Tabassome; Carrat, Fabrice; Brousse, Nicole

2012-11-01

It remains to be shown whether inflammatory bowel disease (IBD) is associated with an increased risk of primary intestinal lymphoproliferative disorders (PILD). We assessed this risk in the CESAME French nationwide prospective observational cohort. In all, 680 gastroenterologists enrolled 19,486 patients with IBD (Crohn's disease in 60.3%) from May 2004 to June 2005. Follow-up ended on 31 December 2007. Available biopsy samples and surgical specimens from patients with PILD (n = 14) were centralized for review. The reference incidence of PILD in the general population was obtained from the Côte d'Or registry and was used as a comparator to assess the standardized incidence ratio (SIR). The influence of thiopurine exposure was explored in a nested case-control study. In the CESAME population the crude incidence of PILD was 0.12/1000 patient-years, with a corresponding SIR of 17.51 (95% confidence interval [CI], 6.43-38.11; P < 0.0001). The risk was highest in patients exposed to thiopurines (SIR 49.52, 95% CI 13.49-126.8; P < 0.0001), while it did not reach statistical significance in patients naïve to thiopurines (SIR 4.83, 95% CI, 0.12-26.91; P = 0.37). The odds ratio associated with ongoing thiopurine exposure (vs. naïve) was 2.97 (95% CI, 0.30-infinity; P = 0.38). All 14 cases of PILD were non-Hodgkin's B-cell LD, 78.6% occurred in males, 85.7% arose in IBD lesions, and 45.5% were Epstein-Barr virus-positive. Eleven cases occurred in patients with Crohn's disease. Mean (SD) age at PILD diagnosis was 55.1 (5.6) years and the median time since IBD onset was 8.0 years (interquartile range, 3.0-15.8). Patients with IBD have an increased risk of developing PILD. Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.

Response to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.

PubMed

Styczynski, Jan; Gil, Lidia; Tridello, Gloria; Ljungman, Per; Donnelly, J Peter; van der Velden, Walter; Omar, Hamdy; Martino, Rodrigo; Halkes, Constantijn; Faraci, Maura; Theunissen, Koen; Kalwak, Krzysztof; Hubacek, Petr; Sica, Simona; Nozzoli, Chiara; Fagioli, Franca; Matthes, Susanne; Diaz, Miguel A; Migliavacca, Maddalena; Balduzzi, Adriana; Tomaszewska, Agnieszka; Camara, Rafael de la; van Biezen, Anja; Hoek, Jennifer; Iacobelli, Simona; Einsele, Hermann; Cesaro, Simone

2013-09-01

 The objective of this analysis was to investigate prognostic factors that influence the outcome of Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disorder (PTLD) after a rituximab-based treatment in the allogeneic hematopoietic stem cell transplant (HSCT) setting.  A total of 4466 allogeneic HSCTs performed between 1999 and 2011 in 19 European Group for Blood and Marrow Transplantation centers were retrospectively analyzed for PTLD, either biopsy-proven or probable disease.  One hundred forty-four cases of PTLD were identified, indicating an overall EBV-related PTLD frequency of 3.22%, ranging from 1.16% for matched-family donor, 2.86% for mismatched family donor, 3.97% in matched unrelated donors, and 11.24% in mismatched unrelated donor recipients. In total, 69.4% patients survived PTLD. Multivariable analysis showed that a poor response of PTLD to rituximab was associated with an age ≥30 years, involvement of extralymphoid tissue, acute GVHD, and a lack of reduction of immunosuppression upon PTLD diagnosis. In the prognostic model, the PTLD mortality increased with the increasing number of factors: 0-1, 2, or 3 factors being associated with mortality of 7%, 37%, and 72%, respectively (P < .0001). Immunosuppression tapering was associated with a lower PTLD mortality (16% vs 39%), and a decrease of EBV DNAemia in peripheral blood during therapy was predictive of better survival.  More than two-thirds of patients with EBV-related PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome, whereas older age, extranodal disease, and acute graft-vs-host disease predicted poor outcome.

Granulomatous Lymphoproliferative Disorders: Granulomatous Slack Skin and Lymphomatoid Granulomatosis.

PubMed

Gangar, Pamela; Venkatarajan, Sangeetha

2015-07-01

Granulomatous cutaneous T-cell lymphomas (CTCL) and lymphomatoid granulomatosis are considered granulomatous lymphoproliferative disorders. The most common types of granulomatous CTCL are granulomatous mycosis fungoides and granulomatous slack skin. Lymphomatoid granulomatosis is a rare Epstein-Barr virus driven lymphoproliferative disorder. This article reviews the etiopathogenesis, clinical presentation, systemic associations, and management of both granulomatous slack skin syndrome and lymphomatoid granulomatosis. Copyright © 2015 Elsevier Inc. All rights reserved.

L-Asparaginase monotherapy for EBV-positive T/NK lymphoproliferative diseases: A pilot Study.

PubMed

Jinta, Minako; Imadome, Ken-Ichi; Komatsu, Honami; Yoshimori, Mayumi; Kurata, Morito; Fujiwara, Shigeyoshi; Miura, Osamu; Arai, Ayako

2015-03-30

We investigated the effects of L-asparaginase (L-asp) on Epstein-Barr virus (EBV)-positive T/NK lymphoproliferative diseases (EBV-T/ NK-LPDs). Seven doses of L-asp (6,000 U/m2) were administered intravenously, with one dose administered on every alternate day. Five consecutive patients were enrolled. Three patients completed the treatment. The clinical symptoms resolved in 1 patient who started the administration 8 months after the onset, being the earliest among the 5 patients. Her EBV-DNA level in whole blood markedly decreased to 0.08 times of that before treatment, and the level in plasma became undetectable. In the other 2 patients whose administration was started 3 and 3.5 years after the onset, however, a remarkable improvement was not detected. Treatment was discontinued in 2 patients because of disease progression or idiopathic dystonia. The mRNA levels of asparagine synthetase in EBV-infected cells were examined. The level from the patient who responded to L-asp treatment was low, but it did not correlate with the effects in the other patients. Liver dysfunction (grades 2 and 3) was observed in 2 patients and neutropenia (grade 3) was noted in 1 patient. In conclusion, the effect of L-asp as monotherapy in EBV-T/NK-LPDs is limited, and early treatment initiation might be effective.

Increased risk of post-transplant malignancy and mortality in transplant tourists: a nationwide population-based cohort study in Taiwan.

PubMed

Chung, Mu-Chi; Wu, Ming-Ju; Chang, Chao-Hsiang; Muo, Chih-Hsin; Yu, Tung-Min; Ho, Hao-Chung; Shu, Kuo-Hsiung; Chung, Chi-Jung

2014-12-01

Information on post-transplant malignancy and mortality risk in kidney transplant tourists remains controversial and is an important concern. The present study aimed to evaluate the incidence of post-transplant malignancy and mortality risk between tourists and domestic transplant recipients using the claims data from Taiwan's universal health insurance. A retrospective study was performed on 2394 tourists and 1956 domestic recipients. Post-transplant malignancy and mortality were defined from the catastrophic illness patient registry by using the International Classification of Diseases, 9th Revision. Cox proportional hazard regression and Kaplan-Meier curves were used for the analyses. The incidence for post-transplant de novo malignancy in the tourist group was 1.8-fold higher than that of the domestic group (21.8 vs 12.1 per 1000 person-years). The overall cancer recurrence rate was approximately 11%. The top 3 post-transplant malignancies, in decreasing order, were urinary tract, kidney, and liver cancers, regardless of the recipient type. Compared with domestic recipients, there was significant higher mortality risk in transplant tourists (adjusted hazard ratio = 1.2, 95% confidence interval: 1.0-1.5). In addition, those with either pre-transplant or post-transplant malignancies were associated with increased mortality risk. We suggest that a sufficient waiting period for patients with pre-transplant malignancies should be better emphasized to eliminate recurrence, and transplant tourists should be discouraged because of the possibility of higher post-transplant de novo malignancy occurrence and mortality.

Characterization of skin blister fluids from children with Epstein-Barr virus-associated lymphoproliferative disease.

PubMed

Wada, Taizo; Toma, Tomoko; Miyazawa, Hanae; Koizumi, Eiko; Shirahashi, Tetsujiro; Matsuda, Yusuke; Yachie, Akihiro

2018-04-01

Epstein-Barr virus (EBV)-associated T- or natural killer (NK)-cell lymphoproliferative disease (LPD) is a heterogeneous group of disorders characterized by chronic proliferation of EBV-infected lymphocytes. Patients may present with severe skin manifestations, including hypersensitivity to mosquito bites (HMB) and hydroa vacciniforme (HV)-like eruption, which are characterized by blister formation and necrotic ulceration. Skin biopsy specimens show inflammatory reactions comprising EBV-infected lymphocytes. However, blister fluids have not been fully assessed in patients with this disease. Blister fluids were collected from three patients with EBV-associated LPD: two with HMB and one with HV. Immunophenotyping of blister lymphocytes and measurement of tumor necrosis factor (TNF)-α in blister fluids were performed. The patients with HMB and HV exhibited markedly increased percentages of NK and γδ T cells, respectively, in both peripheral blood and blister fluids. These NK and γδ T cells strongly expressed the activation marker human leukocyte antigen-DR and were considered to be cellular targets of EBV infections. TNF-α was highly elevated in all blister fluids. Severe local skin reactions of EBV-associated LPD may be associated with infiltrating EBV-infected lymphocytes and a high TNF-α concentration in blister fluids. © 2018 Japanese Dermatological Association.

Epstein-Barr virus associated T-cell lymphoproliferative disease misdiagnosed as ulcerative colitis: a case report.

PubMed

Zheng, Xiaodan; Xie, Jianlan; Zhou, Xiaoge

2015-01-01

Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disease (LPD) is not uncommon in China, but gastrointestinal involvement is very rare. We report on an immunocompetent patient with EBV-associated T-cell LPD of the colon. The 26-year-old man was initially misdiagnosed with ulcerative colitis (UC). A colon biopsy revealed the presence of small to medium-sized lymphoid cells infiltrating the intestinal wall. The neoplastic cells expressed CD3, CD5, and granzyme B, not CD56. EBV-encoded small ribonucleic acid was detected in the tumor cells of the colon as well as the lymph node, and the T-cell receptor gene rearrangement result displayed δ gene monoclonal rearrangement. The patient died 2 moths after the diagnosis. The clinical course of EBV-associated T-cell LPD is aggressive and the prognosis is poor, the wrong diagnosis may delay treatment. Therefore, we should be very careful to prevent misdiagnosis. When patients have multiple intestinal ulcers that are not typical of UC and the clinical course is unusual, although morphology looks like inflammatory change, pathologist should consider the possibility of EBV-associated LPD. The treatment strategy and prognosis of these two diseases are different.

Follow-up of post-transplant minimal residual disease and chimerism in childhood lymphoblastic leukaemia: 90 d to react.

PubMed

Pochon, Cécile; Oger, Emmanuel; Michel, Gérard; Dalle, Jean-Hugues; Salmon, Alexandra; Nelken, Brigitte; Bertrand, Yves; Cavé, Hélène; Cayuela, Jean-Michel; Grardel, Nathalie; Macintyre, Elizabeth; Margueritte, Geneviève; Méchinaud, Françoise; Rohrlich, Pierre; Paillard, Catherine; Demeocq, François; Schneider, Pascale; Plantaz, Dominique; Poirée, Marilyne; Eliaou, Jean-François; Semana, Gilbert; Drunat, Séverine; Jonveaux, Philippe; Bordigoni, Pierre; Gandemer, Virginie

2015-04-01

Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease (MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days -30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions (DLI) were programmed for patients with a pre- or post-transplant MRD status ≥10(-3) . Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival (OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment (P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention. © 2014 John Wiley & Sons Ltd.

The Spectrum of Epstein-Barr Virus-Associated Lymphoproliferative Disease in Korea: Incidence of Disease Entities by Age Groups

PubMed Central

Cho, Eun-Yoon; Kim, Ki-Hyun; Kim, Won-Seog; Yoo, Keon Hee; Koo, Hong-Hoe

2008-01-01

This study is to identify the spectrum of Epstein-Barr virus (EBV)-positive lymphoproliferative diseases (LPD) and relationships between these diseases in Korea. The EBV status and clinicopathology of 764 patients, including acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV (CAEBV) infections, B-LPD arising in chronic latent EBV infection, T & natural killer (NK) cell non-Hodgkin's lymphomas (NHL), B-NHLs, and Hodgkin's lymphomas (HD), were analyzed. T or NK cell NHLs were the most common forms of EBV-positive NHLs (107/167, 64%); among these, nasal-type NK/T cell lymphomas were the most common (89/107, 83%). According to the age, Burkitt's lymphoma was the most common in early childhood; in teenagers, chronic (active) EBV infection-associated LPD was the most common type. The incidence of NK/T cell lymphoma began to increase from the twenties and formed the major type of EBV-associated tumor throughout life. Diffuse large B cell lymphoma formed the major type in the sixties and seventies. In conclusion, primary infections in early childhood are complicated by the development of CAEBV infections that are main predisposing factors for EBV-associated T or NK cell malignancies in young adults. In old patients, decreased immunity associated with old age and environmental cofactors may provoke the development of peripheral T cell lymphoma, unspecified, and diffuse large B cell lymphoma. PMID:18436998

The spectrum of Epstein-Barr virus-associated lymphoproliferative disease in Korea: incidence of disease entities by age groups.

PubMed

Cho, Eun-Yoon; Kim, Ki-Hyun; Kim, Won-Seog; Yoo, Keon Hee; Koo, Hong-Hoe; Ko, Young-Hyeh

2008-04-01

This study is to identify the spectrum of Epstein-Barr virus (EBV)-positive lymphoproliferative diseases (LPD) and relationships between these diseases in Korea. The EBV status and clinicopathology of 764 patients, including acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV (CAEBV) infections, B-LPD arising in chronic latent EBV infection, T & natural killer (NK) cell non-Hodgkin's lymphomas (NHL), B-NHLs, and Hodgkin's lymphomas (HD), were analyzed. T or NK cell NHLs were the most common forms of EBV-positive NHLs (107/167, 64%); among these, nasal-type NK/T cell lymphomas were the most common (89/107, 83%). According to the age, Burkitt's lymphoma was the most common in early childhood; in teenagers, chronic (active) EBV infection-associated LPD was the most common type. The incidence of NK/T cell lymphoma began to increase from the twenties and formed the major type of EBV-associated tumor throughout life. Diffuse large B cell lymphoma formed the major type in the sixties and seventies. In conclusion, primary infections in early childhood are complicated by the development of CAEBV infections that are main predisposing factors for EBV-associated T or NK cell malignancies in young adults. In old patients, decreased immunity associated with old age and environmental cofactors may provoke the development of peripheral T cell lymphoma, unspecified, and diffuse large B cell lymphoma.

IgG4-related Mikulicz's disease is a multiorgan lymphoproliferative disease distinct from Sjögren's syndrome: a Caucasian patient and literature review.

PubMed

Yao, Qingping; Wu, Guiyun; Hoschar, Aaron

2013-01-01

This paper aims to report a case of IgG4-related Mikulicz's disease with a systematic review. The relevant English literature was searched using the keywords 'Mikulicz's disease' and 'IgG4'. Original and review articles were reviewed, and the clinical scenarios were exemplified with a case report. A 49-year-old Caucasian man presented with axillary lymphadenopathy and bilateral parotid/submandibular enlargement. A chest computerized tomography showed mediastinal lymphadenopathy, with low metabolic activity on the position emission tomography. A histopathological study showed an IgG4/IgG ratio of 75% in the plasma cells of the submandibular glands, associated with high levels of total serum IgG and IgG4. He had dry mouth, but minor salivary gland biopsy was negative without xerophthalmia. He had nasal obstruction and dyspnea, notably with supine position/cervical rotation, which substantially improved with glucocorticoid treatment. He had newly diagnosed diabetes mellitus with hyperlipasaemia and diffuse pancreatic swelling supportive of autoimmune pancreatitis. Our case report supports the literature that there are similarities between IgG4-related Mikulicz's disease and Sjögren's syndrome, but the differences are significant. IgG4-related Mikulicz's disease is a multi-organ lymphoproliferative disease distinct from Sjögren's syndrome.

Report of a factor VIII inhibitor in a patient with autoimmune lymphoproliferative syndrome.

PubMed

Fang, B S; Sneller, M C; Straus, S E; Frenkel, L; Dale, J K; Rick, M E

2000-07-01

The occurrence of factor VIII inhibitors in non-hemophilic patients is a rare event with a potentially lethal outcome. Despite its infrequent occurrence, the association of this inhibitor with multiple autoimmune diseases is well recognized. We report the case of a patient with the recently described autoimmune lymphoproliferative syndrome (ALPS) who developed an inhibitor to factor VIII. ALPS is a disease characterized by defective lymphocyte apoptosis due to inherited mutations in genes that regulate apoptosis, with the resulting enlargement of lymphoid organs and a variety of autoimmune manifestations. Published 2000 Wiley-Liss, Inc.

Haploidentical Hematopoietic Stem Cell Transplantation as Platform for Post-transplant Cellular Therapy

PubMed Central

Kongtim, Piyanuch; Lee, Dean A.; Cooper, Laurence J. N.; Kebriaei, Partow; Champlin, Richard E.; Ciurea, Stefan O.

2016-01-01

Haploidentical transplantation can extend the opportunity for transplantation to almost all patients who lack an HLA-matched donor. Advances in the field of haploidentical transplantation have led to a marked decrease in treatment-related mortality, allowing investigators to focus on developing rationale pre- and peri-remission therapies aimed at preventing disease relapse post-transplant. Due to widespread availability, low treatment-related mortality and cost, haploidentical donors may become the preferred “alternative” donors for allogeneic hematopoietic stem cell transplantation. One of the major advantages of using a related donor is the possibility to collect or generate additional cellular products from the same immediate available donor, which will not be rejected. Infusion of these cells in the peri-transplant period, derived from the same immune system, is opening the possibility to markedly enhance the anti-tumor effects of the graft and hasten immunologic reconstitution post-transplant. PMID:26172479

Advances in Understanding the Pathogenesis of Epstein-Barr Virus-Associated Lymphoproliferative Disorders.

PubMed

Yang, Xi; Nishida, Naonori; Zhao, Xiaodong; Kanegane, Hirokazu

2015-10-01

Epstein-Barr virus (EBV) was discovered 50 years ago from an african Burkitt lymphoma cell line. EBV-associated lymphoproliferative disorders (LPDs) are life- threatening diseases, especially in children. In this article, we review EBV-associated LPDs, especially in the area of primary immunodeficiency disease (PID). We searched PubMed for publications with key words including EBV infection, lymphoma, LPDs and PID, and selected the manuscripts written in English that we judged to be relevant to the topic of this review.On the basis of the data in the literature, we grouped the EBV-associated LPDs into four categories: nonmalignant disease, malignant disease, acquired immunodeficiency disease and PID. Each category has its own risk factor for LPD development. EBV-associated LPD is a complex disease, creating new challenges for diagnosis and treatment.

Facial manifestations of Epstein-Barr virus-related lymphoproliferative disease in childhood acute lymphoblastic leukemia in remission: Two atypical presentations.

PubMed

Lu, Benjamin Y; Kojima, Lisa; Huang, Mary S; Friedmann, Alison M; Ferry, Judith A; Weinstein, Howard J

2016-11-01

Epstein-Barr virus-related lymphoproliferative disease (EBV-LPD) rarely occurs in patients with acute lymphoblastic leukemia (ALL), who have not received hematopoietic transplantation. We describe EBV-LPD manifesting as facial lesions in two children with ALL in remission. One patient was a 16-year-old male with T-cell ALL with an EBV-positive angiocentric polymorphous lip lesion presenting as right-sided facial swelling. The other patient was a 12-year-old male with B-cell ALL with an EBV-positive polymorphous lymphoplasmacytic infiltrate presenting as bilateral dacryoadenitis. Neither patient had known primary immunodeficiencies. Both cases improved with immunosuppressant de-escalation. These cases suggest that immunosuppression induced by maintenance chemotherapy is sufficient to promote EBV-LPD. © 2016 Wiley Periodicals, Inc.

Pre-transplant and post-transplant soluble CD30 for prediction and diagnosis of acute kidney allograft rejection.

PubMed

Nafar, Mohsen; Farrokhi, Farhat; Vaezi, Mohammad; Entezari, Amir-Ebrahim; Pour-Reza-Gholi, Fatemeh; Firoozan, Ahmad; Eniollahi, Behzad

2009-01-01

Serum levels of soluble CD30 (sCD30) have been considered as a predictor of acute kidney allograft rejection. We have evaluated the pre-transplant and post-transplant levels of sCD30 with the aim of determining its value in predicting and diagnosing kidney rejection. We measured sCD30 serum levels before kidney transplantation, 5 days post-operatively, and at creatinine elevation episodes. The predictive value of sCD30 for diagnosing acute rejection (AR) within the first 6 post-operative months was assessed in 203 kidney recipients from living donors. Pre-transplant and post-operative levels of serum sCD30 were 58.10 +/- 52.55 and 51.55 +/- 49.65 U/ml, respectively (P = 0.12). Twenty-three patients experienced biopsy-proven acute rejection, and 28 had acute allograft dysfunction due to non-immunologic diseases. The pre-transplant sCD30 level was not different between patients with and without AR. However, post-transplant sCD30 was higher in the AR group. The median serum level of post-transplant sCD30 was 52 U/ml in the AR group and 26.3 U/ml in a control group (P < 0.001). The relative changes of sCD30 on day 5 were higher in patients with AR (P = 0.003). Based on post-transplant sCD30 levels, we were able to differentiate between kidney recipients who experienced an AR within 6 months post-surgery and those without an AR (cutoff value 41 U/ml; sensitivity 70%; specificity 71.7%). The level of sCD30 during periods of elevated serum creatinine was not independently associated with the diagnosis of AR. Post-transplant sCD30 levels and their relative changes are higher in patients experiencing AR. We propose further studies on the post-transplant trend of this marker for the prediction of AR.

A Case Report of NK-Cell Lymphoproliferative Disease With a Wide Involvement of Digestive Tract Develop Into Epstein-Barr Virus Associated NK/T Cell Lymphoma in an Immunocompetent Patient.

PubMed

Chen, Haotian; Zhang, Yu; Jiang, Zhinong; Zhou, Wei; Cao, Qian

2016-03-01

Epstein-Barr virus (EBV) plays an important role in various diseases. EBV-associated lymphoproliferative disease (LPD) is a rare disease with a canceration tendency. It is difficult to differentiate LPD with involvement of digestive tract from Crohn disease due to similar clinical and endoscopic manifestations. We present a case report of multiple ulcers with esophagus, small bowel and the entire colon involved, proved to be NK-Cell LPD, developed into EBV-associated NK/T Cell lymphoma, in an immunocompetent man who was initially misdiagnosed as Crohn disease.This report underscores that intestinal ulcers should be cautiously diagnosed, for it sometimes could be a precancerous lesion.

Risk Factors and Outcomes of De Novo Cancers (Excluding Nonmelanoma Skin Cancer) After Liver Transplantation for Primary Sclerosing Cholangitis.

PubMed

Mouchli, Mohamad A; Singh, Siddharth; Loftus, Edward V; Boardman, Lisa; Talwalkar, Jayant; Rosen, Charles B; Heimbach, Julie K; Wiesner, Russell H; Hasan, Bashar; Poterucha, John J; Kymberly, Watt D

2017-08-01

Patients with primary sclerosing cholangitis (PSC) may be at higher risk of malignancy after liver transplantation (LT) compared to other LT recipients. We aimed to determine the cumulative incidence of/risk factors for long-term cancer-related mortality in patients with PSC after LT. All adult patients underwent LT for PSC without cholangiocarcinoma from 1984 to 2012, with follow-up through June 2015. We estimated cumulative incidence, risk factors, and mortality from de novo malignancies after LT. Two hundred ninety-three patients were identified (mean [SD] age, 47 [12] years; 63.3% males; 2.4% smoking at LT). Over a median of 11.5 years (range, 6.4-18.6 years), 64 patients (21.8%) developed 73 nonskin cancers, including 46 solid-organ cancers (renal, 11; colorectal, 11; prostate, 7; breast, 5; pancreas, 5; ovarian/endometrial/vulvar cancers, 3; and de novo cholangiocarcinoma, 4). Twenty-two patients developed hematologic malignancies (posttransplant lymphoproliferative diseases, 18; Hodgkin disease, 2; and myelodysplastic syndrome, 2). Five patients developed melanoma. The 1-, 5-, 10-, and 20-year cumulative incidences of cancer were 2.1%, 8.6%, 18.7%, and 27%, respectively. Mortality of patients with PSC who developed cancer was higher than that of patients with PSC without cancer (hazard ratio, 2.2; P < 0.01). On multivariate analysis, recipient's age and elevated pre-LT international normalized ratio were associated with increased risk of de novo (nonskin) malignancy. The 10-year cumulative risk of cancer after LT for advanced-stage PSC was 18.7%, with posttransplant lymphoproliferative diseases, colorectal cancer, and renal cell cancer being the most common. Post-LT de novo nonskin cancer decreased overall posttransplant survival. Only recipient's age and elevated international normalized ratio at LT were associated with increased nonskin cancer risk.

Posttransplant sCD30 as a predictor of kidney graft outcome.

PubMed

Süsal, Caner; Döhler, Bernd; Sadeghi, Mahmoud; Salmela, Kaija T; Weimer, Rolf; Zeier, Martin; Opelz, Gerhard

2011-06-27

Reliable markers for assessing the biological effect of immunosuppressive drugs and identification of transplant recipients at risk of developing rejection are not available. In a prospective multicenter study, we investigated whether posttransplant measurement of the T-cell activation marker soluble CD30 (sCD30) can be used for estimating the risk of graft loss in kidney transplant recipients. Pre- and posttransplant sera of 2322 adult deceased-donor kidney recipients were tested for serum sCD30 content using a commercial enzyme-linked immunosorbent assay. sCD30 decreased posttransplant and reached a nadir on day 30. Patients with a high sCD30 of more than or equal to 40 U/mL on day 30 showed a subsequent graft survival rate after 3 years of 78.3±4.1%, significantly lower than the 90.3±1.0% rate in recipients with a low sCD30 on day 30 of less than 40 U/mL (log-rank P<0.001; Cox hazard ratio 2.02, P<0.001). Although an association was found between pre- and posttransplant sCD30 levels, patients with high sCD30 on posttransplant day 30 demonstrated significantly lower 3-year graft survival irrespective of the pretransplant level. Our data suggest that posttransplant measurement of sCD30 on day 30 is a predictor of subsequent graft loss in kidney transplant recipients and that sCD30 may potentially serve as an indicator for adjustment of immunosuppressive medication.

First two decades of paediatric heart transplantation in Sweden - outcome of listing and post-transplant results.

PubMed

Gilljam, Thomas; Higgins, Thomas; Bennhagen, Rolf; Wåhlander, Håkan

2011-11-01

To evaluate outcome in the first generation of children with end-stage heart disease to whom heart transplantation was available. Retrospective review of all 135 Swedish children <18 years old listed for heart transplantation 1989-2009, followed to December 31, 2009, including 74 (55%) with cardiomyopathy and 61 (45%) with congenital heart disease; 34 (25%) were infants (<1 year). Cumulative risk of requiring heart transplantation was 1:17,300 (11 patients who improved were omitted from outcome analysis). Waiting-list mortality was 31% (44% in infants). Median waiting time in 82 transplanted patients was 57 days (0-585 days). Post-transplant follow-up time was median 5.9 years (0.03-20.1 years), and actuarial survival was 92% at 1 year, 82% at 5 years, 76% at 10 years and 58% at 15 years. Survival after listing was 64% at 1 year, 58% at 5 years, 52% at 10 years and 40% at 15 years. Post-transplant complications included rejections (34%), malignancies (12%), renal failure (8%), coronary artery vasculopathy (6%) and re-transplantation (5%). Among 64 survivors, 84% were free of complications affecting prognosis. High waiting-list mortality and post-transplant attrition precluded 60% of this pioneer population from reaching adulthood. Functional status in survivors is generally good. © 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.

Animal in vivo models of EBV-associated lymphoproliferative diseases: special references to rabbit models.

PubMed

Hayashi, K; Teramoto, N; Akagi, T

2002-10-01

Animal models of human EBV-associated diseases are essential to elucidate the pathogenesis of EBV-associated diseases. Here we review those previous models using EBV or EBV-like herpesviruses and describe the details on our two newly-developed rabbit models of lymphoproliferative diseases (LPD) induced by simian EBV-like viruses. The first is Cynomolgus-EBV-induced T-cell lymphomas in rabbits inoculated intravenously (77-90%) and orally (82-89%) during 2-5 months. EBV-DNA was detected in peripheral blood by PCR from 2 days after oral inoculation, while anti-EBV-VCA IgG was raised 3 weeks later. Rabbit lymphomas and their cell lines contained EBV-DNA and expressed EBV-encoded RNA-1 (EBER-1). Rabbit lymphoma cell lines, most of which have specific chromosomal abnormality, showed tumorigenicity in nude mice. The second is the first animal model for EBV-infected T-cell LPD with virus-associated hemophagocytic syndrome (VAHS), using rabbits infected with an EBV-like herpesvirus, Herpesvirus papio (HVP). Rabbits inoculated intravenously with HVP-producing cells showed increased anti-EBV-VCA-IgG titers, and most (85%) subsequently died of fatal LPD and VAHS, with bleeding and hepatosplenomegaly, during 22-105 days. Peroral spray of cell-free HVP induced viral infection with seroconversion in 3 out of 5 rabbits, with 2 of the 3 infected rabbits dying of LPD with VAHS. Atypical T lymphocytes containing HVP-DNA and expressing EBER-1 were observed in many organs. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus. These rabbit models are also useful and inexpensive alternative experimental model systems for studying the biology and pathogenesis of EBV, and prophylactic and therapeutic regimens.

Immune Reconstitution Inflammatory Syndrome Occurring in a Kidney Transplant Patient with Extrapulmonary Tuberculosis

PubMed Central

Ledesma, Kandria Jumil; Liu, Jessie

2017-01-01

Tuberculosis (TB) occurring in solid organ transplantation (SOT) is associated with significant morbidity and mortality usually due to delays in diagnosis, drug toxicity encountered with antimycobacterial therapy, and drug-drug interactions. TB in SOT patients may mimic other infectious and noninfectious posttransplant complications such as posttransplant lymphoproliferative disorder (PTLD) and systemic cytomegalovirus infection. Immune reconstitution inflammatory syndrome (IRIS) is a host response resulting in paradoxical worsening of an infectious disease which occurs after the employment of effective therapy and reversal of an immunosuppressed state. We describe the development of immune reconstitution inflammatory syndrome (IRIS), a unique complication occurring during the treatment of extrapulmonary tuberculosis occurring after transplant which resulted from decreasing immunosuppression in a patient who received Alemtuzumab induction therapy. Although (IRIS) has been originally described in HIV/AIDS patients receiving highly active antiretroviral therapy (HAART), solid organ transplant recipients with diagnosed or occult TB whose immune system may undergo immune reconstitution during their posttransplant course represent a new high risk group. PMID:28367350

Rituximab is not a "magic drug" in post-transplant recurrence of nephrotic syndrome.

PubMed

Grenda, Ryszard; Jarmużek, Wioletta; Rubik, Jacek; Piątosa, Barbara; Prokurat, Sylwester

2016-09-01

Pediatric patients with end-stage renal failure due to severe drug-resistant nephrotic syndrome are at risk of rapid recurrence after renal transplantation. Treatment options include plasmapheresis, high-dose of cyclosporine A/methylprednisolone and more recently-rituximab (anti-B CD20 monoclonal depleting antibody). We report five patients with immediate (1-2 days) post-transplant recurrence of nephrotic syndrome, treated with this kind of combined therapy including 2-4 weekly doses of 375 mg/m(2) of rituximab. Only two (of five) patients have showed full long-term remission, while the partial remission was seen in two cases, and no clinical effect at all was achieved in one patient. The correlation between B CD19 cells depletion and clinical effect was present in two cases only. Severe adverse events were present in two patients, including one fatal rituximab-related acute lung injury. The anti-CD20 monoclonal antibody may be not effective in all pediatric cases of rapid post-transplant recurrence of nephrotic syndrome, and benefit/risk ratio must be carefully balanced on individual basis before taking the decision to use this protocol. • nephrotic syndrome may recur immediately after renal transplantation • plasmapheresis combined with pharmacotherapy is used as rescue management • rituximab was reported as effective drug both in primary and post-transplant nephrotic syndrome What is New: • rituximab may not be effective is several cases of post-transplant nephrotic syndrome due to variety of underlying mechanisms of the disease, which may be or not be responsive to this drug • there may be no correlation between drug-induced depletion of specific B cells and clinical effect; this might suggest B-cell independent manner of rituximab action.

Chest neoplasms with infectious etiologies

PubMed Central

Restrepo, Carlos S; Chen, Melissa M; Martinez-Jimenez, Santiago; Carrillo, Jorge; Restrepo, Catalina

2011-01-01

A wide spectrum of thoracic tumors have known or suspected viral etiologies. Oncogenic viruses can be classified by the type of genomic material they contain. Neoplastic conditions found to have viral etiologies include post-transplant lymphoproliferative disease, lymphoid granulomatosis, Kaposi’s sarcoma, Castleman’s disease, recurrent respiratory papillomatosis, lung cancer, malignant mesothelioma, leukemia and lymphomas. Viruses involved in these conditions include Epstein-Barr virus, human herpes virus 8, human papillomavirus, Simian virus 40, human immunodeficiency virus, and Human T-lymphotropic virus. Imaging findings, epidemiology and mechanism of transmission for these diseases are reviewed in detail to gain a more thorough appreciation of disease pathophysiology for the chest radiologist. PMID:22224176

Chest neoplasms with infectious etiologies.

PubMed

Restrepo, Carlos S; Chen, Melissa M; Martinez-Jimenez, Santiago; Carrillo, Jorge; Restrepo, Catalina

2011-12-28

A wide spectrum of thoracic tumors have known or suspected viral etiologies. Oncogenic viruses can be classified by the type of genomic material they contain. Neoplastic conditions found to have viral etiologies include post-transplant lymphoproliferative disease, lymphoid granulomatosis, Kaposi's sarcoma, Castleman's disease, recurrent respiratory papillomatosis, lung cancer, malignant mesothelioma, leukemia and lymphomas. Viruses involved in these conditions include Epstein-Barr virus, human herpes virus 8, human papillomavirus, Simian virus 40, human immunodeficiency virus, and Human T-lymphotropic virus. Imaging findings, epidemiology and mechanism of transmission for these diseases are reviewed in detail to gain a more thorough appreciation of disease pathophysiology for the chest radiologist.

High-Dose Y-90-Ibritumomab Tiuxetan Added to Reduced-Intensity Allogeneic Stem Cell Transplant Regimen for Relapsed or Refractory Aggressive B-Cell Lymphoma

ClinicalTrials.gov

2017-12-04

Post-Transplant Lymphoproliferative Disorder; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Burkitt Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma; Refractory Burkitt Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

What is the incidence of kidney stones after chemotherapy in patients with lymphoproliferative or myeloproliferative disorders?

PubMed

Mirheydar, Hossein S; Banapour, Pooya; Massoudi, Rustin; Palazzi, Kerrin L; Jabaji, Ramzi; Reid, Erin G; Millard, Frederick E; Kane, Christopher J; Sur, Roger L

2014-01-01

This study describes the incidence and risk factors of de novo nephrolithiasis among patients with lymphoproliferative or myeloproliferative diseases who have undergone chemotherapy. From 2001 to 2011, patients with lymphoproliferative or myeloproliferative disorders treated with chemotherapy were retrospectively identified. The incidence of image proven nephrolithiasis after chemotherapy was determined. Demographic and clinical variables were recorded. Patients with a history of nephrolithiasis prior to chemotherapy were excluded. The primary outcome was incidence of nephrolithiasis, and secondary outcomes were risk factors predictive of de novo stone. Comparative statistics were used to compare demographic and disease specific variables for patients who developed de novo stones versus those who did not. A total of 1,316 patients were identified and the incidence of de novo nephrolithiasis was 5.5% (72/1316; symptomatic stones 1.8% 24/1316). Among patients with nephrolithiasis, 72.2% had lymphoproliferative disorders, 27.8% had myeloproliferative disorders, and 25% utilized allopurinol. The median urinary pH was 5.5, and the mean serum uric acid, calcium, potassium and phosphorus levels were 7.5, 9.6, 4.3, and 3.8 mg/dL, respectively. In univariate analysis, mean uric acid (p=0.013), calcium (p<0.001)), and potassium (p=0.039) levels were higher in stone formers. Diabetes mellitus (p<0.001), hypertension (p=0.003), and hyperlipidemia (p<0.001) were more common in stone formers. In multivariate analysis, diabetes mellitus, hyperuricemia, and hypercalcemia predicted stone. We report the incidence of de novo nephrolithiasis in patients who have undergone chemotherapy. Diabetes mellitus, hyperuricemia, and hypercalcemia are patient-specific risk factors that increase the odds of developing an upper tract stone following chemotherapy.

Cytomegalovirus and polyomavirus BK posttransplant.

PubMed

Egli, Adrian; Binggeli, Simone; Bodaghi, Sohrab; Dumoulin, Alexis; Funk, Georg A; Khanna, Nina; Leuenberger, David; Gosert, Rainer; Hirsch, Hans H

2007-09-01

Virus replication and progression to disease in transplant patients is determined by patient-, graft- and virus-specific factors. This complex interaction is modulated by the net state of immunosuppression and its impact on virus-specific cellular immunity. Due to the increasing potency of immunosuppressive regimens, graft rejections have decreased, but susceptibility to infections has increased. Therefore, cytomegalovirus (CMV) remains the most important viral pathogen posttransplant despite availability of effective antiviral drugs and validated strategies for prophylactic, preemptive and therapeutic intervention. CMV replication can affect almost every organ system, with frequent recurrences and increasing rates of antiviral resistance. Together with indirect long-term effects, CMV significantly reduces graft and patient survival after solid organ and hematopoietic stem cell transplantation. The human polyomavirus called BK virus (BKV), on the other hand, only recently surfaced as pathogen with organ tropism largely limited to the reno-urinary tract, manifesting as polyomavirus-associated nephropathy in kidney transplant and hemorrhagic cystitis in hematopoetic stem cell transplant patients. No licensed anti-polyoma viral drugs are available, and treatment relies mainly on improving immune functions to regain control over BKV replication. In this review, we discuss diagnostic and therapeutic aspects of CMV and BKV replication and disease posttransplantation.

Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication.

PubMed

Bilger, Andrea; Plowshay, Julie; Ma, Shidong; Nawandar, Dhananjay; Barlow, Elizabeth A; Romero-Masters, James C; Bristol, Jillian A; Li, Zhe; Tsai, Ming-Han; Delecluse, Henri-Jacques; Kenney, Shannon C

2017-07-04

EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both "on target" and "off target" mechanisms and is increasingly used to treat these viruses in organ transplant recipients. However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown. We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV-transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication. Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV-induced LPD in patients who have high EBV loads yet require continued immunosuppression.

Blood disorders typically associated with renal transplantation

PubMed Central

Yang, Yu; Yu, Bo; Chen, Yun

2015-01-01

Renal transplantation has become one of the most common surgical procedures performed to replace a diseased kidney with a healthy kidney from a donor. It can help patients with kidney failure live decades longer. However, renal transplantation also faces a risk of developing various blood disorders. The blood disorders typically associated with renal transplantation can be divided into two main categories: (1) Common disorders including post-transplant anemia (PTA), post-transplant lymphoproliferative disorder (PTLD), post-transplant erythrocytosis (PTE), and post-transplant cytopenias (PTC, leukopenia/neutropenia, thrombocytopenia, and pancytopenia); and (2) Uncommon but serious disorders including hemophagocytic syndrome (HPS), thrombotic microangiopathy (TMA), therapy-related myelodysplasia (t-MDS), and therapy-related acute myeloid leukemia (t-AML). Although many etiological factors involve the development of post-transplant blood disorders, immunosuppressive agents, and viral infections could be the two major contributors to most blood disorders and cause hematological abnormalities and immunodeficiency by suppressing hematopoietic function of bone marrow. Hematological abnormalities and immunodeficiency will result in severe clinical outcomes in renal transplant recipients. Understanding how blood disorders develop will help cure these life-threatening complications. A potential therapeutic strategy against post-transplant blood disorders should focus on tapering immunosuppression or replacing myelotoxic immunosuppressive drugs with lower toxic alternatives, recognizing and treating promptly the etiological virus, bacteria, or protozoan, restoring both hematopoietic function of bone marrow and normal blood counts, and improving kidney graft survival. PMID:25853131

Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome

PubMed Central

Teachey, David T.; Greiner, Robert; Seif, Alix; Attiyeh, Edward; Bleesing, Jack; Choi, John; Manno, Catherine; Rappaport, Eric; Schwabe, Dirk; Sheen, Cecilia; Sullivan, Kathleen E.; Zhuang, Hongming; Wechsler, Daniel S.; Grupp, Stephan A.

2010-01-01

Summary We hypothesized that sirolimus, an mTOR inhibitor, may be effective in patients with autoimmune lymphoproliferative syndrome (ALPS) and treated patients who were intolerant to or failed other therapies. Four patients were treated for autoimmune cytopenias; all had a rapid complete or near complete response. Two patients were treated for autoimmune arthritis and colitis, demonstrating marked improvement. Three patients had complete resolution of lymphadenopathy and splenomegaly and all patients had a reduction in double negative T cells, a population hallmark of the disease. Based on these significant responses, we recommend that sirolimus be considered as second-line therapy for patients with steroid-refractory disease. PMID:19208097

Chronic Kidney Disease and Related Long-term Complications Following Liver Transplantation

PubMed Central

Sharma, Pratima; Bari, Khurram

2015-01-01

Liver transplantation (LT) is the standard of care for patients with decompensated cirrhosis. LT recipients have excellent short-term and long-term outcomes including patient and graft survival. Since the adoption of model for end-stage liver disease (MELD) - based allocation policy, the incidence of post-transplant end stage renal disease has risen significantly. Occurrence of stage 4 chronic kidney disease and end stage renal disease substantially increase the risk of post-transplant deaths. Since majority of late post-transplant mortality is due to non-hepatic post-transplant comorbidities, personalized care directed towards risk factor modification may further improve post-transplant survival. PMID:26311603

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

PubMed

Carnevale-Schianca, Fabrizio; Caravelli, Daniela; Gallo, Susanna; Coha, Valentina; D'Ambrosio, Lorenzo; Vassallo, Elena; Fizzotti, Marco; Nesi, Francesca; Gioeni, Luisa; Berger, Massimo; Polo, Alessandra; Gammaitoni, Loretta; Becco, Paolo; Giraudo, Lidia; Mangioni, Monica; Sangiolo, Dario; Grignani, Giovanni; Rota-Scalabrini, Delia; Sottile, Antonino; Fagioli, Franca; Aglietta, Massimo

2017-03-01

Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Pathogenesis of chronic active Epstein-Barr virus infection: is this an infectious disease, lymphoproliferative disorder, or immunodeficiency?

PubMed

Kimura, Hiroshi

2006-01-01

Chronic active Epstein-Barr virus infection (CAEBV) is characterised by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, hepatosplenomegaly, persistent hepatitis and extensive lymphadenopathy. Patients with CAEBV have high viral loads in their peripheral blood and/or an unusual pattern of EBV-related antibodies. This disease is rare but severe with high morbidity and mortality. Nearly three decades have passed since this disease was first identified, and recent advances in technology have increased our understanding of CAEBV pathophysiology. There is accumulating evidence that the clonal expansion of EBV-infected T or natural killer (NK) cells plays a central role in the pathogenesis of CAEBV. However, it remains unclear whether CAEBV is truly a monoclonal lymphoproliferative disorder. EBV-infected T or NK cells are able to evade the host cellular immune system due to the limited expression of viral proteins of reduced antigenicity. Recent studies suggest that infection of T or NK cells is a common event during primary EBV infection. A defect or single nucleotide polymorphism in host immune-modulating genes may allow for the expansion of virus infected cells giving rise to CAEBV. In this review, I summarise our current understanding of the pathogenesis of CAEBV and propose a model of CAEBV pathogenicity.

Molecular Surveillance for Lymphoproliferative Disease Virus in Wild Turkeys (Meleagris gallopavo) from the Eastern United States.

PubMed

Thomas, Jesse M; Allison, Andrew B; Holmes, Edward C; Phillips, Jamie E; Bunting, Elizabeth M; Yabsley, Michael J; Brown, Justin D

2015-01-01

Lymphoproliferative disease virus (LPDV) is a poorly understood, oncogenic avian retrovirus of domestic turkeys that has historically been restricted to Europe and Israel. However, a recent study reported LPDV in multiple wild turkey diagnostic cases from throughout the eastern United States of America (USA). To better understand the distribution of LPDV in the eastern USA, we surveyed 1,164 reportedly asymptomatic hunter-harvested wild turkeys from 17 states for the presence of LPDV proviral DNA by PCR. In total, 564/1,164 (47%) turkeys were positive for LPDV. Wild turkeys from each state had a relatively high prevalence of LPDV, although statewide prevalence varied from 26 to 83%. Phylogenetic analysis revealed two major clades of LPDV in the USA, although one was at a low frequency suggesting restricted transmission, as well as significant clustering by state of isolation. To determine the best tissue to target for diagnostic purposes, liver, spleen, and bone marrow were tested from a subset of 15 hunter-harvested wild turkeys and 20 wild turkey diagnostic cases. Overall, bone marrow provided the highest level of detection for both hunter-harvested turkeys and diagnostic cases. The sensitivity of LPDV detection between tissues was not significantly different for diagnostic cases, but was for hunter-harvested birds. These results indicate that LPDV infection is common and widespread in wild turkey populations throughout the eastern USA, even without overt signs of disease.

Bone metabolism dynamics in the early post-transplant period following kidney and liver transplantation.

PubMed

Schreiber, Peter W; Bischoff-Ferrari, Heike A; Boggian, Katia; Bonani, Marco; van Delden, Christian; Enriquez, Natalia; Fehr, Thomas; Garzoni, Christian; Hirsch, Hans H; Hirzel, Cédric; Manuel, Oriol; Meylan, Pascal; Saleh, Lanja; Weisser, Maja; Mueller, Nicolas J

2018-01-01

Bone disease contributes to relevant morbidity after solid organ transplantation. Vitamin D has a crucial role for bone metabolism. Activation of vitamin D depends on the endocrine function of both, liver and kidney. Our study assessed key markers of bone metabolism at time of transplantation and 6 months after transplantation among 70 kidney and 70 liver recipients. In 70 kidney recipients 25-OH vitamin D levels did not differ significantly between peri-transplant (median 32.5nmol/l) and 6 months post-transplant (median 41.9nmol/l; P = 0.272). Six months post-transplant median 1, 25-(OH)2 vitamin D levels increased by >300% (from 9.1 to 36.5ng/l; P<0.001) and median intact parathyroid hormone levels decreased by 68.4% (from 208.7 to 66.0 ng/l; P<0.001). Median β-Crosslaps (CTx) and total procollagen type 1 amino-terminal propeptide (P1NP) decreased by 65.1% (from 1.32 to 0.46ng/ml; P<0.001) and 60.6% (from 158.2 to 62.3ng/ml; P<0.001), respectively. Kidney recipients with incident fractures had significantly lower levels of 1, 25-(OH)2 vitamin D at time of transplantation and of intact parathyroid hormone 6 months post-transplant. Among 70 liver recipients, 25-OH vitamin D, 1, 25-(OH)2 vitamin D and intact parathyroid hormone levels were not significantly altered between peri-transplant and 6 months post-transplant. Contrary to kidney recipients, median CTx increased by 60.0% (from 0.45 to 0.72 ng/ml; P = 0.002) and P1NP by 49.3% (from 84.0 to 125.4ng/ml; P = 0.001) in the longitudinal course. Assessed biomarkers didn't differ between liver recipients with and without fractures. To conclude, the assessed panel of biomarkers proved highly dynamic after liver as well as kidney transplantation in the early post-transplant period. After kidney transplantation a significant gain in 1, 25-(OH)2 vitamin D combined with a decline in iPTH, CTx and P1NP, whereas after liver transplantation an increase in CTx and P1NP were characteristic.

Bone metabolism dynamics in the early post-transplant period following kidney and liver transplantation

PubMed Central

Schreiber, Peter W.; Bischoff-Ferrari, Heike A.; Boggian, Katia; Bonani, Marco; van Delden, Christian; Enriquez, Natalia; Fehr, Thomas; Garzoni, Christian; Hirsch, Hans H.; Hirzel, Cédric; Manuel, Oriol; Meylan, Pascal; Saleh, Lanja; Weisser, Maja

2018-01-01

Bone disease contributes to relevant morbidity after solid organ transplantation. Vitamin D has a crucial role for bone metabolism. Activation of vitamin D depends on the endocrine function of both, liver and kidney. Our study assessed key markers of bone metabolism at time of transplantation and 6 months after transplantation among 70 kidney and 70 liver recipients. In 70 kidney recipients 25-OH vitamin D levels did not differ significantly between peri-transplant (median 32.5nmol/l) and 6 months post-transplant (median 41.9nmol/l; P = 0.272). Six months post-transplant median 1, 25-(OH)2 vitamin D levels increased by >300% (from 9.1 to 36.5ng/l; P<0.001) and median intact parathyroid hormone levels decreased by 68.4% (from 208.7 to 66.0 ng/l; P<0.001). Median β-Crosslaps (CTx) and total procollagen type 1 amino-terminal propeptide (P1NP) decreased by 65.1% (from 1.32 to 0.46ng/ml; P<0.001) and 60.6% (from 158.2 to 62.3ng/ml; P<0.001), respectively. Kidney recipients with incident fractures had significantly lower levels of 1, 25-(OH)2 vitamin D at time of transplantation and of intact parathyroid hormone 6 months post-transplant. Among 70 liver recipients, 25-OH vitamin D, 1, 25-(OH)2 vitamin D and intact parathyroid hormone levels were not significantly altered between peri-transplant and 6 months post-transplant. Contrary to kidney recipients, median CTx increased by 60.0% (from 0.45 to 0.72 ng/ml; P = 0.002) and P1NP by 49.3% (from 84.0 to 125.4ng/ml; P = 0.001) in the longitudinal course. Assessed biomarkers didn’t differ between liver recipients with and without fractures. To conclude, the assessed panel of biomarkers proved highly dynamic after liver as well as kidney transplantation in the early post-transplant period. After kidney transplantation a significant gain in 1, 25-(OH)2 vitamin D combined with a decline in iPTH, CTx and P1NP, whereas after liver transplantation an increase in CTx and P1NP were characteristic. PMID:29338022

Predicting Post-Transplant Recurrence of IgA Nephropathy: The Importance of Crescents.

PubMed

Avasare, Rupali S; Rosenstiel, Paul E; Zaky, Ziad S; Tsapepas, Demetra S; Appel, Gerald B; Markowitz, Glen S; Bomback, Andrew S; Canetta, Pietro A

2017-01-01

Most studies that have assessed the predictors of recurrent IgA nephropathy (IgAN) in the renal allograft have focused on post-transplant features. Identifying high-risk pre-transplant features of IgAN is useful for counseling patients and may help in tailoring post-transplant immunosuppression. We investigated the pre-transplant clinical and biopsy features of 62 patients with IgAN who received transplants at Columbia University Medical Center from 2001 to 2012 and compared the characteristics and outcomes of patients with IgAN recurrence to those without recurrence. The primary outcome was time to recurrent IgAN. Secondary outcomes were a composite of doubling of creatinine or allograft failure, and recurrent IgAN as a cause of allograft dysfunction. Of the 62 patients, 14 had recurrent IgAN in the allograft. Mean time to recurrence was 2.75 years. Those with recurrent disease were younger at the time of native kidney biopsy (29 vs. 41 years, p < 0.0009). Black race and Hispanic ethnicity composed a higher proportion of the recurrent disease group. On multivariable analysis, significant predictors of recurrent IgAN included age at diagnosis (hazards ratio (HR) 0.911, 95% CI 0.85-0.98), burden of crescents on native biopsy (HR 1.21 per 10% increase in crescents, 95% CI 1.00-1.47) and allograft rejection (HR 3.59, 95% CI 1.10-11.7). Features of native IgAN can help predict the risk of recurrent disease in the renal allograft. In particular, immunologically active disease represented by earlier age of onset and greater burden of crescents on native biopsy is more likely to recur after transplant. © 2017 S. Karger AG, Basel.

Mutation of FAS, XIAP, and UNC13D genes in a patient with a complex lymphoproliferative phenotype.

PubMed

Boggio, Elena; Aricò, Maurizio; Melensi, Matteo; Dianzani, Irma; Ramenghi, Ugo; Dianzani, Umberto; Chiocchetti, Annalisa

2013-10-01

This article presents a case report for a child presenting with mixed clinical features of autoimmune lymphoproliferative syndrome (ALPS), familial hemophagocytic lymphohistiocytosis (FHL), and X-linked lymphoproliferative (XLP) disease. From 6 months, he exhibited splenomegaly and lymphoadenopathy and from 4 years, he showed recurrent severe autoimmune hemocytopenia and sepsislike bouts of fever, from which he eventually died at the age of 12. Intriguingly, the patient carried mutations in FAS, XIAP, and UNC13D genes, which are involved in ALPS, XLP disease, and FHL, respectively. These mutations were inherited from the mother, who had rheumatoid arthritis but no signs of ALPS. A role for other modifying genes was suggested by the finding that the healthy father exhibited defective Fas function, without mutation of the FAS gene, and had transmitted to the patient an osteopontin (OPN) gene variant previously associated with ALPS. Therefore, several genes might influence the disease outcome in this family. In vitro analyses revealed that the FAS and the XIAP mutations decreased expression of the corresponding proteins, and the UNC13D mutation decreased granule secretion and Munc interaction with Rab-27a. These findings suggest that overlap may exist between ALPS, FHL, and XLP disease, in accordance with the notion that FHL and XLP disease are due to defective natural killer (NK)/NK T-cell function, which involves Fas. Therefore, we propose that NK cell defects should be evaluated in patients with ALPS-like characteristics, and hematopoietic stem cell transplantation should be considered in individuals with severe refractory cytopenia and FHL-like manifestations.

Epstein-Barr virus-associated lymphoproliferative disorder in a patient with rheumatoid arthritis on methotrexate and rofecoxib: idiosyncratic reaction or pharmacogenetics?

PubMed

Vincent, Simi; Slease, R Bradley; Rocca, Peter V

2002-12-01

Rheumatoid arthritis (RA) is an autoimmune disease associated with altered immunoregulation and resulting in a deforming polyarthritis. Methotrexate (MTX) is a commonly used second line agent for RA, and there have been several recent reports of Epstein-Barr virus (EBV)-associated polyclonal B cell lymphoproliferative disorder in MTX-treated RA patients. The patient in this report had long standing RA treated with MTX and had recently begun taking a cyclooxygenase-2 (COX-2) inhibitor. She developed a febrile illness associated with severe pancytopenia and leukocytoclastic vasculitic rash followed by diffuse adenopathy, with serologic and pathologic evidence of EBV infection. Previous studies have demonstrated the interaction of MTX and a variety of non-steroidal, anti-inflammatory drugs (NSAIDs) with various clinical manifestations including acute renal failure, pancytopenia, vomiting, diarrhea, elevated liver transaminases, jaundice, mucosal ulcerations, and pyrexia. However, we have not identified previous reports suggesting interaction between MTX and COX-2 inhibitors. We hypothesize that decreased renal elimination of MTX induced by the COX-2 inhibitor resulted in enhanced hematopoietic toxicity and immunosuppression causing the EBV-associated lymphoproliferative disease.

Risk factors and prognosis in T-cell posttransplantation lymphoproliferative diseases: reevaluation of 163 cases.

PubMed

Tiede, Christina; Maecker-Kolhoff, Britta; Klein, Christoph; Kreipe, Hans; Hussein, Kais

2013-02-15

Posttransplantation lymphoproliferative diseases (PTLD) are mainly Epstein-Barr virus (EBV)-associated disorders of B-cell origin. Due to the rarity of monomorphic T-cell PTLD (T-PTLD), knowledge about pathogenesis, risk factors, therapy, and prognosis relies predominantly on case reports and small series. Therefore, we aimed to provide an overview and a retrospective analysis of this rare PTLD subtype. We analyzed all available articles on T-PTLD in the PubMed database as well as in our own databases (Institute of Pathology/Department of Paediatric Haematology and Oncology, Hannover Medical School) from 1988 to 2010. Reevaluated parameters were gender, age, transplanted organ, immunosuppressant regimen, time between transplantation and T-PTLD manifestation, T-PTLD subtype, virus positivity, localization, therapy, and follow-up. A total of 163 cases were evaluated. We found that hematopoietic stem cell transplantation was associated with early-onset T-PTLD, whereas late onset occurred after immunosuppression with steroids and azathioprine without administration of calcineurin inhibitors. The major independent favorable prognostic factors were T-PTLD of the large granular lymphocytic leukemia subtype, young age, and a combination of radiotherapy/radiochemotherapy and reduced immunosuppression, whereas the hepatosplenic T-cell lymphoma subtype and cases with involvement of bone marrow, the central nervous system, or graft had an adverse prognosis. T-PTLD is a heterogeneous group of different aberrant T-cell proliferations and represents a significant complication following transplantation, showing a uniformly poor prognosis.

Mucosal Healing and Risk of Lymphoproliferative Malignancy in Celiac Disease

PubMed Central

Lebwohl, Benjamin; Granath, Fredrik; Ekbom, Anders; Smedby, Karin Ekström; Murray, Joseph A.; Neugut, Alfred I.; Green, Peter HR; Ludvigsson, Jonas F.

2013-01-01

Background Celiac disease (CD) is associated with an increased risk of lymphoproliferative malignancy (LPM). It is unknown whether this risk is affected by the results of the follow-up intestinal biopsy, performed to document mucosal healing. Objective To examine the association between mucosal healing in CD and later LPM. Design Population-based cohort study Setting We identified patients with CD from all of Sweden’s 28 pathology departments. Patients Individuals with CD who had a follow-up biopsy after initial diagnosis. Measurements We compared the risk of LPM to that of the general population using expected rates; and through Cox regression we compared the rate of LPM in those with persistent villous atrophy to those with mucosal healing. Results Among 7,625 patients with CD and a follow-up biopsy, persistent villous atrophy was present in 3,308 (43%). The overall risk of LPM was increased compared to the general population (Standardized incidence ratio, SIR 2.81; 95%CI 2.10–3.67), but this increase was greater among those with persistent villous atrophy (SIR 3.78; 95%CI 2.71–5.12) as compared to those with mucosal healing (SIR 1.50; 95%CI 0.77–2.62). Persistent villous atrophy compared to mucosal healing was associated with an increased risk of LPM (Hazard ratio, HR 2.26; 95%CI 1.18–4.34). We found an increased risk of T cell lymphoma (HR 3.51; 95%CI 0.75–16.34), but no excess risk of B cell lymphoma (HR 0.97; 95%CI 0.21–4.49). Limitation We had no data on dietary compliance. Conclusions The increased LPM risk in CD is associated with the results of the follow-up biopsy, with a higher risk among those with persistent villous atrophy. Follow-up biopsy may be a means to effectively stratify CD patients regarding subsequent LPM risk. Primary funding source the National Center for Advancing Translational Sciences, National Institutes of Health, The American Scandinavian Foundation, the Celiac Sprue Association, Örebro University Hospital, Karolinska

Hyaline-Vascular Type Castleman's Disease, Sarcoidosis, and Crohns Disease.

PubMed

Gupta, Arjun; Ayyar, Balaji; Zia, Hamid; Chen, Weina; Harris, Samar; Naina, Harris V

2016-06-01

Sarcoidosis and Crohns disease have been associated with increased long term risk of lymphoproliferative disorders, including lymphomas. Newly developed lymphadenopathy in a patient with these disorders should prompt pathological evaluation. Castleman's disease is a lymphoproliferative disorder characterized by enlarged hyperplastic lymph nodes with regressed follicles surrounded by expanded mantle zones of small lymphocytes, and interfollicular vascular proliferation in the hyaline-vascular type. Similar to sarcoidosis and Crohns disease, its etiology is incompletely understood, although immune dysregulation, genetic factors and infectious and environmental factors are thought to play a role in all three diseases. Interleukin-6 is a possible pathological common factor between these three disease processed. Unicentric, hyaline-vascular type Castleman's disease can be treated successfully with complete surgical resection. We report a patient with long history of sarcoidosis and Crohns disease with newly developed lymphadenopathy which was found to be due to Castleman's disease.

Regular monitoring of cytomegalovirus (CMV)-specific cell-mediated immunity in intermediate-risk kidney transplant recipients: predictive value of the immediate post-transplant assessment.

PubMed

Fernández-Ruiz, Mario; Giménez, Estela; Vinuesa, Víctor; Ruiz-Merlo, Tamara; Parra, Patricia; Amat, Paula; Montejo, Miguel; Paez-Vega, Aurora; Cantisán, Sara; Torre-Cisneros, Julián; Fortún, Jesús; Andrés, Amado; San Juan, Rafael; López-Medrano, Francisco; Navarro, David; María Aguado, José

2018-05-24

Previous studies on monitoring of post-transplant cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) are limited by single-center designs and disparate risk categories. We aimed to assess the clinical value of a regular monitoring strategy in a large multicenter cohort of intermediate-risk kidney transplant (KT) recipients. We recruited 124 CMV-seropositive KT recipients with no T-cell-depleting induction preemptively managed at four Spanish institutions. CMV-specific interferon-γ-producing CD4 + and CD8 + T-cells were enumerated through the first post-transplant year by intracellular cytokine staining after stimulation with pp65 and IE-1 peptides (mean of 6 measurements per patient). The primary outcome was the occurrence of any CMV event (asymptomatic infection and/or disease). Optimal cut-off values for CMV-specific T-cells were calculated at baseline and day 15. Twelve-month cumulative incidence of CMV infection and/or disease was 47.6%. Patients with pre-transplant CMV-specific CD8 + T-cell count <1.0 cells/μL had higher risk of CMV events (adjusted hazard ratio [aHR]: 2.84; P-value = 0.054). When the CMI assessment was performed at the immediate post-transplant period (day 15), the presence of <2.0 CD8 + T-cells/μL (aHR: 2.18; P-value = 0.034) or <1.0 CD4 + T-cells/μL (aHR: 2.43; P-value = 0.016) also predicted the subsequent development of CMV event. In addition, lower counts of CMV-specific CD4 + (but not CD8 + ) T-cells at days 60 and 180 were associated with a higher incidence of late-onset events. Monitoring for CMV-specific CMI in intermediate-risk KT recipients must be regular to reflect dynamic changes in overall immunosuppression and individual susceptibility. The early assessment at post-transplant day 15 remains particularly informative. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Epstein-Barr Virus-positive T-cell Lymphoproliferative Disease Following Umbilical Cord Blood Transplantation for Acute Myeloid Leukemia.

PubMed

Yui, Shunsuke; Yamaguchi, Hiroki; Imadome, Ken-ichi; Arai, Ayako; Takahashi, Mikiko; Ohashi, Ryuji; Tamai, Hayato; Moriya, Keiichi; Nakayama, Kazutaka; Shimizu, Akira; Inokuchi, Koiti

2016-01-01

We report a case of the extremely rare condition Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease (LPD) which occurred after umbilical cord blood transplantation. A 25-year-old Japanese man underwent cord blood transplantation from a male human leukocyte antigen 4/6-matched donor due to acute myeloid leukemia with trisomy 8. Bone marrow examination on day 30 showed chimerism with at least 90% donor cells and complete hematological response. Chronic symptoms of graft-versus-host disease appeared only on the skin and were successfully treated with cyclosporine alone. Three years later, however, the patient experienced repeated cold-like symptoms and was hospitalized with liver dysfunction. A high fever developed and was followed by significant edema of the right side of the face. The EBV DNA copy number in whole peripheral blood was 2×10(4)/mL. Liver biopsy showed invasion of EBV-infected CD8-positive T cells. Southern blotting analysis of the whole peripheral blood showed that the T-cell receptor Cβ1 rearrangement was positive. On the basis of these results, EBV-positive T-cell LPD was diagnosed and treated with prednisolone, cyclosporine, and etoposide, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone. However, the patient died of cardiac function failure, pneumonia, and pulmonary hemorrhage, all of unidentified cause. Most cases of EBV-related LPD after hematopoietic stem cell transplantation consist of EBV-positive B-cell LPD, and, to our knowledge, de novo EBV-positive T-cell LPD subsequent to transplantation has not been previously reported.

Post-Transplant Hypophosphatemia and the Risk of Death-Censored Graft Failure and Mortality after Kidney Transplantation.

PubMed

van Londen, Marco; Aarts, Brigitte M; Deetman, Petronella E; van der Weijden, Jessica; Eisenga, Michele F; Navis, Gerjan; Bakker, Stephan J L; de Borst, Martin H

2017-08-07

Hypophosphatemia is common in the first year after kidney transplantation, but its clinical implications are unclear. We investigated the relationship between the severity of post-transplant hypophosphatemia and mortality or death-censored graft failure in a large cohort of renal transplant recipients with long-term follow-up. We performed a longitudinal cohort study in 957 renal transplant recipients who were transplanted between 1993 and 2008 at a single center. We used a large real-life dataset containing 28,178 phosphate measurements (median of 27; first to third quartiles, 23-34) serial measurements per patient) and selected the lowest intraindividual phosphate level during the first year after transplantation. The primary outcomes were all-cause mortality, cardiovascular mortality, and death-censored graft failure. The median (interquartile range) intraindividual lowest phosphate level was 1.58 (1.30-1.95) mg/dl, and it was reached at 33 (21-51) days post-transplant. eGFR was the main correlate of the lowest serum phosphate level (model R 2 =0.32). During 9 (5-12) years of follow-up, 181 (19%) patients developed graft failure, and 295 (35%) patients died, of which 94 (32%) deaths were due to cardiovascular disease. In multivariable Cox regression analysis, more severe hypophosphatemia was associated with a lower risk of death-censored graft failure (fully adjusted hazard ratio, 0.61; 95% confidence interval, 0.43 to 0.88 per 1 mg/dl lower serum phosphate) and cardiovascular mortality (fully adjusted hazard ratio, 0.37; 95% confidence interval, 0.22 to 0.62) but not noncardiovascular mortality (fully adjusted hazard ratio, 1.33; 95% confidence interval, 0.9 to 1.96) or all-cause mortality (fully adjusted hazard ratio, 1.15; 95% confidence interval, 0.81 to 1.61). Post-transplant hypophosphatemia develops early after transplantation. These data connect post-transplant hypophosphatemia with favorable long-term graft and patient outcomes. Copyright © 2017 by the

Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disease in Japan.

PubMed

Sato, Emiko; Ohga, Shouichi; Kuroda, Hiroshi; Yoshiba, Fumiaki; Nishimura, Miki; Nagasawa, Masayuki; Inoue, Masami; Kawa, Keisei

2008-09-01

Epstein-Barr virus (EBV)-associated T/NK-cell lymphoproliferative disease (LPD) has been linked to several different disorders. Its prognosis is generally poor and a treatment strategy has yet to be established. There are reports, however, that hematopoietic stem cell transplantation (HSCT) can cure this disease. To clarify the current situation regarding allogeneic hematopoietic stem cell transplantation (allo-HSCT) for EBV-associated T/NK-LPD, a nationwide survey was performed in Japan. Data for 74 patients were collected. There were 42 cases of chronic active EBV infection (CAEBV), 10 cases of EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), and 22 cases of EBV-associated lymphoma/leukemia (EBV-lymphoma/leukemia). Of those with CAEBV, 54% had the EBV-infected T-cell type and 59% with EBV-lymphoma/leukemia had the EBV-infected NK-cell type. Most patients with EBV-HLH and EBV-lymphoma/leukemia received allo-HSCT within 1 year after onset compared to only 14% of patients with CAEBV. The event-free survival (EFS) rate following allo-HSCT was 0.561 +/- 0.086 for CAEBV, 0.614 +/- 0.186 for EBV-HLH, and 0.309 +/- 0.107 for EBV-lymphoma/leukemia. The EFS of allo-HSCT with conventional conditioning was 0.488 +/- 0.074 and with reduced-intensity conditioning was 0.563 +/- 0.124. Thus, in a substantial number of cases, EBV-associated T/NK-LPD can be cured by either allogeneic conventional stem cell transplantation or reduced-intensity stem cell transplantation. Copyright 2008 Wiley-Liss, Inc.

Mouse model of Epstein-Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease.

PubMed

Minamitani, Takeharu; Ma, Yijie; Zhou, Hufeng; Kida, Hiroshi; Tsai, Chao-Yuan; Obana, Masanori; Okuzaki, Daisuke; Fujio, Yasushi; Kumanogoh, Atsushi; Zhao, Bo; Kikutani, Hitoshi; Kieff, Elliott; Gewurz, Benjamin E; Yasui, Teruhito

2017-05-02

Epstein-Barr virus (EBV) is a major cause of immunosuppression-related B-cell lymphomas and Hodgkin lymphoma (HL). In these malignancies, EBV latent membrane protein 1 (LMP1) and LMP2A provide infected B cells with surrogate CD40 and B-cell receptor growth and survival signals. To gain insights into their synergistic in vivo roles in germinal center (GC) B cells, from which most EBV-driven lymphomas arise, we generated a mouse model with conditional GC B-cell LMP1 and LMP2A coexpression. LMP1 and LMP2A had limited effects in immunocompetent mice. However, upon T- and NK-cell depletion, LMP1/2A caused massive plasmablast outgrowth, organ damage, and death. RNA-sequencing analyses identified EBV oncoprotein effects on GC B-cell target genes, including up-regulation of multiple proinflammatory chemokines and master regulators of plasma cell differentiation. LMP1/2A coexpression also up-regulated key HL markers, including CD30 and mixed hematopoietic lineage markers. Collectively, our results highlight synergistic EBV membrane oncoprotein effects on GC B cells and provide a model for studies of their roles in immunosuppression-related lymphoproliferative diseases.

Vaccination titres pre- and post-transplant in paediatric renal transplant recipients and the impact of immunosuppressive therapy.

PubMed

Höcker, Britta; Aguilar, Martin; Schnitzler, Paul; Pape, Lars; Bald, Martin; König, Jens; Marks, Stephen D; Genc, Gurkan; Büscher, Anja; Kemper, Markus J; Billing, Heiko; Pohl, Martin; Dello Strologo, Luca; Webb, Nicholas J A; Rieger, Susanne; Mankertz, Annette; Krupka, Kai; Bruckner, Thomas; Fichtner, Alexander; Tönshoff, Burkhard

2018-05-01

Avoidance of vaccine-preventable infections in paediatric renal allograft recipients is of utmost importance. However, the development and maintenance of protective vaccination titres may be impaired in this patient population owing to their need for immunosuppressive medication. In the framework of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN), we therefore performed a multi-centre, multi-national study and analysed vaccination titres pre- and post-transplant in 155 patients with serial titre measurements in comparison with published data in healthy children. The percentage of patients with positive vaccination titres before renal transplantation (RTx) was low, especially for diphtheria (38.5%, control 75%) and pertussis (21.3%, control 96.3%). As few as 58.1% of patients had a hepatitis B antibody (HBsAb) titre >100 IU/L before RTx. 38.1% of patients showed a vaccination titre loss post-transplant. Patients with an HBsAb titre between 10 and 100 IU/L before RTx experienced a significantly (p < 0.05) more frequent hepatitis B vaccination titre loss post-transplant than patients with an HBsAb titre >100 IU/L. The revaccination rate post-transplant was low and revaccination failed to induce positive titres in a considerable number of patients (27.3 to 83.3%). Treatment with rituximab was associated with a significantly increased risk of a vaccination titre loss post-transplant (odds ratio 4.26, p = 0.033). These data show a low percentage of patients with positive vaccination titres pre-transplant, a low revaccination rate post-transplant with limited antibody response, and a high rate of vaccination titre losses.

[Autoimmune lymphoproliferative syndrome].

PubMed

Rodrigues, Vera; Conde, Marta; Figueiredo, António; Vasconcelos, Júlia; Dias, Alexandra

2011-01-01

The Autoimmune Lymphoproliferative Syndrome (ALPS) is an impairment of lymphocyte apoptosis expressed by generalized non-malignant lymphoproliferation, lymphadenopathy and/or splenomegaly. This article describes a seven and 14 year old males. The first one was admitted at 3 years of age with fever, bicytopenia and generalized lymphadenopathy. Hystopathological analysis of lymph nodes showed reactive follicular hyperplasia and marked paracortical expansion. He was readmitted three years later presenting herpes zoster and similar clinical features. High levels of IL-10 and increasing tendency of Fas-L in plasma and serum. The second child was admitted at 13 years of age presenting thigh and gluteus cellulitis, anemia and neutropenia. T lymphocytes aß+CD4-CD8- 3,1%. Hystopathological analysis of lymph nodes showed marked paracortical hyperplasia. Both children are treated with mycophenolate mofetil with good response. ALPS is an underestimated entity that must be considered in non malign lymphoproliferation, autoimmunity and expansion of an unusual population of a/ßCD3+CD4-CD8-(double-negative T cells>1%).

Risk Factors for Post-Transplant Death in Donation after Circulatory Death Liver Transplantation.

PubMed

Liu, Song; Miao, Ji; Shi, Xiaolei; Wu, Yafu; Jiang, Chunping; Zhu, Xinhua; Wu, Xingyu; Ding, Yitao; Xu, Qingxiang

2017-08-22

In spite of the increasing success of liver transplantation, there remains inevitable risk of postoperative complications, re-operations, and even death. Risk factors that correlate with post-transplant death have not been fully identified. We performed a retrospective analysis of 65 adults that received donation after circulatory death liver transplantation. Binary logistic regression and Cox's proportional hazards regression were employed to identify risk factors that associate with postoperative death and the length of survival period. Twenty-two recipients (33.8%) deceased during 392.3 ± 45.6 days. The higher preoperative Child-Pugh score (p = .007), prolonged postoperative ICU stay (p = .02), and more postoperative complications (p = .0005) were observed in deceased patients. Advanced pathological staging (p = .02) with more common nerve invasion (p = .03), lymph node invasion (p = .02), and para-tumor satellite lesion (p = .01) were found in deceased group. The higher pre-transplant Child-Pugh score was a risk factor for post-transplant death (OR = 4.38, p = .011), and was correlated with reduced post-transplant survival period (OR = 0.35, p = .009). Nerve invasion was also a risk factor for post-transplant death (OR = 13.85, p = .014), although it failed to affect survival period. Our study emphasizes the impact of recipient's pre-transplant liver function as well as pre-transplant nerve invasion by recipient's liver cancer cells on postoperative outcome and survival period in patients receiving liver transplantation.

Clinicopathological categorization of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disease: an analysis of 42 cases with an emphasis on prognostic implications.

PubMed

Paik, Jin Ho; Choe, Ji-Young; Kim, Hyojin; Lee, Jeong-Ok; Kang, Hyoung Jin; Shin, Hee Young; Lee, Dong Soon; Heo, Dae Seog; Kim, Chul-Woo; Cho, Kwang-Hyun; Kim, Tae Min; Jeon, Yoon Kyung

2017-01-01

Epstein-Barr virus-positive T/NK-cell lymphoproliferative diseases (EBV-T/NK-LPDs) include several overlapping EBV-related conditions with variably aggressive courses. For prognostic categorization, we retrospectively analyzed 42 EBV-T/NK-LPD cases. Male (79% [33/42]), young (≤40 years; 83% [35/42]) patients and T-cell lineage (81% [34/42]; CD8/CD4 = 1.8) were predominant. Clinicopathologically, three systemic and one cutaneous category were developed: hemophagocytic lymphohistiocytosis (HLH; 26% [11/42]), chronic active EBV infection (CAEBV; 31% [13/42]), systemic unclassifiable disease (24% [10/42]), and hydroa vacciniforme/hydroa vacciniforme-like lymphoma (HV/HVL; 19% [8/42]). Prognostically, cutaneous disease (HV/HVL) was better than systemic disease (p = 0.014; median, 285 vs. 10 months). In systemic diseases, HLH was worst (p = 0.002; 3[HLH] vs. 4[unclassifiable] vs. not reached [CAEBV]). Univariate survival analysis (n = 42) revealed cytopenia (≥one lineage; p < 0.001), onset age (>40 years; p = 0.001), T-cell lineage (p = 0.041), hemophagocytic histiocytes (p = 0.031), elevated lactate dehydrogenase (p = 0.020), and liver dysfunction (p = 0.023) predicted shorter survival. In multivariate analysis, T-cell lineage (p = 0.025 [HR =11.3]) and cytopenia (p = 0.028 [HR =5.4]) were independent prognostic factors. Therefore, EBV-T/NK-LPD could be classified into four prognostic categories.

Treatment of Primary Cutaneous CD4 Small/Medium T cell Lymphoproliferative Disorder with Intralesional Triamcinolone Acetonide.

DTIC Science & Technology

2018-02-15

12. REPORT TYPE 02/15/2018 Poster 4. TITLE AND SUBTITLE Treatment of Primary Cutaneous CD4+ Small/Medium T- cell Lymphoproliferative Disorder with...cutaneous CD4+ small/medium T- cell lymphoproliferative disorder (LPD) is a generally indolent cutaneous T- cell proliferation. Most cases follow a benign...lmmunohistochemistry showed diffuse CD3+ CD4+ T- cells without CD30, TIA1 or CD10. A subset of medium to large cells expressed BCL-6. Small subsets of B- cells and CDB

Diagnostic Utility of a Clonality Test for Lymphoproliferative Diseases in Koreans Using the BIOMED-2 PCR Assay

PubMed Central

Kim, Young; Choi, Yoo Duk; Choi, Chan

2013-01-01

Background A clonality test for immunoglobulin (IG) and T cell receptor (TCR) is a useful adjunctive method for the diagnosis of lymphoproliferative diseases (LPDs). Recently, the BIOMED-2 multiplex polymerase chain reaction (PCR) assay has been established as a standard method for assessing the clonality of LPDs. We tested clonality in LPDs in Koreans using the BIOMED-2 multiplex PCR and compared the results with those obtained in European, Taiwanese, and Thai participants. We also evaluated the usefulness of the test as an ancillary method for diagnosing LPDs. Methods Two hundred and nineteen specimens embedded in paraffin, including 78 B cell lymphomas, 80 T cell lymphomas and 61 cases of reactive lymphadenitis, were used for the clonality test. Results Mature B cell malignancies showed 95.7% clonality for IG, 2.9% co-existing clonality, and 4.3% polyclonality. Mature T cell malignancies exhibited 83.8% clonality for TCR, 8.1% co-existing clonality, and 16.2% polyclonality. Reactive lymphadenitis showed 93.4% polyclonality for IG and TCR. The majority of our results were similar to those obtained in Europeans. However, the clonality for IGK of B cell malignancies and TCRG of T cell malignancies was lower in Koreans than Europeans. Conclusions The BIOMED-2 multiplex PCR assay was a useful adjunctive method for diagnosing LPDs. PMID:24255634

Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders.

PubMed

Park, Sanghui; Ko, Young H

2014-01-01

Primary infection with Epstein-Barr virus (EBV) is usually asymptomatic and, in a normal host, EBV remains latent in B cells after primary infection for the remainder of life. Uncommonly, EBV can infect T or natural killer (NK) cells in a person with a defect in innate immunity, and EBV infection can cause unique systemic lymphoproliferative diseases (LPD) of childhood. Primary infection in young children can be complicated by hemophagocytic lymphohistiocytosis or fulminant systemic T-cell LPD of childhood. Uncommonly, patients can develop chronic active EBV (CAEBV) disease-type T/NK LPD, which includes CAEBV infection of the systemic form, hydroa vacciniforme-like T-cell LPD, and mosquito-bite hypersensitivity. The clinical course of CAEBV disease-type T/NK LPD can be smoldering, persistent or progressive, depending on the balance between viral factors and host immunity. Aggressive NK-cell leukemia, hydroa vacciniforme-like T-cell lymphoma, or uncommonly extranodal NK/T-cell lymphoma can develop in children and young adults with CAEBV disease-type T/NK-cell LPD. Extranodal T/NK-cell lymphoma is a disease of adults, and its incidence begins to increase in the third decade and comprises the major subtype of T/NK LPD throughout life. Aggressive NK-cell leukemia and nodal T/NK-cell lymphoma of the elderly are fulminant diseases, and immune senescence may be an important pathogenetic factor. This review describes the current progress in identifying different types of EBV-associated T/NK-cell LPD and includes a brief presentation of data from Korea. © 2014 Japanese Dermatological Association.

[Cardiac transplantation and neoplasms: experiences at Escola Paulista de Medicina of the Federal University of São Paulo].

PubMed

Mello Junior, Walter Teixeira de; Branco, João Nelson R; Catani, Roberto; Aguiar, Luciano de Figueiredo; Paez, Rodrigo Pereira; Buffolo, Enio

2006-02-01

To study the occurrence and types of neoplasms developed by patients who underwent an orthotopic cardiac transplantation under the Program of Cardiac Transplantation of Escola Paulista de Medicina, Federal University of São Paulo. This is an observational study of 106 patients who underwent orthotopic cardiac transplantation from November 1986 to September 2002 and survived at least thirty days following the procedure. The triple immunosuppressive regimen given included cyclosporin A, azathioprine and a corticosteroid agent. Only two patients received OKT3 in addition to the regimen established. Mean follow-up was 61.4 months (ranging from two months to 192 months). Twenty-three patients (21.3%) developed neoplasms--56.5% of these were skin neoplasm, 30.1%, solid tumors, and 13.4% of post-transplant lymphoproliferative disease (PTLD). Mean interval between transplantation and diagnosis of neoplasm was: 54.9 months for skin neoplasm; 24.8 months for solid tumors and 70.3 months for PTLD. Malignant neoplasms are relatively common in the population studied. Skin cancer was the most common type compared to the other types of neoplasms. Solid tumors were more frequently diagnosed than the lymphoproliferative diseases in the population examined.

Pre- and post-transplant monitoring of soluble CD30 levels as predictor of acute renal allograft rejection.

PubMed

Wang, Dong; Wu, Guo-Jun; Wu, Wei-Zhen; Yang, Shun-Liang; Chen, Jin-Hua; Wang, He; Lin, Wen-Hong; Wang, Qing-Hua; Zeng, Zhang-Xin; Tan, Jian-Ming

2007-06-01

Identification of renal graft candidates at high risk of impending acute rejection (AR) and graft loss may be helpful for patient-tailored immunosuppressive regimens and renal graft survival. To investigate the feasibility with soluble CD30 (sCD30) as predictor of AR, sCD30 levels of 70 patients were detected on day 0 pre-transplant and day 1, 3, 5, 7, 10, 14, 21, and 30 post-transplant. AR episodes in 6 months were recorded and then patients were divided into Group AR (n=11) and Group UC (n=59). Results showed that the patients had higher pre-transplant sCD30 levels than healthy people. A significant decrease of sCD30 was observed on the first day post-transplant and continued until day 14 post-transplant. Soluble CD30 presented a stable level from day 14 to 30 post-transplant. Pre-transplant sCD30 levels of Group AR were much higher than those of Group UC (P<0.001). Patients of Group AR also had higher sCD30 levels than those of Group UC on day 1, 3, 5, 7, 10 and 14 (P<0.001). The sCD30 level presented a significantly delayed decrease in the patients of Group AR. Statistical results showed that the highest value of area under ROC curve (0.95) was obtained on day 5 post-transplant, suggesting that sCD30 levels on day 5 are of high predictive value. Therefore, sCD30 level may be a good marker of increased alloreactivity and of significant predictive value. It's necessary to monitor the variation of sCD30 in the early period post-transplant.

Drug sensitivity profiling identifies potential therapies for lymphoproliferative disorders with overactive JAK/STAT3 signaling

PubMed Central

Kuusanmäki, Heikki; Dufva, Olli; Parri, Elina; van Adrichem, Arjan J.; Rajala, Hanna; Majumder, Muntasir M.; Yadav, Bhagwan; Parsons, Alun; Chan, Wing C.; Wennerberg, Krister; Mustjoki, Satu; Heckman, Caroline A.

2017-01-01

Constitutive JAK/STAT3 signaling contributes to disease progression in many lymphoproliferative disorders. Recent genetic analyses have revealed gain-of-function STAT3 mutations in lymphoid cancers leading to hyperactivation of STAT3, which may represent a potential therapeutic target. Using a functional reporter assay, we screened 306 compounds with selective activity against various target molecules to identify drugs capable of inhibiting the cellular activity of STAT3. Top hits were further validated with additional models including STAT3-mutated natural killer (NK)-cell leukemia/lymphoma cell lines and primary large granular lymphocytic (LGL) leukemia cells to assess their ability to inhibit STAT3 phosphorylation and STAT3 dependent cell viability. We identified JAK, mTOR, Hsp90 and CDK inhibitors as potent inhibitors of both WT and mutant STAT3 activity. The Hsp90 inhibitor luminespib was highly effective at reducing the viability of mutant STAT3 NK cell lines and LGL leukemia patient samples. Luminespib decreased the phosphorylation of mutant STAT3 at Y705, whereas JAK1/JAK2 inhibitor ruxolitinib had reduced efficacy on mutant STAT3 phosphorylation. Additionally, combinations involving Hsp90, JAK and mTOR inhibitors were more effective at reducing cell viability than single agents. Our findings show alternative approaches to inhibit STAT3 activity and suggest Hsp90 as a therapeutic target in lymphoproliferative disorders with constitutively active STAT3. PMID:29228628

A PLC-γ1-independent, RasGRP1-ERK dependent pathway drives lymphoproliferative disease in LAT-Y136F mutant mice

PubMed Central

Kortum, Robert L.; Rouquette-Jazdanian, Alexandre K.; Miyaji, Michihiko; Merrill, Robert K.; Markegard, Evan; Pinski, John M.; Wesselink, Amelia; Nath, Nandan N.; Alexander, Clayton P.; Li, Wenmei; Kedei, Noemi; Roose, Jeroen P.; Blumberg, Peter M.; Samelson, Lawrence E.; Sommers, Connie L.

2012-01-01

Mice expressing a germline mutation in the PLC-γ1 binding site of LAT (linker for activation of T cells) show progressive lymphoproliferation and ultimately die at 4–6 months of age. The hyper-activated T cells in these mice show defective TCR-induced calcium flux, but enhanced Ras/ERK activation that is critical for disease progression. Despite the loss of LAT-dependent PLC-γ1 binding and activation, genetic analysis revealed RasGRP1, and not Sos1 or Sos2, to be the major RasGEF responsible for ERK activation and the lymphoproliferative phenotype in these mice. Analysis of isolated CD4+ T cells from LAT-Y136F mice showed altered proximal TCR-dependent kinase signaling, which activated a Zap70- and LAT-independent pathway. Moreover, LAT-Y136F T cells showed ERK activation that was dependent on Lck and/or Fyn, PKCθ, and RasGRP1. These data demonstrate a novel route to Ras activation in vivo in a pathological setting. PMID:23209318

Epstein-Barr Virus-associated lymphoproliferative disorders: experimental and clinical developments

PubMed Central

Geng, Lingyun; Wang, Xin

2015-01-01

Epstein-Barr Virus (EBV), the first human virus related to oncogenesis, was initially identified in a Burkitt lymphoma cell line in 1964. EBV infects over 90% of the world’s population. Most infected people maintain an asymptomatic but persistent EBV infection lifelong. However, in some individuals, EBV infection has been involved in the development of cancer and autoimmune disease. Nowadays, oncogenic potential of EBV has been intensively studied in a wide range of human neoplasms, including Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), etc. EBV encodes a series of viral protein and miRNAs, promoting its persistent infection and the transformation of EBV-infected cells. Although the exact role of EBV in the oncogenesis remains to be clarified, novel diagnostic and targeted therapeutic approaches are encouraging for the management of EBV-related malignancies. This review mainly focuses on the experimental and clinical advances of EBV-associated lymphoproliferative disorders. PMID:26628948

Posttransplant soluble CD30 as a predictor of acute renal allograft rejection.

PubMed

Kamali, Koosha; Abbasi, Mohammad Amin; Farokhi, Babak; Abbasi, Ata; Fallah, Parvane; Seifee, Mohammad Hasan; Ghadimi, Naime; Rezaie, Alireza R

2009-12-01

Recent results have indicated that high prerenal and postrenal transplant soluble CD30 levels may be associated with an increased acute rejection and graft loss. The aim of this study was to evaluate the feasibility of using serum sCD30 as a marker for predicting acute graft rejection. In this prospective study,we analyzed clinical data of 80 patients, whose pretransplant and posttransplant serum levels of sCD30 were detected by enzyme-linked immunoassay. Eight patients developed acute rejection, 7 patients showed delayed graft function, and 65 recipients experienced an uncomplicated course group. The patients were followed for 12 months, and there were no deaths. Preoperative sCD30 levels of 3 groups were 96.2 -/+ 32.5, 80.2 -/+ 28.3, and 76.8 -/+ 29.8 U/mL (P = .28). After transplant, a significant decrease in the sCD30 level was detected in 3 groups on day 14 posttransplant (P < .001), while sCD30 levels of acute rejection group remained significantly higher than delayed graft function and nonrejecting patients (28.3 -/+ 5.2, 22.1 -/+ 3.2, and 19.8 -/+ 4.7 U/mL) (P = .02). Positive panel reactive antibody was not statistically different among groups (P = .05). Also, hemodialysis did not affect sCD30 levels (P = .05). Receiver operating characteristic curve demonstrated that the sCD30 level on day 14 posttransplant could discriminate patients who subsequently suffered acute allograft rejection (area under receiver operating characteristic curve, 0.95). According to receiver operating characteristic curve, 20 U/mL may be the optimal operational cutoff level to predict impending graft rejection (specificity 93.8%, sensitivity 83.3%). Measurement of the soluble CD30 level on day 14 after transplant might offer a noninvasive means for recognizing patients at risk of acute graft rejection during the early posttransplant period.

Statin therapy is not associated with improved outcomes after heart transplantation in children and adolescents.

PubMed

Greenway, Steven C; Butts, Ryan; Naftel, David C; Pruitt, Elizabeth; Kirklin, James K; Larsen, Ingrid; Urschel, Simon; Knecht, Kenneth; Law, Yuk

2016-04-01

Although used routinely, the pleiotropic benefits of statins remain understudied in children after heart transplantation. We hypothesized that statin therapy would reduce the incidence of rejection, cardiac allograft vasculopathy (CAV) and post-transplant lymphoproliferative disease (PTLD). This study was a retrospective review of 964 pediatric (ages 5 to 18 years) heart transplant recipients in the multicenter Pediatric Heart Transplant Study registry from 2001 to 2012. Patients were excluded if they were undergoing re-transplantation, survived <1 year post-transplant, or had missing data regarding statin use. The effects of statins beyond the first year were estimated by Kaplan-Meier and Cox regression multivariable analysis for freedom from PTLD, rejection requiring treatment, any severity of CAV, and survival. Statin use was variable among participating centers with only 30% to 35% of patients ≥10 years of age started on a statin at <1 year post-transplant. After the first year post-transplant, statin-treated children (average age at transplant 13.24 ± 3.29 years) had significantly earlier rejection (HR 1.42, 95% CI 1.11 to 1.82, p = 0.006) compared with untreated children (transplanted at 12 ± 3.64 years) after adjusting for conventional risk factors for rejection. Freedom from PTLD, CAV and overall survival up to 5 years post-transplant were not affected by statin use, although the number of events was small. Statin therapy did not confer a survival benefit and was not associated with delayed onset of PTLD or CAV. Early (<1 year post-transplant) statin therapy was associated with increased later frequency of rejection. These findings suggest that a prospective trial evaluating statin therapy in pediatric heart transplant recipients is warranted. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

EBV-driven B-cell lymphoproliferative disorders: from biology, classification and differential diagnosis to clinical management

PubMed Central

Ok, Chi Young; Li, Ling; Young, Ken H

2015-01-01

Epstein–Barr virus (EBV) is a ubiquitous herpesvirus, affecting >90% of the adult population. EBV targets B-lymphocytes and achieves latent infection in a circular episomal form. Different latency patterns are recognized based on latent gene expression pattern. Latent membrane protein-1 (LMP-1) mimics CD40 and, when self-aggregated, provides a proliferation signal via activating the nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase pathways to promote cellular proliferation. LMP-1 also induces BCL-2 to escape from apoptosis and gives a signal for cell cycle progression by enhancing cyclin-dependent kinase 2 and phosphorylation of retinoblastoma (Rb) protein and by inhibiting p16 and p27. LMP-2A blocks the surface immunoglobulin-mediated lytic cycle reactivation. It also activates the Ras/PI3K/Akt pathway and induces Bcl-xL expression to promote B-cell survival. Recent studies have shown that ebv-microRNAs can provide extra signals for cellular proliferation, cell cycle progression and anti-apoptosis. EBV is well known for association with various types of B-lymphocyte, T-lymphocyte, epithelial cell and mesenchymal cell neoplasms. B-cell lymphoproliferative disorders encompass a broad spectrum of diseases, from benign to malignant. Here we review our current understanding of EBV-induced lymphomagenesis and focus on biology, diagnosis and management of EBV-associated B-cell lymphoproliferative disorders. PMID:25613729

Minimal disease detection of B-cell lymphoproliferative disorders by flow cytometry: multidimensional cluster analysis.

PubMed

Duque, Ricardo E

2012-04-01

Flow cytometric analysis of cell suspensions involves the sequential 'registration' of intrinsic and extrinsic parameters of thousands of cells in list mode files. Thus, it is almost irresistible to describe phenomena in numerical terms or by 'ratios' that have the appearance of 'accuracy' due to the presence of numbers obtained from thousands of cells. The concepts involved in the detection and characterization of B cell lymphoproliferative processes are revisited in this paper by identifying parameters that, when analyzed appropriately, are both necessary and sufficient. The neoplastic process (cluster) can be visualized easily because the parameters that distinguish it form a cluster in multidimensional space that is unique and distinguishable from neighboring clusters that are not of diagnostic interest but serve to provide a background. For B cell neoplasia it is operationally necessary to identify the multidimensional space occupied by a cluster whose kappa:lambda ratio is 100:0 or 0:100. Thus, the concept of kappa:lambda ratio is without meaning and would not detect B cell neoplasia in an unacceptably high number of cases.

Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8-9 September 2008.

PubMed

Cohen, J I; Kimura, H; Nakamura, S; Ko, Y-H; Jaffe, E S

2009-09-01

Recently novel Epstein-Barr virus (EBV) lymphoproliferative diseases (LPDs) have been identified in non-immunocompromised hosts, both in Asia and Western countries. These include aggressive T-cell and NK-cell LPDs often subsumed under the heading of chronic active Epstein-Barr virus (CAEBV) infection and EBV-driven B-cell LPDs mainly affecting the elderly. To better define the pathogenesis, classification, and treatment of these disorders, participants from Asia, The Americas, Europe, and Australia presented clinical and experimental data at an international meeting. The term systemic EBV-positive T-cell LPD, as adopted by the WHO classification, is preferred as a pathological classification over CAEBV (the favored clinical term) for those cases that are clonal. The disease has an aggressive clinical course, but may arise in the background of CAEBV. Hydroa vacciniforme (HV) and HV-like lymphoma represent a spectrum of clonal EBV-positive T-cell LPDs, which have a more protracted clinical course; spontaneous regression may occur in adult life. Severe mosquito bite allergy is a related syndrome usually of NK cell origin. Immune senescence in the elderly is associated with both reactive and neoplastic EBV-driven LPDs, including EBV-positive diffuse large B-cell lymphomas. The participants proposed an international consortium to facilitate further clinical and biological studies of novel EBV-driven LPDs.

Relative reductions in soluble CD30 levels post-transplant predict acute graft function in islet allograft recipients receiving three different immunosuppression protocols.

PubMed

Hire, Kelly; Hering, Bernhard; Bansal-Pakala, Pratima

2010-08-01

Despite advances in islet transplantation, challenges remain in monitoring for anti-islet immune responses. Soluble CD30 (sCD30) has been investigated as a predictor of acute rejection in kidney, lung, and heart transplantation as well as in a single study in human islet cell recipients. In this study, sCD30 levels were retrospectively assessed in 19 allograft recipients treated with three different immunosuppression induction therapies. Soluble CD30 levels were assessed at pre-transplant; early post-transplant (day 4-day 7); one-month post-transplant; and late post-transplant (day 90-day 120) and then correlated with eventual graft outcomes at 1-year follow-up. Results showed no correlation between mean serum sCD30 levels at any point in time pre- or post-transplant and graft function at 1-year follow-up. However, analysis demonstrated that mean sCD30 levels at day 28 or day 90-day 120 decreased from pre-transplant levels in recipients with long-term islet allograft function compared to recipients with partial or non-graft function (a decrease of 43.6+/-25.6% compared to 16.7+/-35.2%, p<0.05). In another finding, immunosuppression with the ATG protocol led to a greater reduction in sCD30 levels post-transplant overall. A larger reduction post-transplant correlated with full graft function. The results demonstrate that a relative reduction in sCD30 levels post-transplant may be applicable as a biomarker to monitor graft function in islet allograft recipients. Additionally, knowledge of the impact of various immunosuppression protocols on the timing and extent of changes in post-transplant sCD30 levels could aid in patient-specific tailoring of immunosuppression. Copyright © 2010 Elsevier B.V. All rights reserved.

Incidence and risk factors for the metabolic syndrome and posttransplant diabetes in renal transplant recipients taking tacrolimus.

PubMed

Pérez-Flores, I; Sánchez-Fructuoso, A; Calvo, N; Valga, E F; Barrientos, A

2010-10-01

We investigated the incidence and risk factors for the metabolic syndrome (MS) and posttransplant diabetes mellitus (PTDM) among renal transplant recipients on tacrolimus-based immunosuppressive regimens during the first year posttransplant. In addition, we studied the relationship between MS and PTDM with transplant renal function at 1 year. We included the 100 patients who received a renal transplant in our unit between January 2007 and June 2008, collecting demographic, clinical and biochemical characteristics at 1, 6, and 12 months posttransplantation. We excluded 15% of patients with pretransplantation diabetes. MS was defined according to the National Cholesterol Education Program criteria and PTDM according to World Health Organization criteria. Insulin resistance at one year posttransplant was measured using the homeostasis model assessment (HOMA) index. Insulin therapy was required in 46% of patients during the first hospitalization and hyperglycemia was present in 65% of the cases. The incidence of PTDM decreased throughout the first year posttransplant, namely, 44%, 24%, and 13% at 1, 6, and 12 months, respectively. The incidence of MS increased to 33%, 48% and 50% at 1, 6, and 12 months, respectively. Age, body mass index, plasma fasting glucose levels at 1 month posttransplant, and pretransplant fasting triglyceridemia predicted PTDM. Rejection and in-patient hyperglycemia predicted MS. PTDM and MS were closely correlated (P=.004). The HOMA index was higher among patients with MS than other subjects at 1 year posttransplant: 3.2 (1.2) versus 2.3 (0.9; P=.035). Neither PTDM nor MS was associated with impaired plasma creatinine levels at 1 year after kidney transplantation. There was an high incidence of PTDM and MS among kidney transplant recipients treated with tacrolimus as the main immunosuppressive agent. The HOMA index was a good test of insulin resistance in this population. Screening and treatment of risk factors may avoid the development of

Ventricular assist devices as bridge to heart transplantation: impact on post-transplant infections.

PubMed

Héquet, Delphine; Kralidis, Georg; Carrel, Thierry; Cusini, Alexia; Garzoni, Christian; Hullin, Roger; Meylan, Pascal R; Mohacsi, Paul; Mueller, Nicolas J; Ruschitzka, Frank; Tozzi, Piergiorgio; van Delden, Christian; Weisser, Maja; Wilhelm, Markus J; Pascual, Manuel; Manuel, Oriol

2016-07-08

Ventricular assist devices (VAD) are valuable options for patients with heart failure awaiting cardiac transplantation. We assessed the impact of pre-transplant VAD implantation on the incidence of post-transplant infections in a nationwide cohort of heart transplant recipients. Heart transplant recipients included in the Swiss Transplant Cohort Study between May 2008 and December 2012 were analyzed. Cumulative incidence curves were used to calculate the incidence of bacterial or Candida infections (primary endpoint) and of other infections (secondary endpoint) after transplant. Cox regression models treating death as a competing risk were used to identify risk factors for the development of infection after transplant. Overall, 119 patients were included in the study, 35 with a VAD and 84 without VAD. Cumulative incidences of post-transplant bacterial or Candida infections were 37.7 % in VAD patients and 40.4 % in non-VAD patients. In multivariate analysis, the use of cotrimoxazole prophylaxis was the only variable associated with bacterial/Candida infections after transplant (HR 0.29 [95 % CI 0.15-0.57], p < 0.001), but presence of a VAD was not (HR 0.94, [95 % CI 0.38-2.32], p = 0.89, for continuous-flow devices, and HR 0.45 [0.15 - 1.34], p = 0.15, for other devices). Risk for post-transplant viral and all fungal infections was not increased in patients with VAD. One-year survival was 82.9 % (29/35) in the VAD group and 82.1 % (69/84) in the non-VAD group. All 6 patients in the VAD group that died after transplant had a history of pre-transplant VAD infection. In this nationwide cohort of heart transplant recipients, the presence of VAD at the time of transplant had no influence on the development of post-transplant infections.

Rare complications after second hematopoietic stem cell transplantation for thalassemia major.

PubMed

Yanir, Asaf; Yatsiv, Ido; Braun, Jacques; Zilkha, Amir; Brooks, Rebecca; Bouhanna, Dalia; Weintraub, Michael; Stepensky, Polina

2012-07-01

We describe an 11-year-old girl with thalassemia major who underwent a second hematopoietic stem cell transplantation from a matched related donor and who subsequently developed posttransplant lymphoproliferative disorder complicated by severe ascending paralysis resembling Guillian-Barré syndrome. Six months later she developed a massive pericardial effusion. She received a multimodal treatment for these complications and currently, 18 months after transplantation, she is in a good clinical condition, is transfusion independent, with no evidence of graft-versus-host disease and off all treatment. This case highlights the dilemma surrounding second hematopoietic stem cell transplantations in hemoglobinopathies and the need for a careful, well informed, and collaborative decision-making process by patients, families, and medical professionals.

Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients.

PubMed

Ben-Mustapha, Imen; Agrebi, Nourhen; Barbouche, Mohamed-Ridha

2018-03-01

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency disease due to impaired Fas-Fas ligand apoptotic pathway. It is characterized by chronic nonmalignant, noninfectious lymphadenopathy and/or splenomegaly associated with autoimmune manifestations primarily directed against blood cells. Herein, we review the heterogeneous ALPS molecular bases and discuss recent findings revealed by the study of consanguineous patients. Indeed, this peculiar genetic background favored the identification of a novel form of AR ALPS-FAS associated with normal or residual protein expression, expanding the spectrum of ALPS types. In addition, rare mutational mechanisms underlying the splicing defects of FAS exon 6 have been identified in AR ALPS-FAS with lack of protein expression. These findings will help decipher critical regions required for the tight regulation of FAS exon 6 splicing. We also discuss the genotype-phenotype correlation and disease severity in AR ALPS-FAS. Altogether, the study of ALPS molecular bases in endogamous populations helps to better classify the disease subgroups and to unravel the Fas pathway functioning. ©2017 Society for Leukocyte Biology.

Post-transplant increased levels of serum sCD30 is a marker for prediction of kidney allograft loss in a 5-year prospective study.

PubMed

Delgado, Julio C; Pavlov, Igor Y; Shihab, Fuad S

2009-12-01

Levels of sCD30 represent a biomarker for early outcome in kidney transplantation. The purpose of this study was to determine the role of sCD30 levels for prediction of graft loss in the late post-transplant period. Sera were collected immediately pre-transplant and yearly thereafter for up to 5-year post-transplant in 37 primary renal transplant recipients. Levels of serum sCD30 were tested using a fluorescent microsphere assay. Levels of sCD30 significantly decreased after transplantation and remained normal in 34 patients without graft loss up to 5-year post-transplant. Elevated levels of serum sCD30 preceded the increase of serum creatinine in patients with subsequent graft loss. Elevated levels of serum sCD30 post-transplant might be a marker for predicting subsequent graft loss in the post-transplant period.

Modeling the effects of functional performance and post-transplant comorbidities on health-related quality of life after heart transplantation.

PubMed

Butler, Javed; McCoin, Nicole S; Feurer, Irene D; Speroff, Theodore; Davis, Stacy F; Chomsky, Don B; Wilson, John R; Merrill, Walter H; Drinkwater, Davis C; Pierson, Richard N; Pinson, C Wright

2003-10-01

Health-related quality of life and functional performance are important outcome measures following heart transplantation. This study investigates the impact of pre-transplant functional performance and post-transplant rejection episodes, obesity and osteopenia on post-transplant health-related quality of life and functional performance. Functional performance and health-related quality of life were measured in 70 adult heart transplant recipients. A composite health-related quality of life outcome measure was computed via principal component analysis. Iterative, multiple regression-based path analysis was used to develop an integrated model of variables that affect post-transplant functional performance and health-related quality of life. Functional performance, as measured by the Karnofsky scale, improved markedly during the first 6 months post-transplant and was then sustained for up to 3 years. Rejection Grade > or =2 was negatively associated with health-related quality of life, measured by Short Form-36 and reversed Psychosocial Adjustment to Illness Scale scores. Patients with osteopenia had lower Short Form-36 physical scores and obese patients had lower functional performance. Path analysis demonstrated a negative direct effect of obesity (beta = - 0.28, p < 0.05) on post-transplant functional performance. Post-transplant functional performance had a positive direct effect on the health-related quality of life composite score (beta = 0.48, p < 0.001), and prior rejection episodes grade > or =2 had a negative direct effect on this measure (beta = -0.29, p < 0.05). Either directly or through effects mediated by functional performance, moderate-to-severe rejection, obesity and osteopenia negatively impact health-related quality of life. These findings indicate that efforts should be made to devise immunosuppressive regimens that reduce the incidence of acute rejection, weight gain and osteopenia after heart transplantation.

Sirolimus for Autoimmune Disease of Blood Cells

ClinicalTrials.gov

2017-11-02

Autoimmune Pancytopenia; Autoimmune Lymphoproliferative Syndrome (ALPS); Evans Syndrome; Idiopathic Thrombocytopenic Purpura; Anemia, Hemolytic, Autoimmune; Autoimmune Neutropenia; Lupus Erythematosus, Systemic; Inflammatory Bowel Disease; Rheumatoid Arthritis

A Case of Alport Syndrome with Posttransplant Antiglomerular Basement Membrane Disease despite Negative Antiglomerular Basement Membrane Antibodies by EIA Treated with Plasmapheresis and Intravenous Immunoglobulin.

PubMed

Armstead, Sumiko I; Hellmark, Thomas; Wieslander, Jorgen; Zhou, Xin J; Saxena, Ramesh; Rajora, Nilum

2013-01-01

Posttransplant antiglomerular basement membrane (anti-GBM) disease occurs in approximately 5% of Alport patients and usually ends in irreversible graft failure. Recent research has focused on characterizing the structure of the anti-GBM alloepitope. Here we present a case of a 22-year-old male with end-stage renal disease secondary to Alport syndrome, with a previously failed renal allograft, who received a second deceased-donor kidney transplant. Six days after transplantation, he developed acute kidney injury. The serum anti-GBM IgG was negative by enzyme immunoassay (EIA). On biopsy, he had crescentic glomerulonephritis with linear GBM fixation of IgG. With further analysis by western blotting, we were able to detect antibodies to an unidentified protein from the basement membrane. This patient was treated with plasmapheresis twice per week and monthly intravenous immunoglobulin (IVIG) for a total of five months. At the end of treatment, these unknown antibodies were no longer detected. His renal function improved, and he has not required dialysis. We conclude that anti-GBM disease in patients with Alport Syndrome may be caused by circulating antibodies to other components of the basement membrane that are undetectable by routine anti-GBM EIA and may respond to treatment with plasmapheresis and IVIG.

The Epstein-Barr virus lytic protein BZLF1 as a candidate target antigen for vaccine development1

PubMed Central

Hartlage, Alex S.; Liu, Tom; Patton, John T.; Garman, Sabrina L.; Zhang, Xiaoli; Kurt, Habibe; Lozanski, Gerard; Lustberg, Mark E.; Caligiuri, Michael A.; Baiocchi, Robert A.

2015-01-01

The Epstein-Barr virus (EBV) is an oncogenic, γ-herpesvirus associated with a broad spectrum of disease. While most immune-competent individuals can effectivley develop efficient adaptive immune responses to EBV, immunocompromised individuals are at serious risk for developing life threatening diseases such as Hodgkin’s lymphoma and post-transplant lymphoproliferative disorder (PTLD). Given the significant morbidity associated with EBV infection in high-risk populations, there is a need to develop vaccine strategies that restore or enhance EBV-specific immune responses. Here, we identify the EBV immediate-early protein BZLF1 as a potential target antigen for vaccine development. Primary tumors from patients with PTLD and a chimeric human-murine model of EBV-driven lymphoproliferative disorder (EBV-LPD) express BZLF1 protein. Pulsing human dendritic cells (DC) with recombinant BZLF1 followed by incubation with autologous mononuclear cells led to expansion of BZLF1-specific CD8(+) T cells in vitro and primed BZLF1-specific T-cell responses in vivo. In addition, vaccination of hu-PBL-SCID mice with BZLF1-transduced DCs induced specific cellular immunity and significantly prolonged survival from fatal EBV-LPD. These findings identify BZLF1 as a candidate target protein in the immunosurveillance of EBV and provide rationale for considering BZLF1 in vaccine strategies to enhance primary and recall immune responses and potentially prevent EBV-associated diseases. PMID:25735952

Chronic Disease and Childhood Development: Kidney Disease and Transplantation.

ERIC Educational Resources Information Center

Klein, Susan D.; Simmons, Roberta G.

As part of a larger study of transplantation and chronic disease and the family, 124 children (10-18 years old) who were chronically ill with kidney disease (n=72) or were a year or more post-transplant (n=52) were included in a study focusing on the effects of chronic kidney disease and transplantation on children's psychosocial development. Ss…

Epstein-Barr virus and renal transplantation.

PubMed

Le, Jade; Durand, Christine M; Agha, Irfan; Brennan, Daniel C

2017-01-01

Epstein-Barr virus (EBV) is a gamma herpesvirus associated with diseases ranging from asymptomatic viremia to post-transplant malignancies in kidney transplant recipients. EBV specifically is associated with post-transplantation lymphoproliferative disorder (PTLD), in kidney transplant recipients, with increased risk in EBV seronegative patients with EBV seropositive donors on intensified immunosuppression. The diagnosis of PTLD relies on clinical suspicion plus tissue biopsy with polymerase chain reaction (PCR) testing of blood currently used for risk determination in high-risk recipients. Therapeutic strategies for PTLD include reduction of immunosuppression, chemotherapy and rituximab, and consideration of sirolimus-based immunosuppression. Antivirals such as ganciclovir are used to prevent reactivation of cytomegalovirus and other herpes viruses but are not onco-therapeutic. Radiation therapy or surgery is indicated for bulky, disseminated or recalcitrant disease. Prognosis varies depending on the type of malignancy identified and stage of disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Pre- and Posttransplant IgA Anti-Fab Antibodies to Predict Long-term Kidney Graft Survival.

PubMed

Amirzargar, M A; Amirzargar, A; Basiri, A; Hajilooi, M; Roshanaei, G; Rajabi, G; Solgi, G

2015-05-01

Immunologic factors are reliable markers for allograft monitoring, because of their seminal role in rejection process. One of these factors is the immunoglobulin (Ig)A anti-Fab of the IgG antibody. This study aimed to evaluate the predictive value of pre- and posttransplant levels of this marker for kidney allograft function and survival. Sera samples of 59 living unrelated donor kidney recipients were collected before and after transplantation (days 7, 14, and 30) and investigated for IgA anti-Fab of IgG antibody levels using enzyme-linked immunosorbent assay in relation with allograft outcome. Among 59 patients, 15 cases (25%) including 10 with acute rejection and 5 with chronic rejection episodes showed graft failure during a mean of 5 years of follow-up. High posttransplant levels of IgA anti-Fab antibodies were observed more frequently in patients with stable graft function (SGF) compared with patients with graft failure (P = 2 × 10(-6)). None of patients with acute or chronic rejection episodes had high levels of IgA anti-Fab antibodies at day 30 posttransplant compared with the SGF group (P = 10(-6) and P = .01, respectively). In addition, high levels of IgA anti-Fab antibody correlated with lesser concentration of serum creatinine at 1 month posttransplantation (P = .01). Five-year graft survival was associated with high levels of pre- and posttransplant IgA anti-Fab antibodies (P = .02 and P = .003, respectively). Our findings indicate the protective effect of higher levels of IgA anti-Fab antibodies regarding to kidney allograft outcomes and long-term graft survival. Copyright © 2015 Elsevier Inc. All rights reserved.

Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells

ClinicalTrials.gov

2017-01-12

Stem Cell Transplantation; Bone Marrow Transplantation; Peripheral Blood Stem Cell Transplantation; Allogeneic Transplantation; Genetic Diseases; Thalassemia; Pediatrics; Diamond-Blackfan Anemia; Combined Immune Deficiency; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; X-linked Lymphoproliferative Disease; Metabolic Diseases

Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis.

PubMed

Alsultan, Abdulrahman; Basher, Enas; Alqanatish, Jubran; Mohammed, Reem; Alfadhel, Majid

2018-04-01

Adenosine deaminase-2 (ADA2) deficiency (DADA2) is associated with early onset polyarteritis nodosa and vasculopathy. Classic presentation includes livedo reticularis, vasculitis, and stroke. However, the phenotype and disease severity are variable. We present a 5-year-old female who presented with features that mimicked autoimmune lymphoproliferative syndrome (ALPS) in the absence of classic features of DADA2. Exome sequencing identified a novel homozygous splicing variant in ADA2 c.882-2A > G. Patient responded to anti- tumor necrosis factor medication and is in complete remission. Hematologists should be aware of various hematological presentations of DADA2, including ALPS-like disorder, that might lack vasculitis and livedo reticularis to prevent delay in initiating optimal therapy. © 2017 Wiley Periodicals, Inc.

Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia

PubMed Central

Zhang, Mei-Jie; Bacigalupo, Andrea A.; Bashey, Asad; Appelbaum, Frederick R.; Aljitawi, Omar S.; Armand, Philippe; Antin, Joseph H.; Chen, Junfang; Devine, Steven M.; Fowler, Daniel H.; Luznik, Leo; Nakamura, Ryotaro; O’Donnell, Paul V.; Perales, Miguel-Angel; Pingali, Sai Ravi; Porter, David L.; Riches, Marcie R.; Ringdén, Olle T. H.; Rocha, Vanderson; Vij, Ravi; Weisdorf, Daniel J.; Champlin, Richard E.; Horowitz, Mary M.; Fuchs, Ephraim J.; Eapen, Mary

2015-01-01

We studied adults with acute myeloid leukemia (AML) after haploidentical (n = 192) and 8/8 HLA-matched unrelated donor (n = 1982) transplantation. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate, and posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88 received reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737 received reduced intensity conditioning regimens. In the myeloablative setting, day 30 neutrophil recovery was lower after haploidentical compared with matched unrelated donor transplants (90% vs 97%, P = .02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96% (P = .25). In the myeloablative setting, 3-month acute grade 2-4 (16% vs 33%, P < .0001) and 3-year chronic GVHD (30% vs 53%, P < .0001) were lower after haploidentical compared with matched unrelated donor transplants. Similar differences were observed after reduced intensity conditioning transplants, 19% vs 28% (P = .05) and 34% vs 52% (P = .002). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 45% (95% CI, 36-54) and 50% (95% CI, 47-53) after haploidentical and matched unrelated donor transplants (P = .38). Corresponding rates after reduced intensity conditioning transplants were 46% (95% CI, 35-56) and 44% (95% CI, 0.40-47) (P = .71). Although statistical power is limited, these data suggests that survival for patients with AML after haploidentical transplantation with posttransplant cyclophosphamide is comparable with matched unrelated donor transplantation. PMID:26130705

Epidemic Pseudomonas aeruginosa infection in patients with cystic fibrosis is not a risk factor for poor clinical Outcomes following lung transplantation.

PubMed

Pritchard, Julia; Thakrar, Mitesh V; Somayaji, Ranjani; Surette, Michael G; Rabin, Harvey R; Helmersen, Doug; Lien, Dale; Purighalla, Swathi; Waddell, Barbara; Parkins, Michael D

2016-05-01

Epidemic strains of Pseudomonas aeruginosa (ePA) causing infection in cystic fibrosis (CF) have been commonly identified from clinics around the world. ePA disproportionally impacts CF patient pre-transplant outcomes manifesting in increased exacerbation frequency, worsened treatment burden and increased rate of lung function decline, and disproportionally leads to death and/or transplantation. As other CF factors such as pre-transplant infection with multi-resistant organisms, and isolation of P. aeruginosa in the post transplant graft, may impact post-transplant outcomes, we sought to determine if infection with ePA similarly adversely impact post-transplant outcomes. Between 1991-2014, 53 CF patients from our center received lung transplants. Bacterial strain typing was performed retrospectively on isolates collected prior to transplantation. Comprehensive chart reviews were performed to obtain baseline patient characteristics and post-transplant outcomes. Of the 53 transplanted patients, 57% of patients were infected with ePA prior to transplant; the other 43% of patients had unique strains of P. aeruginosa. Mean age at transplant was 29.0years for ePA and 33.3years for unique (p=0.04). There were no differences in overall survival (HR=0.75, 95% CI 0.31-1.79), bronchiolitis obliterans syndrome (BOS) free survival (HR 1.43, 95% CI 0.54-4.84) or all other assessed outcomes including exacerbation frequency, chronic renal failure, acute cellular rejections, Aspergillus infection, airway stenosis, and post-transplant lymphoproliferative disorder. Unlike pre-transplant outcomes, CF patients infected with ePA do not experience worse post-transplant outcomes than those infected with unique strains. Therefore, lung transplantation should be considered for all patients with P. aeruginosa infection and end stage lung disease, irrespective of infection with ePA. Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

A multivariate analysis of pre-, peri-, and post-transplant factors affecting outcome after pediatric liver transplantation.

PubMed

McDiarmid, Sue V; Anand, Ravinder; Martz, Karen; Millis, Michael J; Mazariegos, George

2011-07-01

The purpose of this study was to identify significant, independent factors that predicted 6 month patient and graft survival after pediatric liver transplantation. The Studies of Pediatric Liver Transplantation (SPLIT) is a multicenter database established in 1995, of currently more than 4000 US and Canadian children undergoing liver transplantation. Previous published analyses from this data have examined specific factors influencing outcome. This study analyzes a comprehensive range of factors that may influence outcome from the time of listing through the peri- and postoperative period. A total of 42 pre-, peri- and posttransplant variables evaluated in 2982 pediatric recipients of a first liver transplant registered in SPLIT significant at the univariate level were included in multivariate models. In the final model combining all baseline and posttransplant events, posttransplant complications had the highest relative risk of death or graft loss. Reoperation for any cause increased the risk for both patient and graft loss by 11 fold and reoperation exclusive of specific complications by 4 fold. Vascular thromboses, bowel perforation, septicemia, and retransplantation, each independently increased the risk of patient and graft loss by 3 to 4 fold. The only baseline factor with a similarly high relative risk for patient and graft loss was recipient in the intensive care unit (ICU) intubated at transplant. A significant center effect was also found but did not change the impact of the highly significant factors already identified. We conclude that the most significant factors predicting patient and graft loss at 6 months in children listed for transplant are posttransplant surgical complications.

Factors involved in the generation of memory CD8+ T cells in patients with X-linked lymphoproliferative disease (XLP)

PubMed Central

Belmonte, L; Parodi, C; Baré, P; Malbrán, A; Ruibal-Ares, B; de E de Bracco, María M

2007-01-01

We have analysed the phenotype of T lymphocytes in two X-linked lymphoproliferative disease (XLP) patients with the same SH2D1A mutation differing in initial exposure to Epstein–Barr virus (EBV) and treatment. While memory T lymphocytes (with low CCR7 and CD62L expression) prevailed in both XLP patients, in patient 9, who developed acute infectious mononucleosis (AIM) and received B cell ablative treatment, the predominant phenotype was that of late effector CD8 T cells (CD27–, CD28–, CCR7–, CD62L–, CD45 RA+, perforin+), while in patient 4 (who did not suffer AIM) the prevalent phenotype of CD8 T lymphocytes was similar to that of normal controls (N) or to that of adult individuals who recovered from AIM: CD27+, CD28+, CCR7–, CD62L–, CD45 RO+ and perforin–. CD57 expression (related to senescence) was also higher in CD8 T cells from patient 9 than in patient 4, AIM or N. Persistently high EBV viral load was observed in patient 9. The results obtained from this limited number of XLP patients suggest that events related to the initial EBV encounter (antigen load, treatment, cytokine environment) may have more weight than lack of SH2D1A in determining the long-term differentiation pattern of CD8 memory T cells. PMID:17302894

Clinicopathological characteristics of four cases of EBV positive T-cell lymphoproliferative disorders of childhood in China

PubMed Central

Huang, Wenting; Lv, Ning; Ying, Jianming; Qiu, Tian; Feng, Xiaoli

2014-01-01

A new category, “EBV positive T-cell lymphoproliferative disorders (LPD) of childhood”, was proposed in the 2008 World Health Organization’s (WHO) classifications of lymphoma. This series of lymphoproliferative disorders is rare. There are two major types of this series of disorders: systemic EBV positive T-cell LPD of childhood and hydroa vacciniforme-like lymphoma (HVLL). In this study, we describe the distinct features of four cases of EBV positive T-cell LPD of childhood in China. Two were systemic EBV positive T-cell LPD of childhood, one was HVLL and one was chronic active EBV (CAEBV). The main manifestations were lymphadenopathy, fever, hepatosplenomegaly and skin rashes. The structure of the lymph nodes in the patients ranged from preserved to partially or totally destroyed. Small- to medium-sized, atypical T cells had infiltrated the lymph nodes. In HVLL, the neoplastic cells had infiltrated the dermis and subcutaneous region surrounding sweat glands and nerves. All of the cases tested positive for CD8, other T cells, cytotoxic markers and EBV-encoded RNA (EBER) without CD56 expression. Molecular analysis was performed in three cases. All of the three analyses showed a TCRγ rearrangement and one case also had an IGH rearrangement. One of the patients with systemic EBV positive T-cell LPD of childhood experienced rapid evolved and died within five months of onset. CAEBV, systemic EBV-positive T-cell LPD of childhood and HVLL are distinct but overlapping diseases within the category of EBV-positive T-cell LPD of childhood. They constitute a continuous spectrum of EBV-infected associated disorders. PMID:25197370

Epstein–Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8–9 September 2008

PubMed Central

Cohen, J. I.; Kimura, H.; Nakamura, S.; Ko, Y.-H.; Jaffe, E. S.

2009-01-01

Background: Recently novel Epstein–Barr virus (EBV) lymphoproliferative diseases (LPDs) have been identified in non-immunocompromised hosts, both in Asia and Western countries. These include aggressive T-cell and NK-cell LPDs often subsumed under the heading of chronic active Epstein–Barr virus (CAEBV) infection and EBV-driven B-cell LPDs mainly affecting the elderly. Design: To better define the pathogenesis, classification, and treatment of these disorders, participants from Asia, The Americas, Europe, and Australia presented clinical and experimental data at an international meeting. Results: The term systemic EBV-positive T-cell LPD, as adopted by the WHO classification, is preferred as a pathological classification over CAEBV (the favored clinical term) for those cases that are clonal. The disease has an aggressive clinical course, but may arise in the background of CAEBV. Hydroa vacciniforme (HV) and HV-like lymphoma represent a spectrum of clonal EBV-positive T-cell LPDs, which have a more protracted clinical course; spontaneous regression may occur in adult life. Severe mosquito bite allergy is a related syndrome usually of NK cell origin. Immune senescence in the elderly is associated with both reactive and neoplastic EBV-driven LPDs, including EBV-positive diffuse large B-cell lymphomas. Conclusion: The participants proposed an international consortium to facilitate further clinical and biological studies of novel EBV-driven LPDs. PMID:19515747

Research update: Avian Disease and Oncology Laboratory avian tumor viruses

USDA-ARS?s Scientific Manuscript database

Genomics and Immunogenetics Use of genomics to identify QTL, genes, and proteins associated with resistance to Marek’s disease. Marek’s disease (MD), a lymphoproliferative disease caused by the highly oncogenic herpesvirus Marek's disease virus (MDV), continues to be a major disease concern to the p...

Hodgkin's Lymphoma in Crohn's Disease Treated with Infliximab

PubMed Central

Carvalho, Diana; Russo, Pedro; Bernardes, Carlos; Saiote, Joana; Ramos, Gonçalo; Mascarenhas, Luís; Borges, Nuno; Ramos, Jaime

2017-01-01

Introduction Lymphoproliferative disorders, particularly non-Hodgkin's and Hodgkin's lymphomas, are rare in patients with inflammatory bowel diseases. The use of thiopurines and infection by Epstein-Barr virus are well-known cofactors that can raise its prevalence. Other risk factors such as disease activity and biological treatment are the subject of discussion, without enough data in the literature to confirm a potential association. Methods We report a case of Hodgkin's lymphoma in a patient who had been treated with azathioprine and was on long-term monotherapy with infliximab. Conclusions We stress the importance of recognizing the possible occurrence of a lymphoproliferative disorder in association with anti-tumor necrosis factor-α therapy PMID:29255769

Research update: Avian Disease and Oncology Laboratory avian tumor viruses

USDA-ARS?s Scientific Manuscript database

Genomics and Immunogenetics Marek’s disease (MD), a lymphoproliferative disease caused by the highly oncogenic herpesvirus Marek's disease virus (MDV), continues to be a major disease concern to the poultry industry. The fear of MD is further enhanced by unpredictable vaccine breaks that result in ...

De novo malignancy after pancreas transplantation in Japan.

PubMed

Tomimaru, Y; Ito, T; Marubashi, S; Kawamoto, K; Tomokuni, A; Asaoka, T; Wada, H; Eguchi, H; Mori, M; Doki, Y; Nagano, H

2015-04-01

Long-term immunosuppression is associated with an increased risk of cancer. Especially, the immunosuppression in pancreas transplantation is more intensive than that in other organ transplantation because of its strong immunogenicity. Therefore, it suggests that the risk of post-transplant de novo malignancy might increase in pancreas transplantation. However, there have been few studies of de novo malignancy after pancreas transplantation. The aim of this study was to analyze the incidence of de novo malignancy after pancreas transplantation in Japan. Post-transplant patients with de novo malignancy were surveyed and characterized in Japan. Among 107 cases receiving pancreas transplantation in Japan between 2001 and 2010, de novo malignancy developed in 9 cases (8.4%): post-transplant lymphoproliferative disorders in 6 cases, colon cancer in 1 case, renal cancer in 1 case, and brain tumor in 1 case. We clarified the incidence of de novo malignancy after pancreas transplantation in Japan. Copyright © 2015 Elsevier Inc. All rights reserved.

Recipient body surface area as a predictor of posttransplant renal allograft evolution.

PubMed

Moreso, F; Serón, D; Anunciada, A I; Hueso, M; Ramón, J M; Fulladosa, X; Gil-Vernet, S; Alsina, J; Grinyó, J M

1998-03-15

The aim of the present study was to analyze whether minor differences in recipient body surface area have any predictive value on renal allograft evolution. For this study, we considered 236 pairs of recipients who received a kidney from the same donor at our center between March 1985 and December 1995. Pairs in whom at least one patient presented any of the following events were excluded: graft loss during the first year of follow-up, diabetes mellitus, noncompliance with treatment, chronic pyelonephritis, and recurrent or de novo glomerulonephritis. Recipients of each pair were classified as large or small according to their body surface area (BSA). The percentage difference of BSA in each pair was calculated, and two cohorts of pairs were defined: BSA difference < or = 10% (n=76 pairs) and BSA difference >10% (n=70 pairs). The large recipients of the cohort with a BSA difference >10% showed a higher incidence of posttransplant delayed graft function (22/70 vs. 12/70, P=0.075), hypertension at 1 year of follow-up (51/70 vs. 35/70, P=0.006), and a higher serum creatinine level at 1-year follow-up (173 vs. 142 micromol/L, P=0.003), whereas in the cohort with a BSA difference < or = 10%, posttransplant evolution in large and small recipients was not different. Multivariate analysis showed that recipient BSA was an independent predictor of delayed graft function, posttransplant hypertension, and serum creatinine at 1-year follow-up. Relatively small differences in recipient BSA influence renal allograft evolution. Consequently, our data support that recipient size should be taken into consideration for renal allograft allocation.

Pharmacogenetics of posttransplant diabetes mellitus.

PubMed

Lancia, P; Adam de Beaumais, T; Jacqz-Aigrain, E

2017-06-01

Many factors (physiological, pathological, environmental or genetic) are associated with variability in drug effect. Most patients respond to a standard treatment but the drug may be ineffective or toxic. In this review, we focused on genetic markers of posttransplant diabetes mellitus (PTDM) after renal transplantation, a frequent complication of immunosuppressive therapy and important risk factor of graft loss and mortality. An initial literature search identified 100 publications and among them 32 association studies were retrieved under 'Pharmacogenetics and PTDM'. Thirty-five variants in 25 genes with an impact on insulin secretion, disposition or effect were significantly associated with PTDM. The population studied, immunosuppressive regimen, follow-up, PTDM diagnostic and genetic variations tested were highly variable between studies. Although pharmacogenetic biomarkers are key tools of great promise for preventing toxicities and improving event-free survival rates, replication studies are required to select validated biomarkers linked to the occurrence of PTDM and select appropriate immusuppressive treatment to improve renal graft and patient outcome.

Influence of Marek’s disease virus on the core-gut microbiome of chickens resistant or susceptible to Marek’s disease

USDA-ARS?s Scientific Manuscript database

Marek’s disease virus (MDV) is an a-herpesvirus and the causative agent for the lymphoproliferative disease of chickens known as Marek’s disease (MD). Worldwide poultry industry losses due to MD amount to $1-2 billion per year. Presently, there is limited knowledge on the potential influence of MDV ...

Busulfan, Fludarabine, and Thiotepa Conditioning Regimen for Non Malignant Disease

ClinicalTrials.gov

2018-06-20

Bone Marrow Failure Syndrome; Thalassemia; Sickle Cell Disease; Diamond Blackfan Anemia; Acquired Neutropenia in Newborn; Acquired Anemia Hemolytic; Acquired Thrombocytopenia; Hemophagocytic Lymphohistiocytoses; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; Common Variable Immunodeficiency; X-linked Lymphoproliferative Disease; Severe Combined Immunodeficiency; Hurler Syndrome; Mannosidosis; Adrenoleukodystrophy

Chicks and SNPs--an entree into identifying genes conferring disease resistance in chicken

USDA-ARS?s Scientific Manuscript database

With high-density chicken rearing, control of infectious diseases are critical for economic viability and maintaining public confidence in poultry products. Among poultry diseases, Marek’s disease (MD), a lymphoproliferative disease caused by the highly oncogenic herpesvirus Marek's disease virus (M...

Marek’s disease virus-induced transient cecal tonsil atrophy

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a lymphoproliferative disease of domestic chickens that is caused by a highly cell-associated oncogenic '-herpesvirus, Marek’s disease virus (MDV). MDV replicates in chicken lymphocytes and establishes a latent infection within CD4+ T cells. MD is characterized by bursal/th...

Atypical hydroa vacciniforme-like epstein-barr virus associated T/NK-cell lymphoproliferative disorder.

PubMed

Lee, Hye Young; Baek, Jin Ok; Lee, Jong Rok; Park, Sang Hui; Jeon, In Sang; Roh, Joo Young

2012-12-01

Epstein-Barr virus (EBV)-associated T-cell/natural killer (NK)-cell lymphoproliferative disorders (EBV-T/NK-LPDs) accompany severe chronic active EBV infection (CAEBV) or comprise the CAEBV disease entity. The CAEBV disease entity has the common feature of lymphoproliferation of T or NK cells (primarily), and B cells (rarely), with chronic activation of EBV infection. The disease is rare and seems to be more prevalent in East Asian countries. The CAEBV disease entity encompasses heterogenous disorders, including hydroa vacciniforme (HV), hypersensitivity to mosquito bites, EBV-associated hemophagocytic syndrome, NK/T-cell lymphoma, and NK-cell leukemia. Atypical HV-like eruptions are present on sun-exposed and nonexposed areas with facial edema, fever, and hepatosplenomegaly, unlike classic HV. Recently, it has been suggested that classic HV and atypical HV-like eruptions are variants within the same disease spectrum of EBV-T/NK-LPD. We report a Korean boy with an atypical HV-like eruption and various systemic manifestations, including fever, sore throat, abdominal pain, headaches, seizures, and hematologic abnormalities for 2 years. After the initial mild eruption, which resembled a viral exanthem, ulceronecrotic skin lesions gradually developed and were associated with a high-grade fever and constitutional symptoms. He had a CAEBV infection, which showed a predominant proliferation of NK cells with high EBV DNA levels in the peripheral blood. However, in the skin lesions, there were nonneoplastic CD4 T-cell infiltrations predominantly showing a monoclonal T-cell receptor-γ gene rearrangement and positive EBV in situ hybridization.

Salvia Hispanica Seed in Reducing Risk of Disease Recurrence in Patients With Non-Hodgkin Lymphoma

ClinicalTrials.gov

2018-02-05

Adult Nasal Type Extranodal NK/T-Cell Lymphoma; Adult T-Cell Leukemia/Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-Cell Lymphoma; B Lymphoblastic Leukemia/Lymphoma; Blastic Plasmacytoid Dendritic Cell Neoplasm; Burkitt Leukemia; Central Nervous System Lymphoma; Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Associated T-Cell Lymphoma; Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Grade 1 Follicular Lymphoma; Grade 2 Follicular Lymphoma; Grade 3 Follicular Lymphoma; Hepatosplenic T-Cell Lymphoma; Lymphoplasmacytic Lymphoma; Mantle Cell Lymphoma; Mediastinal (Thymic) Large B-Cell Lymphoma; Mycosis Fungoides; Nasal Type Extranodal NK/T-Cell Lymphoma; Nodal Marginal Zone Lymphoma; Peripheral T-Cell Lymphoma, Not Otherwise Specified; Post-Transplant Lymphoproliferative Disorder; Primary Cutaneous Anaplastic Large Cell Lymphoma; Primary Effusion Lymphoma; Sezary Syndrome; Splenic Marginal Zone Lymphoma; Subcutaneous Panniculitis-Like T-Cell Lymphoma; Systemic Anaplastic Large Cell Lymphoma; T Lymphoblastic Leukemia/Lymphoma; Transformed Recurrent Non-Hodgkin Lymphoma

How I treat autoimmune lymphoproliferative syndrome

PubMed Central

Oliveira, João Bosco

2011-01-01

Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis, permitting accumulation of lymphoid mass and persistence of autoreactive cells that often manifest in childhood with chronic nonmalignant lymphadenopathy, hepatosplenomegaly, and recurring multilineage cytopenias. Cytopenias in these patients can be the result of splenic sequestration as well as autoimmune complications manifesting as autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia. More than 300 families with hereditary ALPS have now been described; nearly 500 patients from these families have been studied and followed worldwide over the last 20 years by our colleagues and ourselves. Some of these patients with FAS mutations affecting the intracellular portion of the FAS protein also have an increased risk of B-cell lymphoma. The best approaches to diagnosis, follow-up, and management of ALPS, its associated cytopenias, and other complications resulting from infiltrative lymphoproliferation and autoimmunity are presented. This trial was registered at www.clinicaltrial.gov as #NCT00001350. PMID:21885601

Early post-transplant immune monitoring can predict long-term kidney graft survival: soluble CD30 levels, anti-HLA antibodies and IgA-anti-Fab autoantibodies.

PubMed

Amirzargar, Mohammad Ali; Amirzargar, Aliakbar; Basiri, Abbas; Hajilooi, Mehrdad; Roshanaei, Ghodratollah; Rajabi, Gholamreza; Mohammadiazar, Sina; Solgi, Ghasem

2014-01-01

This study aimed to investigate the predictive power of anti-HLA antibodies, sCD30 levels and IgA-anti-Fab autoantibody before and early after transplantation in relation to long-term kidney allograft survival. Pre- and post-transplant sera samples of 59 living-unrelated donor kidney recipients were tested for above risk factors by enzyme-linked immunoabsorbent assay. 15 out of 59 cases experienced rejection episodes (failure group). Pre- and post-transplant high sCD30 levels were significantly associated with graft failure (P=0.02 and P=0.004) and decreased 4 year graft survival (P = 0.009 and P = 0.001). Higher frequency of post-transplant HLA class-II antibody in the absence of class-I antibody was observed in failure group (P=0.007). Patients with post-transplant HLA class-I and class-II antibodies either alone or in combination showed significant lower 4 year graft survival. Recipients with high sCD30 levels in the presence of HLA class-I or class-II antibodies within 2 weeks post-transplant had poor graft survival (P = 0.004 and P = 0.002, respectively). High levels of post-transplant IgA-anti-Fab antibody was more frequent in functioning-graft patients (P = 0.00001), correlated with decreased serum creatinine levels (P = 0.01) and associated with improved graft survival (P = 0.008). Our findings indicate the deleterious effect of early post-transplant HLA antibodies and increased sCD30 levels dependently and protective effect of IgA-anti-Fab antibodies on long-term renal graft outcomes. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Marek’s disease virus induces transient atrophy of cecal tonsils

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a lymphoproliferative disease of domestic chickens caused by an immunosupperessive alpha herpesvirus, Marek’s disease virus (MDV). Clinical signs of MD include bursal/thymic atrophy and neurological disorders. The cecal tonsils (CT) are the largest lymphoid aggregates of avia...

Expansion of somatically reverted memory CD8+ T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus

PubMed Central

Low, Carol; Bell, Andrew I.; Abbott, Rachel J.M.; Phan, Tri Giang; Riminton, D. Sean; Choo, Sharon; Smart, Joanne M.; Lougaris, Vassilios; Giliani, Silvia; Buckley, Rebecca H.; Grimbacher, Bodo; Alvaro, Frank; Klion, Amy D.; Nichols, Kim E.; Adelstein, Stephen; Rickinson, Alan B.

2012-01-01

Patients with the primary immunodeficiency X-linked lymphoproliferative disease (XLP), which is caused by mutations in SH2D1A, are highly susceptible to Epstein-Barr virus (EBV) infection. Nonetheless, some XLP patients demonstrate less severe clinical manifestations after primary infection. SH2D1A encodes the adaptor molecule SLAM-associated protein (SAP), which is expressed in T and natural killer cells and is required for cytotoxicity against B cells, the reservoir for EBV. It is not known why the clinical presentation of XLP is so variable. In this study, we report for the first time the occurrence of somatic reversion in XLP. Reverted SAP-expressing cells resided exclusively within the CD8+ T cell subset, displayed a CD45RA−CCR7− effector memory phenotype, and were maintained at a stable level over time. Importantly, revertant CD8+ SAP+ T cells, but not SAP− cells, proliferated in response to EBV and killed EBV-infected B cells. As somatic reversion correlated with EBV infection, we propose that the virus exerts a selective pressure on the reverted cells, resulting in their expansion in vivo and host protection against ongoing infection. PMID:22493517

Monitoring of Epstein-Barr viral load in pediatric heart and lung transplant recipients by real-time polymerase chain reaction.

PubMed

Benden, Christian; Aurora, Paul; Burch, Michael; Cubitt, David; Lloyd, Cathryn; Whitmore, Pauline; Neligan, Sophie L; Elliott, Martin J

2005-12-01

Elevation in Epstein-Barr virus (EBV) load measured in peripheral blood has been proposed as a marker for development of post-transplant lymphoproliferative disease (PTLD), but there are few published data examining this relationship. We report the longitudinal surveillance of EBV for all recipients of heart (HTx), heart-lung (HLTx) and lung (LTx) transplants at our institution. The study population included all patients transplanted between January 2003 and July 2004. EBV load was serially measured in peripheral blood by real-time polymerase chain reaction (PCR). Results were correlated with recipient pre-transplant EBV status and development of PTLD. Forty-four transplant operations were performed, including 33 HTx, 6 HLTx and 5 LTx. Thirty-two (73%) of the patients were EBV seropositive pre-transplant. Nineteen (44%) pediatric recipients developed EB viremia, including 17 HTx, 1 HLTx and 1 LTx. Eleven (58%) of these patients were EBV seropositive pre-transplant. EBV was first detected at a median of 30.5 days (range 2 to 81) post-transplant. The median peak EBV load in that group was 10,099 copies/ml (range 5,935 to 255,466) whole blood. One patient with cystic fibrosis post-LTx developed PTLD localized in the colon. This patient was EBV seronegative pre-transplant; peak EBV load was 14,513 copies/ml. Acute infectious mononucleosis was seen in 1 case. Positive pre-transplant EBV status did not predict post-transplant EB viremia (positive predictive value 0.03). Contrary to earlier reports, our data demonstrate that a high EBV load does not lead to PTLD early post-transplant. These results do not support the practice of pre-emptively reducing immunosuppression in patients with raised EBV load.

Epstein-Barr virus and rheumatoid arthritis.

PubMed

Balandraud, Nathalie; Roudier, Jean

2018-03-01

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, with a 0.5% worldwide prevalence. The cause of RA remains unknown, however both genetic and environmental factors may contribute to its development. Among these is the Epstein-Barr virus (EBV). Here, we discuss several aspects of the close relationship between EBV and RA. Patients with RA have impaired control of EBV infection. Indeed, they have high titres of antibodies against EBV antigens. Their peripheral blood T lymphocytes are less efficient at controlling the outgrowth of EBV-infected B cells. RA patients have more EBV-infected B cells than normal controls, leading to a 10-fold systemic EBV overload. Post-transplant lymphoproliferative disorder (PTLPD) is a polyclonal EBV-positive B lymphocyte proliferation, which can evolve into an EBV-positive B cell lymphoma. RA patients also have an increased risk of developing EBV-associated lymphoproliferative disorder (LPD). Hence the need to monitor EBV load when treating RA patients with immunosuppressors. EBV, a widespread virus, highly recognized by antibodies but never eliminated, is an ideal candidate to trigger chronic immune complex disease. Anti-EBV antibody responses should be considered as one of the chronic autoantibody responses linked to the development of RA, in the same way as anti-citrullinated protein antibodies. Copyright © 2017 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

HLA is not predictive of posttransplant diabetes mellitus.

PubMed

Torres-Romero, L F; Santiago-Delpín, E A; de Echegaray, Sally; Solis, D R; Rodriguez-Trinidad, A T; Gonzalez-Caraballo, Z A; Morales-Otero, L A

2006-04-01

New-onset posttransplant diabetes mellitus (PTDM) is a frequent complication of kidney transplantation. The goal of this study was to identify if the tendency to develop PTDM was associated to the HLA, as is seen in the general population. A retrospective study was made of 525 patients who underwent renal transplantation between 1997 and 2004. They were divided into three categories depending on the diabetic status before and after kidney transplantation. The HLA profile of each patient was identified for class 1 and class 2 antigens including HLA-A, HLA-B, and DR-R. Antigen frequencies were calculated and gene frequencies derived. These were compared among the three groups and with the published data for the Puerto Rico population. Other variables studied included weight, age, gender, and family history. Seventy-two of 526 (13.7%) were diabetic before transplantation; 92/453 (20.3%) developed PTDM after kidney transplantation. Pretransplant diabetics showed a higher incidence of A3 (0.1102 vs 0.0869 vs 0.0361), DR4 (0.3334 vs 0.1932 vs 0.2124), and DR-13 (0.1835 vs 0.1115 vs 0.1175) than nondiabetics and the normal Puerto Rican population. Posttransplant diabetics showed a higher A3 (0.1154) and a higher DR3 (0.0675 vs 0.0295 vs 0.0022) than nondiabetics and normal population. PTDM was not associated statistically with the HLA in this group of transplant recipients, although A3 and DR3 were higher. Patients with the phenotype that is related to diabetes in the normal population did not have a higher incidence of diabetes in this series.

Common Variable Immunodeficiency Non-Infectious Disease Endotypes Redefined Using Unbiased Network Clustering in Large Electronic Datasets.

PubMed

Farmer, Jocelyn R; Ong, Mei-Sing; Barmettler, Sara; Yonker, Lael M; Fuleihan, Ramsay; Sullivan, Kathleen E; Cunningham-Rundles, Charlotte; Walter, Jolan E

2017-01-01

Common variable immunodeficiency (CVID) is increasingly recognized for its association with autoimmune and inflammatory complications. Despite recent advances in immunophenotypic and genetic discovery, clinical care of CVID remains limited by our inability to accurately model risk for non-infectious disease development. Herein, we demonstrate the utility of unbiased network clustering as a novel method to analyze inter-relationships between non-infectious disease outcomes in CVID using databases at the United States Immunodeficiency Network (USIDNET), the centralized immunodeficiency registry of the United States, and Partners, a tertiary care network in Boston, MA, USA, with a shared electronic medical record amenable to natural language processing. Immunophenotypes were comparable in terms of native antibody deficiencies, low titer response to pneumococcus, and B cell maturation arrest. However, recorded non-infectious disease outcomes were more substantial in the Partners cohort across the spectrum of lymphoproliferation, cytopenias, autoimmunity, atopy, and malignancy. Using unbiased network clustering to analyze 34 non-infectious disease outcomes in the Partners cohort, we further identified unique patterns of lymphoproliferative (two clusters), autoimmune (two clusters), and atopic (one cluster) disease that were defined as CVID non-infectious endotypes according to discrete and non-overlapping immunophenotypes. Markers were both previously described {high serum IgE in the atopic cluster [odds ratio (OR) 6.5] and low class-switched memory B cells in the total lymphoproliferative cluster (OR 9.2)} and novel [low serum C3 in the total lymphoproliferative cluster (OR 5.1)]. Mortality risk in the Partners cohort was significantly associated with individual non-infectious disease outcomes as well as lymphoproliferative cluster 2, specifically (OR 5.9). In contrast, unbiased network clustering failed to associate known comorbidities in the adult USIDNET cohort

Expression of Marek's disease virus oncoprotein Meq during infection in the natural host

USDA-ARS?s Scientific Manuscript database

Marek's disease virus (MDV, Gallid herpesvirus 2) causes a lymphoproliferative disease known as Marek's disease (MD), which is unique among alphaherpesviruses as the viral genome encodes an oncoprotein, Meq. Previous studies, using cultured fibroblasts and MDV-transformed lymphoblastoid cell lines, ...

Alternative donor hematopoietic stem cell transplantation for sickle cell disease

PubMed Central

Eckrich, Michael J.; Epstein, Stacy; Barnhart, Carrie; Cannon, Mark; Fukes, Tracy; Hyland, Michelle; Shah, Krishna; Grochowski, Darci; Champion, Elizabeth; Ivanova, Anastasia

2017-01-01

Most patients who could be cured of sickle cell disease (SCD) with stem cell transplantation do not have a matched sibling donor. Successful use of alternative donors, including mismatched family members, could provide a donor for almost all patients with SCD. The use of a reduced-intensity conditioning regimen may decrease late adverse effects. Ten patients with symptomatic SCD underwent CD34+ cell-selected, T-cell–depleted peripheral blood stem cell transplantation from a mismatched family member or unrelated donor. A reduced-intensity conditioning regimen including melphalan, thiotepa, fludarabine, and rabbit anti-thymocyte globulin was used. Patients were screened for a companion study for immune reconstitution that included a donor lymphocyte infusion given 30-42 days after transplant with intravenous methotrexate as graft-versus-host disease (GVHD) prophylaxis. Seven eligible patients were treated on the companion study. Nine of 10 patients are alive with a median follow-up of 49 months (range, 14-60 months). Surviving patients have stable donor hematopoietic engraftment (mean donor chimerism, 99.1% ± 0.7%). There were no sickle cell complications after transplant. Two patients had grade II-IV acute GVHD. One patient had chronic GVHD. Epstein-Barr virus–related posttransplant lymphoproliferative disorder (PTLD) occurred in 3 patients, and 1 patient died as a consequence of treatment of PTLD. Two-year overall survival was 90%, and event-free survival was 80%. A reduced-intensity conditioning regimen followed by CD34+ cell-selected, T-cell–depleted alternative donor peripheral blood stem cell transplantation achieved primary engraftment in all patients with a low incidence of GVHD, although PTLD was problematic. This trial was registered at clinicaltrials.gov as #NCT00968864. PMID:29296761

Successful Posttransplant Treatment of Hepatitis C With Ledipasvir-Sofosbuvir in HIV+ Kidney Transplant Recipients.

PubMed

Sawinski, Deirdre; Lee, Dong H; Doyle, Alden M; Blumberg, Emily A

2017-05-01

Ledipasvir-sofosbuvir is effective at eradicating hepatitis C virus (HCV) infection in the general population and in HCV-monoinfected kidney transplant recipients, but there are no data to guide its use in human immunodeficiency virus/HCV coinfected kidney transplant patients. We treated 6 human immunodeficiency virus/HCV coinfected kidney transplant recipients with ledipasvir-sofosbuvir at our 2 centers. All were infected with genotype 1 and 66% had received kidneys from HCV+ donors. All patients cleared the virus while on therapy and 100% have achieved a sustained virologic response at 12 weeks after completion of ledipasvir-sofosbuvir. Tacrolimus dosing required adjustment during and after ledipasvir-sofosbuvir therapy but antiretroviral regimens did not. Ledipasvir-sofosbuvir was well tolerated. Although all patients in our series were treated posttransplant, the ideal timing of HCV therapy in this population is unknown, and the impact of HCV clearance on posttransplant outcomes is yet to be determined.

Clinical evolution of post-transplant diabetes mellitus.

PubMed

Porrini, Esteban L; Díaz, Jose M; Moreso, Francisco; Delgado Mallén, Patricia I; Silva Torres, Irene; Ibernon, Meritxell; Bayés-Genís, Beatriz; Benitez-Ruiz, Rocío; Lampreabe, Ildefonso; Lauzurrica, Ricardo; Osorio, Jose M; Osuna, Antonio; Domínguez-Rollán, Rosa; Ruiz, Juan C; Jiménez-Sosa, Alejandro; González-Rinne, Ana; Marrero-Miranda, Domingo; Macía, Manuel; García, Javier; Torres, Armando

2016-03-01

The long-term clinical evolution of prediabetes and post-transplant diabetes mellitus (PTDM) is unknown. We analysed, in this cohort study, the reversibility, stability and progression of PTDM and prediabetes in 672 patients using repeated oral glucose tolerance tests (OGTTs) for ≤5 years. Most patients were on tacrolimus, steroids and mycophenolate. About half developed either PTDM or prediabetes. The incidence of PTDM was 32% and bimodal: early PTDM (≤3 months) and late PTDM. Early PTDM reverted in 31%; late PTDM developed in patients with post-transplant prediabetes. The use of OGTTs was necessary to detect around half of PTDM. Pretransplant obesity was a major risk factor for early PTDM, for its persistence and for late PTDM {odds ratio [OR] 1.18 [95% confidence interval (CI) 1.09-1.28]}. At 3 months, higher HbA1c promoted [OR 2.37 (95% CI 1.38-4.06)], while insulin sensitivity protected against [OR 0.64 (95% CI 0.48-0.86)] late PTDM. At 3 months, 28% had prediabetes; of these, 36% remained stable, 43% normalized and 21% developed late PTDM. Pretransplant obesity [OR 1.20 (95% CI 1.04-1.39)] and higher HbA1c [OR 3.80 (95% CI 1.45-9.94)] at 3 months promoted while insulin sensitivity protected against [OR 0.57 (95% CI 0.34-0.95)] evolution from prediabetes to late PTDM. Immunosuppressive levels or acute rejection did not influence PTDM. Most (84%) of the patients with normal tests at 3 months remained stable without evolving into PTDM; 14% developed prediabetes. PTDM and prediabetes are very common in renal transplantation. Classic metabolic factors like obesity, prediabetes and insulin resistance promote the evolution of PTDM and prediabetes. Patients with normal glucose metabolism rarely develop PTDM. OGTT is necessary to detect PTDM and prediabetes and thus should be included in clinical practice. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Hemopoietic progenitor cell function after HLA-identical sibling bone marrow transplantation: influence of chronic graft-versus-host disease.

PubMed

Atkinson, K; Norrie, S; Chan, P; Zehnwirth, B; Downs, K; Biggs, J

1986-05-01

We examined hemopoietic reconstitution during the first 12 months post-transplant in 31 patients given high-dose cyclophosphamide, total body irradiation and an HLA-identical sibling marrow transplant for hematological malignancy. Unexpectedly, we found marrow CFU-gm and marrow CFU-e cells to be denser than normal throughout the first year post-transplant. While functionally adequate neutrophil and platelet counts were achieved in the first six weeks post-transplant, there were defects in hemopoietic progenitor cell function during the first year post-transplant. Although we could detect no influence from acute graft-versus-host disease (GVHD), chronic GVHD adversely affected the growth of both myeloid and erythroid blood progenitor cells.

Temporal transcriptome changes induced by MDV in Marek's disease-resistant and -susceptible inbred chickens

USDA-ARS?s Scientific Manuscript database

Mareks disease (MD) is a lymphoproliferative disease in chickens caused by Marek's disease virus (MDV) and characterized by T cell lymphoma and infiltration of lymphoid cells into various organs such as liver, spleen, peripheral nerves and muscle. Resistance to MD and disease risk have long been tho...

Post-transplant survival in idiopathic pulmonary fibrosis patients concurrently listed for single and double lung transplantation.

PubMed

Chauhan, Dhaval; Karanam, Ashwin B; Merlo, Aurelie; Tom Bozzay, P A; Zucker, Mark J; Seethamraju, Harish; Shariati, Nazly; Russo, Mark J

2016-05-01

Lung transplantation is a widely accepted treatment for patients with end-stage lung disease related to idiopathic pulmonary fibrosis (IPF). However, there are conflicting data on whether double lung transplant (DLT) or single lung transplant (SLT) is the superior therapy in these patients. The purpose of this study was to determine whether actuarial post-transplant graft survival among IPF patients concurrently listed for DLT and SLT is greater for recipients undergoing the former or the latter. The United Network for Organ Sharing provided de-identified patient-level data. Analysis included lung transplant candidates with IPF listed between January 1, 2001 and December 31, 2009 (n = 3,411). The study population included 1,001 (29.3%) lung transplant recipients concurrently listed for DLT and SLT, all ≥18 years of age. The primary outcome measure was actuarial post-transplant graft survival, expressed in years. Among the study population, 433 (43.26%) recipients underwent SLT and 568 (56.74%) recipients underwent DLT. The analysis included 2,722.5 years at risk, with median graft survival of 5.31 years. On univariate (p = 0.317) and multivariate (p = 0.415) regression analyses, there was no difference in graft survival between DLT and SLT. Among IPF recipients concurrently listed for DLT and SLT, there is no statistical difference in actuarial graft survival between recipients undergoing DLT vs SLT. This analysis suggests that increased use of SLT for IPF patients may increase the availability of organs to other candidates, and thus increase the net benefit of these organs, without measurably compromising outcomes. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Marek's Disease Virus-Induced Immunosuppression: Array Analysis of Chicken Immune Response Gene Expression Profiling

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a lymphoproliferative disease of chickens induced by a highly cell-associated oncogenic alpha-herpesvirus, Marek’s disease virus (MDV). MDV replicates in chicken lymphocytes and establishes a latency infection within CD4+ T cells. Host-virus interaction, immune responses to...

Immune deficiency as a risk factor in Epstein-Barr virus-induced malignant diseases.

PubMed Central

Purtilo, D T; Okano, M; Grierson, H L

1990-01-01

Epstein-Barr virus (EBV) is a ubiquitous DNA virus that normally infects silently, establishing lifelong latency. Substantial empirical observations support the view that immunodeficiency is permissive in EBV-induced lymphoproliferative diseases (LPD). Primary immune deficient patients such as those with X-linked lymphoproliferative disease and individuals with acquired immune deficiency secondary to immunosuppressive drugs for organ transplantation or individuals infected with human immunodeficiency virus are also at very high risk for lethal LPD. The importance of immunodeficiency and EBV in the development of head and neck carcinomas and uterine cervical carcinoma is less clear. Methods are available for detecting immunodeficiency and EBV genome and thus preventive strategies are being developed to preclude LPD from occurring. PMID:2176975

An evaluation of the impact of donor BMI on survival and post-transplant obesity in pediatric liver transplant recipients

PubMed Central

Perito, Emily Rothbaum; Rhee, Sue; Glidden, Dave; Roberts, John Paul; Rosenthal, Philip

2012-01-01

Introduction In adult liver transplant recipients, donor BMI is associated with post-transplant obesity but not graft or patient survival. Given the U.S. obesity epidemic and already-limited supply of liver donors, clarifying whether donor BMI affects pediatric outcomes is important. Methods UNOS data on pediatric U.S. liver transplants 1990-2010 was evaluated. Data on transplants 2004-2010 (n=3788) was used for survival analysis with Kaplan-Meier and Cox proportional hazards models and for post-transplant obesity analysis with generalized estimating equations. Results For children receiving adult donor livers, donor BMI 25-35 kg/m2 was not associated with graft or patient survival in univariate or multivariate analyses. Donor BMI>35 kg/m2 increased the risk of graft loss (HR 2.54, 95%CI 1.29-5.01, p=0.007) and death (HR 3.56, 95%CI 1.64-7.72, p=0.001). For pediatric donors, donor BMI was not associated with graft loss or mortality in univariate or multivariate analysis. Donor overweight/obesity was not a risk factor for post-transplant obesity. Conclusions Overweight/obesity is common among liver transplant donors. This analysis suggests that for adult donors, BMI 25-35 should not by itself be a contraindication to liver donation. Severe obesity (BMI>35) in adult donors increased the risk of graft loss and mortality, even after adjustment for recipient, donor, and transplant risk factors. Post-transplant obesity was not associated with donor BMI in this analysis. Further research is needed to clarify the impact of donor obesity on pediatric liver transplant recipients. PMID:22467594

Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes.

PubMed

Shivaswamy, Vijay; Boerner, Brian; Larsen, Jennifer

2016-02-01

Post-transplant diabetes mellitus (PTDM) is a frequent consequence of solid organ transplantation. PTDM has been associated with greater mortality and increased infections in different transplant groups using different diagnostic criteria. An international consensus panel recommended a consistent set of guidelines in 2003 based on American Diabetes Association glucose criteria but did not exclude the immediate post-transplant hospitalization when many patients receive large doses of corticosteroids. Greater glucose monitoring during all hospitalizations has revealed significant glucose intolerance in the majority of recipients immediately after transplant. As a result, the international consensus panel reviewed its earlier guidelines and recommended delaying screening and diagnosis of PTDM until the recipient is on stable doses of immunosuppression after discharge from initial transplant hospitalization. The group cautioned that whereas hemoglobin A1C has been adopted as a diagnostic criterion by many, it is not reliable as the sole diabetes screening method during the first year after transplant. Risk factors for PTDM include many of the immunosuppressant medications themselves as well as those for type 2 diabetes. The provider managing diabetes and associated dyslipidemia and hypertension after transplant must be careful of the greater risk for drug-drug interactions and infections with immunosuppressant medications. Treatment goals and therapies must consider the greater risk for fluctuating and reduced kidney function, which can cause hypoglycemia. Research is actively focused on strategies to prevent PTDM, but until strategies are found, it is imperative that immunosuppression regimens are chosen based on their evidence to prolong graft survival, not to avoid PTDM.

Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes

PubMed Central

Shivaswamy, Vijay; Boerner, Brian

2016-01-01

Post-transplant diabetes mellitus (PTDM) is a frequent consequence of solid organ transplantation. PTDM has been associated with greater mortality and increased infections in different transplant groups using different diagnostic criteria. An international consensus panel recommended a consistent set of guidelines in 2003 based on American Diabetes Association glucose criteria but did not exclude the immediate post-transplant hospitalization when many patients receive large doses of corticosteroids. Greater glucose monitoring during all hospitalizations has revealed significant glucose intolerance in the majority of recipients immediately after transplant. As a result, the international consensus panel reviewed its earlier guidelines and recommended delaying screening and diagnosis of PTDM until the recipient is on stable doses of immunosuppression after discharge from initial transplant hospitalization. The group cautioned that whereas hemoglobin A1C has been adopted as a diagnostic criterion by many, it is not reliable as the sole diabetes screening method during the first year after transplant. Risk factors for PTDM include many of the immunosuppressant medications themselves as well as those for type 2 diabetes. The provider managing diabetes and associated dyslipidemia and hypertension after transplant must be careful of the greater risk for drug-drug interactions and infections with immunosuppressant medications. Treatment goals and therapies must consider the greater risk for fluctuating and reduced kidney function, which can cause hypoglycemia. Research is actively focused on strategies to prevent PTDM, but until strategies are found, it is imperative that immunosuppression regimens are chosen based on their evidence to prolong graft survival, not to avoid PTDM. PMID:26650437

Droplet Digital PCR-Based Chimerism Analysis for Primary Immunodeficiency Diseases.

PubMed

Okano, Tsubasa; Tsujita, Yuki; Kanegane, Hirokazu; Mitsui-Sekinaka, Kanako; Tanita, Kay; Miyamoto, Satoshi; Yeh, Tzu-Wen; Yamashita, Motoi; Terada, Naomi; Ogura, Yumi; Takagi, Masatoshi; Imai, Kohsuke; Nonoyama, Shigeaki; Morio, Tomohiro

2018-04-01

In the current study, we aimed to accurately evaluate donor/recipient or male/female chimerism in samples from patients who underwent hematopoietic stem cell transplantation (HSCT). We designed the droplet digital polymerase chain reaction (ddPCR) for SRY and RPP30 to detect the male/female chimerism. We also developed mutation-specific ddPCR for four primary immunodeficiency diseases. The accuracy of the male/female chimerism analysis using ddPCR was confirmed by comparing the results with those of conventional methods (fluorescence in situ hybridization and short tandem repeat-PCR) and evaluating dilution assays. In particular, we found that this method was useful for analyzing small samples. Thus, this method could be used with patient samples, especially to sorted leukocyte subpopulations, during the early post-transplant period. Four mutation-specific ddPCR accurately detected post-transplant chimerism. ddPCR-based male/female chimerism analysis and mutation-specific ddPCR were useful for all HSCT, and these simple methods contribute to following the post-transplant chimerism, especially in disease-specific small leukocyte fractions.

RISK FACTORS FOR AND SPATIAL DISTRIBUTION OF LYMPHOPROLIFERATIVE DISEASE VIRUS (LPDV) IN WILD TURKEYS (MELEAGRIS GALLOPAVO) IN NEW YORK STATE, USA.

PubMed

Alger, Katrina; Bunting, Elizabeth; Schuler, Krysten; Whipps, Christopher M

2017-07-01

Lymphoproliferative disease virus (LPDV) is an oncogenic avian retrovirus that was previously thought to exclusively infect domestic turkeys but was recently shown to be widespread in Wild Turkeys ( Meleagris gallopavo ) throughout most of the eastern US. In commercial flocks, the virus spreads between birds housed in close quarters, but there is little information about potential risk factors for infection in wild birds. Initial studies focused on distribution of LPDV nationally, but investigation of state-level data is necessary to assess potential predictors of infection and detect patterns in disease prevalence and distribution. We tested wild turkey bone marrow samples (n=2,538) obtained from hunter-harvested birds in New York State from 2012 to 2014 for LPDV infection. Statewide prevalence for those 3 yr was 55% with a 95% confidence interval (CI) of 53-57%. We evaluated a suite of demographic, anthropogenic, and land cover characteristics with logistic regression to identify potential predictors for infection based on odds ratio (OR). Age (OR=0.16, 95% CI=0.13-0.19) and sex (OR=1.3, 95% CI=1.03-1.24) were strong predictors of LPDV infection, with juveniles less likely to test positive than adults, and females more likely to test positive than males. The number of birds released during the state's 40-yr translocation program (OR=0.993, 95% CI=0.990-0.997) and the ratio of agriculture to forest cover (OR=1.13, 95% CI=1.03-1.19) were also predictive of LPDV infection. Prevalence distribution was analyzed using dual kernel density smoothing to produce a risk surface map, combined with Kulldorff's spatial scan statistic and the Anselin Local Moran's I to identify statistically significant geographic clusters of high or low prevalence. These methods revealed the prevalence of LPDV was high (>50%) throughout New York State, with regions of variation and several significant clusters. We revealed new information about the risk factors and distribution of LPDV in New

Evaluation and identification of Marek’s disease virus BAC clones as standardized reagents for research

USDA-ARS?s Scientific Manuscript database

Marek’s disease virus (MDV) is an alphaherpesvirus that causes Marek’s disease (MD), a lymphoproliferative disease in chickens. Understanding of MDV gene function advanced significantly following the cloning of the MDV genome as either a series of overlapping cosmids or as a bacterial artificial chr...

Autoimmune Lymphoproliferative Syndrome-FAS Patients Have an Abnormal Regulatory T Cell (Treg) Phenotype but Display Normal Natural Treg-Suppressive Function on T Cell Proliferation.

PubMed

Mazerolles, Fabienne; Stolzenberg, Marie-Claude; Pelle, Olivier; Picard, Capucine; Neven, Benedicte; Fischer, Alain; Magerus-Chatinet, Aude; Rieux-Laucat, Frederic

2018-01-01

Autoimmune lymphoproliferative syndrome (ALPS) with FAS mutation (ALPS-FAS) is a nonmalignant, noninfectious, lymphoproliferative disease with autoimmunity. Given the central role of natural regulatory T cells (nTregs) in the control of lymphoproliferation and autoimmunity, we assessed nTreg-suppressive function in 16 patients with ALPS-FAS. The proportion of CD25 high CD127 low Tregs was lower in ALPS-FAS patients than in healthy controls. This subset was correlated with a reduced CD25 expression in CD3 + CD4 + T cells from ALPS patients and thus an abnormally low proportion of CD25 high FOXP3 + Helios + T cells. The ALPS patients also displayed a high proportion of naïve Treg (FOXP3 low CD45RA + ) and an unusual subpopulation (CD4 + CD127 low CD15s + CD45RA + ). Despite this abnormal phenotype, the CD25 high CD127 low Tregs' suppressive function was unaffected. Furthermore, conventional T cells from FAS -mutated patients showed normal levels of sensitivity to Treg suppression. An abnormal Treg phenotype is observed in circulating lymphocytes of ALPS patients. However, these Tregs displayed a normal suppressive function on T effector proliferation in vitro . This is suggesting that lymphoproliferation observed in ALPS patients does not result from Tregs functional defect or T effector cells insensitivity to Tregs suppression.

Umbilical cord blood as an alternative source of reduced-intensity hematopoietic stem cell transplantation for chronic Epstein-Barr virus-associated T or natural killer cell lymphoproliferative diseases.

PubMed

Sawada, Akihisa; Inoue, Masami; Koyama-Sato, Maho; Kondo, Osamu; Yamada, Kayo; Shimizu, Mariko; Isaka, Kanako; Kimoto, Tomiko; Kikuchi, Hiroaki; Tokimasa, Sadao; Yasui, Masahiro; Kawa, Keisei

2014-02-01

Chronic Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases represented by chronic active Epstein-Barr virus infection are lethal but are curable with several courses of chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Recently, we reported that reduced-intensity conditioning (RIC) provided better outcomes than myeloablative conditioning because RIC was less toxic. However, it was unclear whether cord blood transplantation (CBT) works in the context of RIC. We retrospectively analyzed 17 patients who underwent RIC followed by bone marrow transplantation (RIC-BMT) and 15 patients who underwent RIC followed by CBT (RIC-CBT). The representative regimen was fludarabine and melphalan based. The overall survival rates with RIC-BMT and RIC-CBT were 92.9% ± 6.9% and 93.3% ± 6.4%, respectively (P = .87). One patient died of lung graft-versus-host disease after RIC-BMT, and 1 patient died of multiple viral infections after RIC-CBT. Although cytotoxic chemotherapy was also immunosuppressive and might contribute to better donor cell engraftment after RIC-HSCT, the rate of engraftment failure after RIC-CBT was still higher than that after RIC-BMT (not significant); however, patients who had experienced graft failure were successfully rescued with a second HSCT. Unrelated cord blood can be an alternative source for RIC-HSCT if a patient has no family donor. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

CD30 expression is rare in myeloid leukemia cutis; a study of 55 cases and implications for routine diagnostic algorithms

PubMed Central

Ogunrinade, Olakunle; Terrano, David; Chiu, April; Pulitzer, Melissa

2016-01-01

Expression of CD30 in blastoid cutaneous infiltrates typically signifies a CD30+ lymphoproliferative disorder, often requiring minimal immunohistochemical work-up, if clinically consonant. However, myeloid and other hematologic malignancies often express CD30. We retrospectively examined the prevalence of CD30 expression in 41 patients (median age 59) and 55 biopsies with the diagnosis of leukemia cutis (LC) to determine whether an extensive immunohistochemical workup is warranted in all large, round cell CD30+ cutaneous infiltrates. Each patient had refractory or recurrent disease, the histologic presence of a large mononuclear cell infiltrate, and varied cytogenetics. CD30+ mononuclear cells within the infiltrate ranged from rare to many in twenty-two biopsies (22/55). In eighteen biopsies, CD30+ cells were interpreted as lymphocytic based on morphology, strong cytoplasmic and Golgi staining for CD30, and negative CD34 and CD117 staining. One case showing 3+ staining of lymphocytes was identified as a post-transplant lymphoproliferative disorder. The second 3+ case was favored to represent a subset CD30-positive AML. Three other cases with 1+ membranous and cytoplasmic staining were interpreted as myeloid leukemia. In conclusion, CD30 positivity in myeloid leukemia in the skin is rare and does not often exhibit the strong membranous (2+ or 3+) and/or Golgi staining seen in reactive lymphocytes. AML or myeloid LC may occasionally show 1+ (and rarely 2-3+) cytoplasmic/membranous or non-specific blush nuclear CD30 labeling. Strong diffuse staining for CD30 should prompt consideration of a reactive lymphoid/lymphoproliferative process, and, when the clinical likelihood of CD30+ leukemia cutis is low, may obviate the need for further immunohistochemistry. PMID:27893466

Characterizing the molecular basis of attenuation of Marek’s disease virus via in vitro serial passage

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a lymphoproliferative disease of chickens caused by the oncogenic Gallid herpesvirus 2, commonly known as Marek’s disease virus (MDV). MD vaccines, the primary control method, are often generated by repeated in vitro serial passage of this highly cell-associated virus to atte...

Benefits of PEGylation in the early post-transplant period of intraportal islet transplantation as assessed by magnetic resonance imaging of labeled islets.

PubMed

Jin, Sang-Man; Oh, Seung-Hoon; Oh, Bae Jun; Suh, Sunghwan; Bae, Ji Cheol; Lee, Jung Hee; Lee, Myung-Shik; Lee, Moon-Kyu; Kim, Kwang-Won; Kim, Jae Hyeon

2014-01-01

While a few studies have demonstrated the benefit of PEGylation in islet transplantation, most have employed renal subcapsular models and none have performed direct comparisons of islet mass in intraportal islet transplantation using islet magnetic resonance imaging (MRI). In this study, our aim was to demonstrate the benefit of PEGylation in the early post-transplant period of intraportal islet transplantation with a novel algorithm for islet MRI. Islets were PEGylated after ferucarbotran labeling in a rat syngeneic intraportal islet transplantation model followed by comparisons of post-transplant glycemic levels in recipient rats infused with PEGylated (n = 12) and non-PEGylated (n = 13) islets. The total area of hypointense spots and the number of hypointense spots larger than 1.758 mm(2) of PEGylated and non-PEGylated islets were quantitatively compared. The total area of hypointense spots (P < 0.05) and the number of hypointense spots larger than 1.758 mm(2) (P < 0.05) were higher in the PEGylated islet group 7 and 14 days post translation (DPT). These results translated into better post-transplant outcomes in the PEGylated islet group 28 DPT. In validation experiments, MRI parameters obtained 1, 7, and 14 DPT predicted normoglycemia 4 wk post-transplantation. We directly demonstrated the benefit of islet PEGylation in protection against nonspecific islet destruction in the early post-transplant period of intraportal islet transplantation using a novel algorithm for islet MRI. This novel algorithm could serve as a useful tool to demonstrate such benefit in future clinical trials of islet transplantation using PEGylated islets.

Everolimus and Lenalidomide in Treating Patients With Relapsed or Refractory Non-Hodgkin or Hodgkin Lymphoma

ClinicalTrials.gov

2018-02-07

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Splenic Marginal Zone Lymphoma; Waldenstrom Macroglobulinemia

Cellular Immunotherapy Following Chemotherapy in Treating Patients With Recurrent Non-Hodgkin Lymphomas, Chronic Lymphocytic Leukemia or B-Cell Prolymphocytic Leukemia

ClinicalTrials.gov

2018-04-20

Post-transplant Lymphoproliferative Disorder; B-Cell Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma; Recurrent Lymphoplasmacytic Lymphoma

Posttransplantation lymphoproliferative disorder in lung transplant recipients: a 15-year single institution experience.

PubMed

Muchtar, Eli; Kramer, Mordechai R; Vidal, Liat; Ram, Ron; Gurion, Ronit; Rosenblat, Yivgenia; Bakal, Ilana; Shpilberg, Ofer

2013-10-15

Posttransplantation lymphoproliferative disorder (PTLD) is a well-recognized complication after solid-organ transplantation. Historically, most cases of PTLD among lung transplant recipients occurred within the first year from transplantation and were associated with Epstein-Barr virus (EBV) infection. However, there are increasing reports on a late-onset form of PTLD. We reviewed all charts of patients undergoing either lung or heart-lung transplantation in a tertiary transplantation center between the years 1997 and 2012 and compared clinical and pathologic parameters between early- and late-onset PTLD. Ten patients with PTLD were identified. Median (range) time from transplantation to PTLD diagnosis was 41 (4-128) months. Three patients developed early PTLD. All were pretransplantation EBV seronegative and asymptomatic when diagnosed during surveillance chest imaging. In contrast, the seven patients with late-onset PTLD were all EBV seropositive before transplantation and were symptomatic at diagnosis. Although early-onset PTLD uniformly involved the transplanted lung, this was relatively rare in late-onset PTLD (3 of 3 vs. 1 of 7). All patients were initially treated with reduction of immunosuppression, with at least one additional treatment modality used, mainly chemoimmunotherapy. Eight patients attained complete remission. With a median follow-up of 17 months, 8 patients died, mainly from treatment-related causes rather than disease progression. Our cohort of lung transplant recipients demonstrates a trend of late-onset PTLD with the majority of patients who died of treatment-related causes rather than disease progression. Therefore, substantial efforts should be focused on treatment-related mortality reduction.

Approaches to Managing Autoimmune Cytopenias in Novel Immunological Disorders with Genetic Underpinnings Like Autoimmune Lymphoproliferative Syndrome

PubMed Central

Rao, V. Koneti

2015-01-01

Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of apoptosis. It is frequently caused by mutations in FAS (TNFRSF6) gene. Unlike most of the self-limiting autoimmune cytopenias sporadically seen in childhood, multi lineage cytopenias due to ALPS are often refractory, as their inherited genetic defect is not going to go away. Historically, more ALPS patients have died due to overwhelming sepsis following splenectomy to manage their chronic cytopenias than due to any other cause, including malignancies. Hence, current recommendations underscore the importance of avoiding splenectomy in ALPS, by long-term use of corticosteroid-sparing immunosuppressive agents like mycophenolate mofetil and sirolimus. Paradigms learnt from managing ALPS patients in recent years is highlighted here and can be extrapolated to manage refractory cytopenias in patients with as yet undetermined genetic bases for their ailments. It is also desirable to develop international registries for children with rare and complex immune problems associated with chronic multilineage cytopenias in order to elucidate their natural history and long-term comorbidities due to the disease and its treatments. PMID:26258116

Severe right ventricular dysfunction is an independent predictor of pre- and post-transplant mortality among candidates for heart transplantation.

PubMed

Ravis, Eleonore; Theron, Alexis; Mancini, Julien; Jaussaud, Nicolas; Morera, Pierre; Chalvignac, Virginie; Guidon, Catherine; Grisoli, Dominique; Gariboldi, Vlad; Riberi, Alberto; Habib, Gilbert; Mouly-Bandini, Annick; Collart, Frederic

2017-03-01

Heart transplantation is the gold-standard treatment for end-stage heart failure. However, the shortage of grafts has led to longer waiting times and increased mortality for candidates without priority. To study waiting-list and post-transplant mortality, and their risk factors among patients registered for heart transplantation without initial high emergency procedure. All patients registered on the heart transplantation waiting list (2004-2015) without initial high emergency procedure were included. Clinical, biological, echocardiographic and haemodynamic data were collected. Waiting list and 1-year post-transplant survival were analysed with a Kaplan-Meier model. Of 221 patients enrolled, 168 (76.0%) were men. Mean age was 50.0±12.0 years. Forty-seven patients died on the waiting list, resulting in mortality rates of 11.2±2.7% at 1 year, 31.9±5.4% at 2 years and 49.4±7.1% at 3 years. Median survival was 36.0±4.6 months. In the multivariable analysis, left ventricular ejection fraction<30% (hazard ratio [HR]: 3.76, 95% confidence interval [CI]: 1.38-10.24; P=0.010) and severe right ventricular systolic dysfunction (HR: 2.89, 95% CI: 1.41-5.92; P=0.004) were associated with increased waiting-list mortality. The post-transplant survival rate was 73.1±4.4% at 1 year. Pretransplant severe right ventricular dysfunction and age>50 years were strong predictors of death after transplantation (HR: 5.38, 95% CI: 1.38-10.24 [P=0.020] and HR: 6.16, 95% CI: 1.62-9.32 [P=0.0130], respectively). Mortality among candidates for heart transplantation remains high. Patients at highest risk of waiting-list mortality have to be promoted, but without compromising post-transplant outcomes. For this reason, candidates with severe right ventricular dysfunction are of concern, because, for them, transplantation is hazardous. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Humanized Mouse Models of Epstein-Barr Virus Infection and Associated Diseases

PubMed Central

Fujiwara, Shigeyoshi; Matsuda, Go; Imadome, Ken-Ichi

2013-01-01

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus infecting more than 90% of the adult population of the world. EBV is associated with a variety of diseases including infectious mononucleosis, lymphoproliferative diseases, malignancies such as Burkitt lymphoma and nasopharyngeal carcinoma, and autoimmune diseases including rheumatoid arthritis (RA). EBV in nature infects only humans, but in an experimental setting, a limited species of new-world monkeys can be infected with the virus. Small animal models, suitable for evaluation of novel therapeutics and vaccines, have not been available. Humanized mice, defined here as mice harboring functioning human immune system components, are easily infected with EBV that targets cells of the hematoimmune system. Furthermore, humanized mice can mount both cellular and humoral immune responses to EBV. Thus, many aspects of human EBV infection, including associated diseases (e.g., lymphoproliferative disease, hemophagocytic lymphohistiocytosis and erosive arthritis resembling RA), latent infection, and T-cell-mediated and humoral immune responses have been successfully reproduced in humanized mice. Here we summarize recent achievements in the field of humanized mouse models of EBV infection and show how they have been utilized to analyze EBV pathogenesis and normal and aberrant human immune responses to the virus. PMID:25436886

SRTR center-specific reporting tools: Posttransplant outcomes.

PubMed

Dickinson, D M; Shearon, T H; O'Keefe, J; Wong, H-H; Berg, C L; Rosendale, J D; Delmonico, F L; Webb, R L; Wolfe, R A

2006-01-01

Measuring and monitoring performance--be it waiting list and posttransplant outcomes by a transplant center, or organ donation success by an organ procurement organization and its partnering hospitals--is an important component of ensuring good care for people with end-stage organ failure. Many parties have an interest in examining these outcomes, from patients and their families to payers such as insurance companies or the Centers for Medicare and Medicaid Services; from primary caregivers providing patient counseling to government agencies charged with protecting patients. The Scientific Registry of Transplant Recipients produces regular, public reports on the performance of transplant centers and organ procurement organizations. This article explains the statistical tools used to prepare these reports, with a focus on graft survival and patient survival rates of transplant centers--especially the methods used to fairly and usefully compare outcomes of centers that serve different populations. The article concludes with a practical application of these statistics--their use in screening transplant center performance to identify centers that may need remedial action by the OPTN/UNOS Membership and Professional Standards Committee.

Role of the CD34+ 38- cells in posttransplant hematopoietic recovery.

PubMed

Hénon, P; Sovalat, H; Bourderont, D; Ojeda-Uribe, M; Arkam, Y; Wunder, E; Raidot, J P; Husseini, F; Audhuy, B

1998-01-01

Using three different statistical tests in parallel, we showed in a preliminary study that neither mononuclear cells, CD34+ 33+ or 33- cells, nor CD34+ 38+ cells significantly correlated with engraftment kinetics following autologous blood cell transplantation (ABCT). We additionally demonstrated here, in a series of patients suffering from malignant diseases, that the graft content in CD34+ 38- cells is individually a more sensitive indicator of the earliest, as well as the latest post-ABCT trilineage hematopoietic recovery than the colony-forming units-granulocyte-macrophage and even the total CD34+ cell content. This suggests that the CD34+ 38- cell population is itself subdivided into two more subsets, one being already lineage-committed and responsible for short-term engraftment, the other containing only very primitive hematopoietic cells responsible for sustained engraftment. Strong arguments favor the probability that these subsets correspond to HLA-DR+ and DR cells, respectively. We also defined an optimal threshold value of 0.05 x 10(6) CD34+ 38- cells/kg of the patient's body weight (b.w.) above which a rapid and sustained trilineage engraftment safely occurs. In fact, infusion of lower numbers of cells seems to have a more significant impact on long-term compared to short-term neutrophil recovery and on platelet kinetics engraftment. We additionally looked for the eventual influence on engraftment time of the type of disease, and of post-ABCT administration of hematopoietic growth factors (HGF). When the type of disease appeared to have no influence on the engraftment time, posttransplant HGF administration significantly reduced the time to trilineage engraftment in patients transplanted with < 0.05 x 10(6) CD34+ 38- cells, thus justifying it in case of reinfusion of low numbers of CD34+ 38- cells. On the other hand, the administration of HGF after infusion of more than 0.05 x 10(6) CD34+ 38- cells/kg b.w. did not hasten more, or only very little, the

Primary distal femur T-cell lymphoma after allogeneic haematopoietic stem cell transplantation for chronic myeloid leukaemia: a rare case report and literature review.

PubMed

Han, Qiaoyan; Sun, Miao; Wu, Lingyu; Chen, Jing; Wang, Wei; Liu, Chunhua; Chen, Haoyue; Du, Guibin

2014-04-01

Post-transplant lymphoproliferative disorders originating from T lymphocytes are a rare complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) that are not usually associated with Epstein-Barr virus infection. A male patient diagnosed at the age of 15 years with chronic myeloid leukaemia (in the chronic phase) was initially treated with oral hydroxyurea. The disease entered an accelerated phase when the patient was 22 years old. Complete remission was achieved after one course of homoharringtonine and cytarabine. The patient then underwent human leucocyte antigen-matched sibling donor allo-HSCT. Just over 6.5 years after the allo-HSCT, a second primary tumour was located in the distal femur and diagnosed as T-cell non-Hodgkin's lymphoma (stage IV, group B). This was treated with various chemotherapy and radiotherapy regimens, but the outcomes were poor and the disease progressed. The T-cell lymphoma invaded many sites, including the skeleton, spleen and skin, and the patient died within 8 months of the diagnosis. This current case report highlights the need for the early detection and prevention of subsequent primary malignancies after allo-HSCT.

Marek's disease virus immunosuppression alters host cellular responses and immune gene expression in the skin of infected chickens

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a highly contagious lymphoproliferative and neuropathic disease of chickens. The feather follicle epithelium (FFE) is the only anatomical site within the host where infectious enveloped cell-free MD virus (MDV) particles are produced and disseminated into the environment. MD ...

Synergistic defects of novo FAS and homozygous UNC13D leading to autoimmune lymphoproliferative syndrome-like disease: A 10-year-old Chinese boy case report.

PubMed

Gu, Hao; Ma, Jie; Chen, Zhenping; Wang, Jing; Zhang, Rui; Wu, Runhui

2018-06-01

Autoimmune lymphoproliferative syndrome (ALPS) usually presents in childhood with fever, nonmalignant splenomegaly and lymphadenopathy along with hemocytopenia. This case report describes a 10-year-old boy presenting with signs of autoimmune disease, splenomegaly, hepatomegaly and resistant hemocytopenia. Sirolimus controlled the relapsed thrombocytopenia after splenectomy. Sequencing of the FAS gene identified two spontaneous heterozygous mutations (c.234 T > G, p.D78E) (c.236dupA, p.P80Tfs*26). The boy's homozygous missense variation (c.2588G > A, p.G863D) (rs140184929) in UNC13D gene had been identified as being related to familial hemophagocytic lymphohistiocytosis (FHL). TCRαβ + CD4/CD8 double-negative T cells (markers of ALPS) were not significantly increased from the outset. Elevated cytokines, such as interferon (IFN)-γ, interleukin (IL)-6 and tumor necrosis factor α decreased to normal levels after splenectomy whereas IL-10 remained high. Immunological analysis of the patient revealed a marked depletion of forkhead-box P3 + expressing regulatory T cells (Treg) and Th17 cells. The obtained data demonstrate that mutations to FAS and UNC13D which result in overwhelming T-cell and macrophage activation, one associated with inhibited Treg cell development and a severe ALPS-like symptom. Therefore, we propose that variations of UND13D may be a risk factor of ALPS development. Copyright © 2017. Published by Elsevier B.V.

Occupation and hematopoietic and lymphoproliferative malignancies among women: a linked registry study.

PubMed

Linet, M S; McLaughlin, J K; Malker, H S; Chow, W H; Weiner, J A; Stone, B J; Ericsson, J L; Fraumeni, J F

1994-11-01

Using a nationwide linked registry, we evaluated the incidence of several hematopoietic and lymphoproliferative (HLP) malignancies among Swedish women from 1961 to 1979 by industry and occupation. The risks of one or more types of HLP cancers (including the leukemias, non-Hodgkin's lymphoma, multiple myeloma, and mycosis fungoides) were significantly increased among women working in the agriculture and textile industries, housekeepers, and post office employees. Limitations of these linked-registry data include lack of detailed information on specific exposures and duration of employment, and the relatively small sizes of specific occupational cohorts. Nevertheless, as the proportion of women entering the workforce continues to increase, this data resource may provide additional clues to occupational determinants of HLP and other malignancies.

Protective efficacy of a recombinant bacterial artificial chromosome clone of a very virulent Marek’s disease virus containing a reticuloendotheliosis virus long terminal repeat

USDA-ARS?s Scientific Manuscript database

Marek’s disease virus (MDV), an alphaherpesvirus, causes Marek’s disease (MD), a lymphoproliferative disease in poultry characterized by T-cell lymphomas, nerve lesions and mortality. Vaccination is used worldwide to control MD, but increasingly virulent field strains can overcome this protection, d...

Pretransplant soluble CD30 is a better predictor of posttransplant development of donor-specific antibodies and acute vascular rejection than panel reactive antibodies.

PubMed

Vaidya, Smita; Partlow, David; Barnes, Titus; Gugliuzza, Kristine

2006-12-27

This study tests a hypothesis that pretransplant concentration of soluble CD30 (sCD30) is a better predictor of posttransplant development of donor-specific HLA antibodies (DSA) and acute vascular rejection (AVR) than panel reactive HLA antibodies (PRA). Pretransplant sera from 115 patients were evaluated for their PRA and sCD30 concentrations. All patients received calcineurin-inhibitor based immunosuppressive therapy. Objective measurements for rejection were biopsy-proven AVR episodes within first 6 months of the transplant. Posttransplant sera of patients with or without AVR were tested for the presence of DSA. AVR rate was 16% (18/115). Patients positive for PRA and sCD30 tests were at significantly higher risk for AVR compared to those patients negative for both tests (36% versus 5%, p = 0.01). Among negative PRA patients risk for AR was significantly elevated if they were also tested positive for sCD30 concentrations (21% versus 5%, p = 0.04). Of the 18 patients with AVR, 14 were positive for sCD30, and 13 of them (93%) developed DSA posttransplant (p = 0.001) Nineteen patients without AVR were tested for DSA and sCD30 concentrations. Only two of these 19 patients were positive for sCD30 and DSA. AVR was strongly associated with the patients tested positive for both the tests: DSA and sCD30 (p = 0.00007). Furthermore, patients with AVR are more likely to produce DSA than those without AVR (p = 0.02). These data support our hypothesis that patients positive for sCD30 contents are at high risk the development of DSA and AVR posttransplant regardless of their pretransplant PRA.

Employment after heart transplantation among adults with congenital heart disease.

PubMed

Tumin, Dmitry; Chou, Helen; Hayes, Don; Tobias, Joseph D; Galantowicz, Mark; McConnell, Patrick I

2017-12-01

Adults with congenital heart disease may require heart transplantation for end-stage heart failure. Whereas heart transplantation potentially allows adults with congenital heart disease to resume their usual activities, employment outcomes in this population are unknown. Therefore, we investigated the prevalence and predictors of work participation after heart transplantation for congenital heart disease. Retrospective review of a prospective registry. United Network for Organ Sharing registry of transplant recipients in the United States. Adult recipients of first-time heart transplantation with a primary diagnosis of congenital heart disease, performed between 2004 and 2015. None. Employment status reported by transplant centers at required follow-up intervals up to 5 y posttransplant. Among 470 patients included in the analysis (mean follow-up: 5 ± 3 y), 127 (27%) worked after transplant, 69 (15%) died before beginning or returning to work, and 274 (58%) survived until censoring, but did not participate in paid work. Multivariable competing-risks regression analysis examined characteristics associated with posttransplant employment, accounting for mortality as a competing outcome. In descriptive and multivariable analysis, pretransplant work participation was associated with a greater likelihood of posttransplant employment, while the use of Medicaid insurance at the time of transplant was associated with a significantly lower likelihood of working after transplant (subhazard ratio compared to private insurance: 0.55; 95% confidence interval: 0.32, 0.95; P = .032). Employment was rare after heart transplantation for congenital heart disease, and was significantly less common than in the broader population of adults with congenital heart disease. Differences in return to work were primarily related to pretransplant employment and the use of public insurance, rather than clinical characteristics. © 2017 Wiley Periodicals, Inc.

Epstein–barr virus vaccines

PubMed Central

Cohen, Jeffrey I

2015-01-01

Epstein–Barr virus (EBV) is the primary cause of infectious mononucleosis (IM) and is associated with epithelial cell malignancies such as nasopharyngeal carcinoma and gastric carcinoma, as well as lymphoid malignancies including Hodgkin lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma and post-transplant lymphoproliferative disorder. EBV vaccines to prevent primary infection or disease, or therapeutic vaccines to treat EBV malignancies have not been licensed. Most efforts to develop prophylactic vaccines have focused on EBV gp350, which is the major target of neutralizing antibody. A single phase 2 trial of an EBV gp350 vaccine has been reported; the vaccine reduced the rate of IM but not virus infection. The observation that infusion of EBV-specific T cells can reduce disease due to Hodgkin lymphoma and nasopharyngeal carcinoma provides a proof of principle that a therapeutic vaccine for these and other EBV-associated malignancies might be effective. Most therapeutic vaccines have targeted EBV LMP2 and EBV nuclear antigen-1. As EBV is associated with nearly 200 000 new malignancies each year worldwide, an EBV vaccine to prevent these diseases is needed. PMID:25671130

Long-term outcome for immune suppression and immune related lymphoproliferative disorder: prospective data from the United Kingdom Children's Leukaemia and Cancer Group registry 1994-2004.

PubMed

Taj, Mary M; Hadzic, Nedim; Height, Susan E; Wotherspoon, Andrew; Burke, Margaret; Hobson, Rachel; Viskaduraki, Maria; Pinkerton, C Ross

2012-05-01

Prospective national registry data on 98 patients were studied to determine the long-term outcome of immune related lymphoproliferative disease (LPD) and define prognostic factors. Seventy-three developed LPD following organ transplant (26 liver, 21 heart, 15 kidney, nine bone marrow [BM], two bowel). Twenty-five had non-transplant related immunosuppression. Age was 1.1-17 years (median 8.6). Fifty-eight patients had lymphomatous, 21 systemic and 17 lymphadenopathic disease. Sixty (73%) were disseminated and 22 (27%) localized. Thirty-three (54%) were monoclonal. Seventy-three (83%) were Epstein-Barr virus (EBV) positive. Median follow-up was 7.6 years. LPD developed earlier after liver and BM as compared to heart or kidney transplant. Five-year overall survival (OS) was 58%. Prognosis was best after liver and kidney transplant (OS >77%). Mortality was higher following heart (2.5 times) and BM transplant (5 times). Adverse prognostic factors were disseminated or lymphomatous disease and lack of reduction of immunosuppression. With appropriate reduction of immunosuppression, rituximab and low-dose chemotherapy, long-term survival is high.

Severe necrotic dermatitis in the combs of line 6-3 chickens is associated with Marek's disease virus-induced immunosuppression

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD), a lymphoproliferative disorder of domestic chickens is characterized by bursal–thymic atrophy and rapid onset of T-cell lymphomas that infiltrate lymphoid tissues, visceral organs, and peripheral nerves. Marek’s disease virus (MDV), the etiological agent of MD, is a highly cel...

Mobilized Peripheral Blood Stem Cells Versus Unstimulated Bone Marrow As a Graft Source for T-Cell-Replete Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide.

PubMed

Bashey, Asad; Zhang, Mei-Jie; McCurdy, Shannon R; St Martin, Andrew; Argall, Trevor; Anasetti, Claudio; Ciurea, Stefan O; Fasan, Omotayo; Gaballa, Sameh; Hamadani, Mehdi; Munshi, Pashna; Al Malki, Monzr M; Nakamura, Ryotaro; O'Donnell, Paul V; Perales, Miguel-Angel; Raj, Kavita; Romee, Rizwan; Rowley, Scott; Rocha, Vanderson; Salit, Rachel B; Solh, Melhem; Soiffer, Robert J; Fuchs, Ephraim Joseph; Eapen, Mary

2017-09-10

Purpose T-cell-replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and Methods A total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. Results Hematopoietic recovery was similar after transplantation of BM and PB (28-day neutrophil recovery, 88% v 93%, P = .07; 100-day platelet recovery, 88% v 85%, P = .33). Risks of grade 2 to 4 acute (hazard ratio [HR], 0.45; P < .001) and chronic (HR, 0.35; P < .001) graft-versus-host disease were lower with transplantation of BM compared with PB. There were no significant differences in overall survival by graft type (HR, 0.99; P = .98), with rates of 54% and 57% at 2 years after transplantation of BM and PB, respectively. There were no differences in nonrelapse mortality risks (HR, 0.92; P = .74) but relapse risks were higher after transplantation of BM (HR, 1.49; P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of BM were limited to patients with leukemia (HR, 1.73; P = .002) and not lymphoma (HR, 0.87; P = .64). Conclusion PB and BM grafts are suitable for haploidentical transplantation with the post-transplant cyclophosphamide approach but with differing patterns of treatment failure. Although, to our knowledge, this is the most comprehensive comparison, these findings must be validated in a randomized prospective comparison with adequate follow-up.

Post-transplant soluble CD30 levels are associated with early subclinical rejection in kidney transplantation.

PubMed

Grenzi, Patricia C; Campos, Érika F; Silva, Hélio T; Felipe, Claudia R; Franco, Marcelo F; Soares, Maria F; Medina-Pestana, José O; Gerbase-DeLima, Maria

2015-03-01

Several studies have shown association of high pre- or post-transplant levels of soluble CD30 (sCD30) with acute rejection and poor late kidney transplant outcome. Our goal was to investigate whether sCD30 levels at month-3 post-transplant are associated with subclinical rejection, presence of CD30(+) cells within the graft, and expression of immune response genes in peripheral blood mononuclear cells. The study comprised 118 adult first kidney graft recipients, transplanted at a single center, receiving tacrolimus in low concentration. All were submitted to a protocol biopsy at month-3. Subclinical rejection was identified in 10 biopsies and sCD30 levels ≥ 61.88 ng/mL (P = 0.004), younger recipient age (P = 0.030) and non-Caucasian ethnicity (P = 0.011) were independently associated with this outcome. Rare CD30(+) cells were present in only two biopsies. There was a correlation between sCD30 levels and CD30 gene expression in peripheral blood mononuclear cells (r = 0.385, P = 0.043). These results show that high sCD30 levels are independent predictors of graft dysfunction and may contribute to patient selection protocols by indicating those who could benefit from a more thorough evaluation. Copyright © 2015 Elsevier B.V. All rights reserved.

Posttransplant malignancies in renal transplant recipients: 22-years experience from a single center in Pakistan.

PubMed

Yunus, Mahira; Aziz, Tahir; Mubarak, Muhammed

2012-01-01

To study the incidence, types and distribution pattern of malignant tumors in renal transplant recipients at a single center in Pakistan. This retrospective study was conducted at Sindh Institute of Urology and Transplantation (SIUT) and included all transplant patients on regular follow-up from November 1986 to December 2008. The original biopsy reports and case files of all patients who developed posttransplant malignancies were reviewed and relevant demographic, clinical, radiological, and histopathological data were retrieved and analyzed. SPSS version 10.0 was used for statistical analysis. Over 22 years of study period, 1816 renal transplants were carried out at our center. Among these, 44 patients developed malignancies constituting an overall incidence rate of 2.4%. All patients in this study were males with a mean age of 34.9±9.5 years (range: 9 to 60 years). The most common type of malignancy was lymphoma (27 patients, 61.4%), followed by Kaposi's sarcoma (11 patients, 25%) and skin malignancies (3 patients, 6.8%). One case each of adenocarcinoma of the gallbladder, acute myeloid leukemia (AML), conjunctival carcinoma-in-situ and seminoma were also diagnosed. Posttransplant malignancies occurring in our renal transplant recipients show different incidence rates and patterns as compared with western studies.

Post-transplant HLA class II antibodies and high soluble CD30 levels are independently associated with poor kidney graft survival.

PubMed

Langan, L L; Park, L P; Hughes, T L; Irish, A; Luxton, G; Witt, C S; Christiansen, F T

2007-04-01

HLA-specific antibodies (HSA) and soluble CD30 (sCD30) were measured in 208 renal transplant recipients with functioning grafts at least 1 year after transplantation (median 8.2 years) to investigate the predictive value of HSA and sCD30 on subsequent graft outcome. HSA (class I and class II) were detected by both ELISA LAT-M and Luminex LabScreen assays. Data on graft outcome was collected with a median follow-up time of 3.5 years after antibody and sCD30 measurement. Recipients with post-transplant HLA class II antibodies had particularly poor graft outcome with a hazard ratio (HR) of 7.8 (p < 0.0001) when detected by ELISA, and a HR of 6.0 (p < 0.0001) when detected by Luminex. A high post-transplant sCD30 level >or=100 U/mL was associated with increased risk of subsequent graft failure (HR 2.7, p = 0.03). sCD30 and HSA had an independent and additive association with graft outcome. Recipients with HLA class II antibody and high sCD30 had the highest risk of subsequent graft failure (HR 43.4, p < 0.0001 and HR 18.1, p = 0.0008 for ELISA and Luminex, respectively). These data show that detection of HSA and serum sCD30 measured at least 1-year post-transplant provides valuable and predictive information regarding subsequent graft outcome.

Epstein-Barr virus-associated T-cell lymphoproliferative disorder affecting skin and lung in an elderly patient.

PubMed

Hoshino, Tomomi; Tatsuno, Kazuki; Shimauchi, Takatoshi; Okada, Satoko; Ito, Taisuke; Ono, Takaaki; Ohshima, Koichi; Tokura, Yoshiki

2014-09-01

A 70-year-old man presented with papular skin lesions and was diagnosed with Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder (T-LPD). The patient showed infiltration of a large number of EBV-encoded RNA-positive T cells in the skin and lung, presence of EBV load in the peripheral blood, and expansion of clonal EBV-infected γδ T cells and CD8(+) T cells in the blood and skin, as assessed by EBV-terminal repeat Southern blot, T-cell receptor polymerase chain reaction and flow cytometric analyses. In the Japanese or East Asian fatal cases of EBV-associated T/natural killer (NK)-LPD, there are two peaks in age at death, approximately 20 years and 60 years. The former age group is associated with chronic active EBV infection (CAEBV), and the latter group typically suffers from extranodal NK/T-cell lymphoma. Our case is characterized not only by the unique skin and lung manifestations but also the late onset age of the disease, indicating that the skin manifestation of CAEBV can be seen even in elderly patients. © 2014 Japanese Dermatological Association.

Decrease of lymphoproliferative response by amphetamine is mediated by dopamine from the nucleus accumbens: influence on splenic met-enkephalin levels.

PubMed

Assis, María Amparo; Valdomero, Analía; García-Keller, Constanza; Sotomayor, Claudia; Cancela, Liliana Marina

2011-05-01

Despite the mesocorticolimbic dopaminergic pathway being one of the main substrates underlying stimulating and reinforcing effects induced by psychostimulant drugs, there is little information regarding its role in their effects at the immune level. We have previously demonstrated that acute exposure to amphetamine (5 mg/kg, i.p.) induced an inhibitory effect on the splenic T-cell proliferative response, along with an increase in the methionine(met)-enkephalin content at limbic and immune levels, 4 days after drug administration. In this study, we investigated if a possible dopamine mechanism underlies these amphetamine-induced effects by administering D1 and D2 dopaminergic antagonists or a dopaminergic terminal neurotoxin before the drug. Pre-treatment with either SCH-23390 (0.1 mg/kg, i.p.) or raclopride (0.1 mg/kg, i.p.), a D1 or D2 dopaminergic receptor antagonist, respectively, abrogated the effects of amphetamine on the lymphoproliferative response and on met-enkephalin levels of the spleen. The amphetamine-induced increase in limbic met-enkephalin content was suppressed by SCH-23390 but not by raclopride pre-treatment. Finally, an intra-accumbens 6-hydroxy-dopamine injection administered 2 weeks previously prevented amphetamine-induced effects on the lymphoproliferative response and on met-enkephalin levels in the prefrontal cortex and spleen. These findings strongly suggest that D1 and D2 dopaminergic receptors are involved in amphetamine-induced effects at immune level as regards the lymphoproliferative response and the changes in spleen met-enkephalin content, whereas limbic met-enkephalin levels were modulated only by the D1 dopaminergic receptors. In addition, this study showed that a mesolimbic component modulated amphetamine-induced effects on the immune response, as previously shown at a behavioral level. Copyright © 2011 Elsevier Inc. All rights reserved.

The effect of pre-transplant pain and chronic disease self-efficacy on quality of life domains in the year following hematopoietic stem cell transplantation.

PubMed

O'Sullivan, Madeline L; Shelby, Rebecca A; Dorfman, Caroline S; Kelleher, Sarah A; Fisher, Hannah M; Rowe Nichols, Krista A; Keefe, Francis J; Sung, Anthony D; Somers, Tamara J

2018-04-01

Pain is common for hematopoietic stem cell transplant (HSCT) patients and may be experienced pre-transplant, acutely post-transplant, and for months or years following transplant. HSCT patients with persistent pain may be at risk for poor quality of life following transplant; however, the impact of pre-transplant pain on quality of life post-transplant is not well understood. Self-efficacy for chronic disease management is associated with quality of life among cancer patients and may impact quality of life for HSCT patients. The primary aim was to examine the effect of pre-transplant pain and self-efficacy on quality of life domains in the year following transplant. One hundred sixty-six HSCT patients completed questionnaires providing information on pain, self-efficacy, and quality of life prior to transplant, at discharge, and 3-, 6-, and 12-months post-transplant as part of a longitudinal, observational study. Linear mixed modeling examined the trajectories of these variables and the effect of pre-transplant pain and self-efficacy on post-transplant quality of life. Pain and social and emotional quality of life remained stable in the year following transplant while self-efficacy and physical and functional quality of life improved. Pre-transplant pain was significantly related to lower physical well-being post-transplant. Lower pre-transplant self-efficacy was related to lower quality of life across all domains post-transplant. Above and beyond the effect of pre-transplant pain, self-efficacy for managing chronic disease is important in understanding quality of life following transplant. Identifying patients with pain and/or low self-efficacy pre-transplant may allow for early intervention with self-management strategies.

Spectrum of Epstein-Barr virus-associated T-cell lymphoproliferative disorder in adolescents and young adults in Taiwan

PubMed Central

Wang, Ren-Ching; Chang, Sheng-Tsung; Hsieh, Yen-Chuan; Huang, Wan-Ting; Hsu, Jeng-Dong; Tseng, Chih-En; Wang, Ming-Chung; Hwang, Wei-Shou; Wang, John; Chuang, Shih-Sung

2014-01-01

Epstein-Barr Virus (EBV) is a herpesvirus usually infecting B-cells but may occasionally infect T- or natural killer (NK)-cells. EBV-associated T- or NK-cell lymphoproliferations represent a continuous spectrum of diseases ranging from asymptomatic infection, infectious mononucleosis (IM), to clonal and malignant lymphoproliferations including systemic EBV-positive T/NK-cell lymphoproliferative disease (EBV-T/NK-LPD) of childhood and hydroa-vacciniforme-like lymphoma of the skin. The clonal diseases are more prevalent in East Asia and exhibit overlapping clinical and pathological features with chronic active EBV infection. Here we report our experience on 10 cases of EBV-associated T-cell lymphoproliferation from Taiwan including five males and five females with a median age of 18 years old (range, 15-28). The most common clinical symptoms were fever, neck mass and hepatosplenomegaly. Eight of these patients showed elevated lactate dehydrogenase level and half of the patients had cytopenia. All patients had either elevated EBV antibody titers or increased serum EBV DNA levels. Five cases were clinically IM-like with polyclonal (3 cases) or clonal (2 cases) T-cell lymphoproliferation. Two patients each had chronic active EBV infection (CAEBV) and hemophagocytic lymphohistiocytosis (HLH). One patient had both CAEBV and HLH. One of the HLH patients with marrow infiltration by intra-sinusoidal large atypical lymphocytes experienced a fulminant course. In a median follow-up time of 21.5 months, seven patients were free of disease, one was alive with disease, and two died of disease in 31 and 3 months, respectively, despite chemotherapy. We confirmed a wide clinicopathological range of EVB-associated T-cell lymphoproliferation in Taiwan. Furthermore, monomorphic LPD and the single case with fulminant course as defined by Ohshima et al (Pathol Int 2018) as categories A3 and B, respectively, died of disease despite chemotherapy. Our report, the largest series in the recent

Spectrum of Epstein-Barr virus-associated T-cell lymphoproliferative disorder in adolescents and young adults in Taiwan.

PubMed

Wang, Ren-Ching; Chang, Sheng-Tsung; Hsieh, Yen-Chuan; Huang, Wan-Ting; Hsu, Jeng-Dong; Tseng, Chih-En; Wang, Ming-Chung; Hwang, Wei-Shou; Wang, John; Chuang, Shih-Sung

2014-01-01

Epstein-Barr Virus (EBV) is a herpesvirus usually infecting B-cells but may occasionally infect T- or natural killer (NK)-cells. EBV-associated T- or NK-cell lymphoproliferations represent a continuous spectrum of diseases ranging from asymptomatic infection, infectious mononucleosis (IM), to clonal and malignant lymphoproliferations including systemic EBV-positive T/NK-cell lymphoproliferative disease (EBV-T/NK-LPD) of childhood and hydroa-vacciniforme-like lymphoma of the skin. The clonal diseases are more prevalent in East Asia and exhibit overlapping clinical and pathological features with chronic active EBV infection. Here we report our experience on 10 cases of EBV-associated T-cell lymphoproliferation from Taiwan including five males and five females with a median age of 18 years old (range, 15-28). The most common clinical symptoms were fever, neck mass and hepatosplenomegaly. Eight of these patients showed elevated lactate dehydrogenase level and half of the patients had cytopenia. All patients had either elevated EBV antibody titers or increased serum EBV DNA levels. Five cases were clinically IM-like with polyclonal (3 cases) or clonal (2 cases) T-cell lymphoproliferation. Two patients each had chronic active EBV infection (CAEBV) and hemophagocytic lymphohistiocytosis (HLH). One patient had both CAEBV and HLH. One of the HLH patients with marrow infiltration by intra-sinusoidal large atypical lymphocytes experienced a fulminant course. In a median follow-up time of 21.5 months, seven patients were free of disease, one was alive with disease, and two died of disease in 31 and 3 months, respectively, despite chemotherapy. We confirmed a wide clinicopathological range of EVB-associated T-cell lymphoproliferation in Taiwan. Furthermore, monomorphic LPD and the single case with fulminant course as defined by Ohshima et al (Pathol Int 2018) as categories A3 and B, respectively, died of disease despite chemotherapy. Our report, the largest series in the recent

Concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine: a dimorphic presentation of iatrogenic immunodeficiency-associated lymphoproliferative disorder with evidence suggestive of multiclonal transformability of B cells by Epstein-Barr virus.

PubMed

Foo, Wen-Chi; Huang, Qin; Sebastian, Siby; Hutchinson, Charles B; Burchette, Jim; Wang, Endi

2010-12-01

A small fraction of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma develop Epstein-Barr virus-positive B-cell lymphoproliferative disorders. These Epstein-Barr virus-B-cell lymphoproliferative disorders are thought to be related to immune suppression induced by fludarabine/other chemotherapeutic regimens. As in other immunodeficiency-associated lymphoproliferative disorders, these disorders demonstrate a heterogeneous histological spectrum that ranges from polymorphic to monomorphic to classical Hodgkin lymphoma-like lesions. We report a case of concurrent classical Hodgkin lymphoma and plasmablastic lymphoma in a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with fludarabine. Both classical Hodgkin lymphoma and plasmablastic lymphoma were positive for Epstein-Barr virus-encoded RNA, whereas classical Hodgkin lymphoma was also positive for Epstein-Barr virus- latent membrane protein 1, suggesting a different viral latency. Immunoglobulin gene rearrangement studies demonstrated distinct clones in the plasmablastic lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. These findings suggest biclonal secondary lymphomas associated with iatrogenic immunodeficiency. Epstein-Barr virus-B-cell lymphoproliferative disorders in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma, in particular those arising after chemotherapy, should be separated from true Richter's transformation, and be categorized as (iatrogenic) immunodeficiency-associated lymphoproliferative disorder. Copyright © 2010 Elsevier Inc. All rights reserved.

Epstein-Barr virus-positive mucocutaneous ulcer in Crohn's disease. A condition to consider in immunosuppressed IBD patients.

PubMed

Juan, Alba; Lobatón, Triana; Tapia, Gustavo; Mañosa, Míriam; Cabré, Eduard; Domènech, Eugeni

2017-08-01

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a little known entity that can affect the oropharyngeal mucosa, the gastrointestinal tract and the skin. The main risk factor for the development of this lesion is immunosuppression. Because its features are similar to other Epstein-Barr virus-associated lymphoproliferative disorders, a differential diagnosis can sometimes prove challenging. Here, we report the case of a man diagnosed with Crohn's disease and treated with azathioprine and infliximab who developed ulceration at the rectum that was refractory to conventional medical treatment. Although the histological characteristics were suggestive of an EBVMCU, lymphoproliferative disease could not be ruled out. The patient did not improve after discontinuation of the treatment, a proctectomy was performed and the diagnosis of this disease was confirmed. Although very few cases of EBVMCU affecting the colon have been reported, its diagnosis should be always considered in refractory cases of inflammatory bowel disease with patients undergoing immunosuppressive treatment. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Association of high post-transplant soluble CD30 serum levels with chronic allograft nephropathy.

PubMed

Grenzi, Patricia C; Campos, Érika F; Tedesco-Silva, Hélio; Felipe, Claudia R; Franco, Marcello F; Soares, Maria Fernanda; Medina-Pestana, José Osmar; Gerbase-Delima, Maria

2013-12-01

The purpose of this study was to evaluate the association of post-transplant soluble CD30 (sCD30) levels, isolated or in combination with of anti-HLA class II antibodies and of serum creatinine levels, with kidney graft loss due to chronic allograft nephropathy (CAN), and type of lesions in graft biopsies for cause. The study comprised 511 first kidney graft recipients, transplanted at a single center, with a graft functioning for at least 2.8 years. A single blood sample was collected from each patient. sCD30 levels were determined by ELISA, and HLA antibodies by Luminex assay. The minimum follow-up after testing was 9.3 years. High sCD30 levels, set at sCD30 ≥ 34.15 ng/mL, the presence of HLA class II antibodies, and serum creatinine ≥ 1.9 mg/dL were independently associated with CAN-graft loss (P values <0.0001, 0.05, <0.0001, respectively), and the combined hazard ratio for CAN-graft loss was 20.2. Analyses of 166 biopsies for cause showed that high sCD30 levels and creatinine were independently associated with interstitial lesions. Post-transplant sCD30 serum levels, especially in conjunction with information regarding HLA class II antibodies and serum creatinine levels, provide valuable information regarding graft outcome and could be useful for the management of kidney transplant recipients. © 2013.

Maintenance steroid use at 30 days post-transplant and outcomes of pediatric heart transplantation: A propensity matched analysis of the Pediatric Heart Transplant Study database.

PubMed

Auerbach, Scott R; Kukreja, Manisha; Gilbert, Deborah; Bastardi, Heather; Feingold, Brian; Knecht, Kenneth; Kaufman, Beth D; Brown, Robert N; Miyamoto, Shelley D

2015-08-01

Maintenance steroid (MS) use in pediatric heart transplantation is variable. The purpose of this study was to evaluate the impact of MS use on graft outcomes. All patients <18 years old in the Pediatric Heart Transplant Study database at the time of first heart transplant between 1993 and 2011 who survived ≥30 days post-transplant and were from centers with a protocolized approach to MS use were included (N = 2,178). Patients were grouped by MS use at 30 days post-transplant as MS+ or MS- (no MS use). Propensity score analysis was used to generate matched groups of MS+ and MS- patients based on pre-transplant and peri-transplant factors. Kaplan-Meier survival analysis was used to compare freedom from graft loss, graft loss secondary to rejection, rejection, rejection with severe hemodynamic compromise (RSHC), malignancy, and infection between groups. Of patients, 1,393 (64%) were MS+ and 785 (36%) were MS-. There were 315 MS- patients who had propensity matched MS+ controls. Kaplan-Meier estimates showed no difference in graft loss (p = 0.9) or graft loss secondary to rejection (p = 0.09). At 1 year post-transplant, there was no difference in freedom from rejection (p = 0.15) or malignancy (p = 0.07), but there was lower freedom from RSHC and infection in the MS- group (p = 0.05 and p = 0.02, respectively). MS use at 30 days post-transplant was not associated with enhanced graft survival after pediatric heart transplant. MS- patients had a higher incidence of RSHC and infection. These risks should be taken into consideration when determining MS use for pediatric recipients of heart transplants. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Dynamics of Epstein-Barr virus DNA levels in serum during EBV-associated disease.

PubMed

Berger, C; Day, P; Meier, G; Zingg, W; Bossart, W; Nadal, D

2001-08-01

A real-time polymerase chain reaction assay for quantitation of Epstein-Barr virus (EBV) DNA in serum was developed. This assay detected EBV DNA in 24 (89%) of 27 sera from patients with infectious mononucleosis, but only in 9 (18%) of 51 sera from EBV carriers (P < 0.001) and in none of the sera from 32 EBV-seronegative individuals. EBV DNA levels were higher in sera from infectious mononucleosis (median 8,000, range 1833-150,069 copies/ml) than from carriers (median < 2, range < 2-2980; P < 0.001). In sera of 36 children with infectious mononucleosis followed prospectively, EBV DNA levels correlated inversely with the duration of symptoms. Among 18 children with tumors including Hodgkin's disease (n = 7), non-Hodgkin's lymphoma (n = 6), Burkitt's lymphoma (n = 1), lymphoproliferative disorder (n = 4), and osteosarcoma (n = 1), EBV DNA was detected in serum from those 9 (100%) expressing EBV in the tumor (Hodgkin's disease, 3; non-Hodgkin's lymphoma, 2; lymphoproliferative disorder, 4), the levels peaking at diagnosis and correlating with disease activity. Quantitation of EBV DNA in serum may offer a simple means of monitoring patients at risk of EBV-associated lymphoproliferation. Copyright 2001 Wiley-Liss, Inc.

Epstein–Barr Virus-Positive T/NK-Cell Lymphoproliferative Disorders Manifested as Gastrointestinal Perforations and Skin Lesions

PubMed Central

Xiao, Hai-Juan; Li, Ji; Song, Hong-Mei; Li, Zheng-Hong; Dong, Mei; Zhou, Xiao-Ge

2016-01-01

Abstract Systemic Epstein–Barr virus (EBV)-positive T-cell lymphoproliferative disorders (LPDs) of childhood is a highly aggressive EBV-positive T/natural killer (NK)-cell LPD, which emerges in the background of chronic active EBV infection (CAEBV) or shortly after primary acute EBV infection. The clinical presentations of CAEBV are varied; patients with atypical manifestations are easily misdiagnosed. We described a 14-year-old boy suffering from digestive disorders and intermittent fever for 1 year and 9 months, whose conditions worsened and skin lesions occurred 2 months before hospitalization. He was diagnosed as inflammatory bowel diseases (IBD) and treated accordingly. His other clinical features, hepatosplenomegaly, lymphadenopathy, anemia, hypoalbuminemia, and elevated inflammatory marks, were found in hospitalization. The boy suffered from repeatedly spontaneous intestinal perforations shortly after hospitalization and died of intestinal hemorrhea. The pathological results of intestine and skin both showed EBV-positive T/NK-cell LPD (lymphoma stage). There are rare studies reporting gastrointestinal perforations in EBV-positive T/NK-cell LPD, let alone repeatedly spontaneous perforations. Based on the clinical features and pathological results of this patient, the disease progressed from CAEBV (T-cell type) to systemic EBV-positive T-cell LPD of childhood (lymphoma). Not all the patients with CAEBV could have unusual patterns of anti-EBV antibodies. However, the presence of high EBV loads (EBV-encoded early small ribonucleic acid (RNA) (EBER) in affected tissues and/or EBV deoxyribonucleic acid (DNA) in peripheral blood) is essential for diagnosing CAEBV. Maybe because of his less common clinical features for CAEBV and negative anti-EBV antibodies, the boy was not diagnosed correctly. We should have emphasized the test for EBER or EBV-DNA. Meanwhile, for the IBD patients whose manifestations were not typical, and whose conditions were not improved by

Endoscopic therapy of posttransplant biliary stenoses after right-sided adult living donor liver transplantation.

PubMed

Zoepf, Thomas; Maldonado-Lopez, Evelyn J; Hilgard, Philip; Schlaak, Joerg; Malago, Massimo; Broelsch, Christoph E; Treichel, Ulrich; Gerken, Guido

2005-11-01

Endoscopic treatment of biliary strictures after liver transplantation is a therapeutic challenge. In particular, outcomes of endoscopic therapy of biliary complications in the case of duct-to-duct anastomosis after living related liver transplantation are limited. The aim of this study was to evaluate the feasibility and success of an endoscopic treatment approach to posttransplant biliary strictures (PTBS) after right-sided living donor liver transplantation (RLDLT) with duct-to-duct anastomosis. Ninety patients who received adult-to-adult RLDLT in our center were screened retrospectively with respect to endoscopic treatment of PTBS. Therapy was judged as successful when cholestasis parameters returned to normal and bile duct narrowing was reduced significantly after the completion of therapy. Forty of 90 RLDLT patients received duct-to-duct anastomosis, 12 (30%) showed PTBS. Seven of 12 patients were treated successfully by endoscopy; the remaining 5 patients were treated primarily by surgery. Most patients were treated by balloon dilatation followed by insertion of endoprostheses. A median of 2.5 dilatation sessions were necessary and the median treatment duration was 8 months. One patient developed endoscopy-treatable recurrent stenosis, no surgical intervention was necessary. Mild pancreatitis occurred in 7.9% and cholangitis in 5.3% of the procedures. One minor bleeding episode occurred during sphincterotomy. Bleeding was managed endoscopically. Endoscopic therapy of adult-to-adult right living related liver transplantation with duct-to-duct anastomosis is feasible and frequently is successful. The duct-to-duct anastomosis offers the possibility of endoscopic treatment. Endoscopic treatment of posttransplant biliary strictures is safe, with a low specific complication rate.

Long-Term Outcomes of Kidney Transplantation in Fabry Disease.

PubMed

Ersözlü, Sara; Desnick, Robert J; Huynh-Do, Uyen; Canaan-Kühl, Sima; Barbey, Frédéric; Genitsch, Vera; Müller, Thomas; Cheetham, Marcus; Flammer, Andreas; Schaub, Stefan; Nowak, Albina

2018-04-24

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene that obliterate or markedly reduce α-galactosidase A activity. This results in the systemic accumulation of its glycosphingolipid substrates in body fluids and organs, including the kidney. Fabry nephropathy can lead to end-stage renal disease requiring kidney transplantation. Little is known about its long-term outcomes and the overall patient survival after kidney transplantation. Here, we report 17 Fabry patients (15 males, 2 females) who received kidney transplants and their long-term treatment and follow-up at 4 specialized Fabry centers. The posttransplant follow-up ranged to 25 years, with a median of 11.5 [range 0.8-25.5] years. Graft survival was similar and death-censored graft survival was superior to matched controls. Fabry patients died with functioning kidneys, mostly from cardiac causes. In 2 males 14 and 23 years posttransplant, the grafts had a few typical FD lamellar inclusions, presumably originating from invading host macrophages and vascular endothelial cells. We conclude that kidney transplantation has an excellent long-term outcome in Fabry disease.

Insertion of reticuloendotheliosis virus long terminal repeat into the genome of CVI988 strain of Marek’s disease virus results in enhanced growth and protection

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a lymphoproliferative disease of chicken caused by serotype 1 MD virus (MDV). Vaccination of commercial poultry has drastically reduced losses from MD and the poultry industry cannot be sustained without the use of vaccines. Retrovirus insertion into herpesviruses genome is a...

Rare splicing defects of FAS underly severe recessive autoimmune lymphoproliferative syndrome.

PubMed

Agrebi, N; Ben-Mustapha, I; Matoussi, N; Dhouib, N; Ben-Ali, M; Mekki, N; Ben-Ahmed, M; Larguèche, B; Ben Becher, S; Béjaoui, M; Barbouche, M R

2017-10-01

Autoimmune lymphoproliferative syndrome (ALPS) is a prototypic disorder of impaired apoptosis characterized by autoimmune features and lymphoproliferation. Heterozygous germline or somatic FAS mutations associated with preserved protein expression have been described. Very rare cases of homozygous germline FAS mutations causing severe autosomal recessive form of ALPS with a complete defect of Fas expression have been reported. We report two unrelated patients from highly inbred North African population showing a severe ALPS phenotype and an undetectable Fas surface expression. Two novel homozygous mutations have been identified underlying rare splicing defects mechanisms. The first mutation breaks a branch point sequence and the second alters a regulatory exonic splicing site. These splicing defects induce the skipping of exon 6 encoding the transmembrane domain of CD95. Our findings highlight the requirement of tight regulation of FAS exon 6 splicing for balanced alternative splicing and illustrate the importance of such studies in highly consanguineous populations. Copyright © 2017 Elsevier Inc. All rights reserved.

Live Donor Renal Anatomic Asymmetry and Posttransplant Renal Function.

PubMed

Tanriover, Bekir; Fernandez, Sonalis; Campenot, Eric S; Newhouse, Jeffrey H; Oyfe, Irina; Mohan, Prince; Sandikci, Burhaneddin; Radhakrishnan, Jai; Wexler, Jennifer J; Carroll, Maureen A; Sharif, Sairah; Cohen, David J; Ratner, Lloyd E; Hardy, Mark A

2015-08-01

Relationship between live donor renal anatomic asymmetry and posttransplant recipient function has not been studied extensively. We analyzed 96 live kidney donors, who had anatomical asymmetry (>10% renal length and/or volume difference calculated from computerized tomography angiograms) and their matching recipients. Split function differences (SFD) were quantified with technetium-dimercaptosuccinic acid renography. Implantation biopsies at time 0 were semiquantitatively scored. A comprehensive model using donor renal volume adjusted to recipient weight (Vol/Wgt), SFD, and biopsy score was used to predict recipient estimated glomerular filtration rate (eGFR) at 1 year. Primary analysis consisted of a logistic regression model of outcome (odds of developing eGFR>60 mL/min/1.73 m(2) at 1 year), a linear regression model of outcome (predicting recipient eGFR at one-year, using the chronic kidney disease-epidemiology collaboration formula), and a Monte Carlo simulation based on the linear regression model (N=10,000 iterations). In the study cohort, the mean Vol/Wgt and eGFR at 1 year were 2.04 mL/kg and 60.4 mL/min/1.73 m(2), respectively. Volume and split ratios between 2 donor kidneys were strongly correlated (r = 0.79, P < 0.001). The biopsy scores among SFD categories (<5%, 5%-10%, >10%) were not different (P = 0.190). On multivariate models, only Vol/Wgt was significantly associated with higher odds of having eGFR > 60 mL/min/1.73 m (odds ratio, 8.94, 95% CI 2.47-32.25, P = 0.001) and had a strong discriminatory power in predicting the risk of eGFR less than 60 mL/min/1.73 m(2) at 1 year [receiver operating curve (ROC curve), 0.78, 95% CI, 0.68-0.89]. In the presence of donor renal anatomic asymmetry, Vol/Wgt appears to be a major determinant of recipient renal function at 1 year after transplantation. Renography can be replaced with CT volume calculation in estimating split renal function.

Castleman's Disease: An Interesting Cause of Hematuria.

PubMed

Tolofari, Sotonye Karl; Chow, Wai-Man; Hussain, Basharat

2015-03-01

Castleman's disease is a rare benign lymphoproliferative disorder, characterized by benign growths of the lymph node tissue. It is associated with a number of malignancies, including Kaposi sarcoma, non-Hodgkin's and Hodgkins lymphoma, and POEMS syndrome. This report describes the case of a 38 year old gentleman, presenting with painless hematuria. Initial investigations, including flexible cystoscopy were unremarkable. However, subsequent imaging including CT Urogram and MR pelvis revealed multiple prevesical lesions. Histology obtained from excision biopsy revealed histological features consistent with Castleman's disease. In this report we discuss the nature, presentation and treatment modalities of this rare condition.

Castleman's disease associated with a cerebellar chordoid meningioma and intestinal lymphangiectasia.

PubMed

Jeon, Chul Jin; Kim, Mi Jin; Lee, Jong Seung; Lee, Ji Hyuk; Kong, Doo-Sik; Shin, Hyung Jin; Suh, Yeon Lim; Kim, Kyoung Mee; Choe, Yon Ho

2010-11-01

Castleman's disease (CD) is a rare nonneoplastic lymphoproliferative disorder of unknown etiology. It is characterized by enlarged hyperplastic lymph nodes, usually presenting as a localized mass. Although an intracranial location is very uncommon, it should be considered in the differential diagnosis of a chordoid meningioma. We describe a pediatric case of CD with a cerebellar chordoid meningioma and intestinal lymphangiectasia.

Fever after peripheral blood stem cell infusion in haploidentical transplantation with post-transplant cyclophosphamide.

PubMed

Arango, Marcos; Combariza, Juan F

2017-06-01

Noninfection-related fever can occur after peripheral blood stem cell infusion in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide. The objective of this study was to analyze the incidence of fever and characterize some clinical features of affected patients. A retrospective case-series study with 40 patients who received haploidentical hematopoietic stem cell transplantation was carried out. Thirty-three patients (82.5%) developed fever; no baseline characteristic was associated with its development. Median time to fever onset was 25.5h (range, 9.5-100h) and median peak temperature was 39.0°C (range, 38.1-40.5°C). Not a single patient developed hemodynamic or respiratory compromise that required admission to the intensive care unit. Fever was not explained by infection in any case. Ninety-one percent of the febrile episodes resolved within 96h of cyclophosphamide administration. No significant difference in overall survival, event-free survival, or graft versus host disease-free/relapse-free survival was found in the group of febrile individuals after peripheral blood stem cell infusion. Fever after peripheral blood stem cell infusion in this clinical setting was common; it usually subsides with cyclophosphamide administration. The development of fever was not associated with an adverse prognosis. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Deconvoluting Post-Transplant Immunity: Cell Subset-Specific Mapping Reveals Pathways for Activation and Expansion of Memory T, Monocytes and B Cells

PubMed Central

Grigoryev, Yevgeniy A.; Kurian, Sunil M.; Avnur, Zafi; Borie, Dominic; Deng, Jun; Campbell, Daniel; Sung, Joanna; Nikolcheva, Tania; Quinn, Anthony; Schulman, Howard; Peng, Stanford L.; Schaffer, Randolph; Fisher, Jonathan; Mondala, Tony; Head, Steven; Flechner, Stuart M.; Kantor, Aaron B.; Marsh, Christopher; Salomon, Daniel R.

2010-01-01

A major challenge for the field of transplantation is the lack of understanding of genomic and molecular drivers of early post-transplant immunity. The early immune response creates a complex milieu that determines the course of ensuing immune events and the ultimate outcome of the transplant. The objective of the current study was to mechanistically deconvolute the early immune response by purifying and profiling the constituent cell subsets of the peripheral blood. We employed genome-wide profiling of whole blood and purified CD4, CD8, B cells and monocytes in tandem with high-throughput laser-scanning cytometry in 10 kidney transplants sampled serially pre-transplant, 1, 2, 4, 8 and 12 weeks. Cytometry confirmed early cell subset depletion by antibody induction and immunosuppression. Multiple markers revealed the activation and proliferative expansion of CD45RO+CD62L− effector memory CD4/CD8 T cells as well as progressive activation of monocytes and B cells. Next, we mechanistically deconvoluted early post-transplant immunity by serial monitoring of whole blood using DNA microarrays. Parallel analysis of cell subset-specific gene expression revealed a unique spectrum of time-dependent changes and functional pathways. Gene expression profiling results were validated with 157 different probesets matching all 65 antigens detected by cytometry. Thus, serial blood cell monitoring reflects the profound changes in blood cell composition and immune activation early post-transplant. Each cell subset reveals distinct pathways and functional programs. These changes illuminate a complex, early phase of immunity and inflammation that includes activation and proliferative expansion of the memory effector and regulatory cells that may determine the phenotype and outcome of the kidney transplant. PMID:20976225

Deconvoluting post-transplant immunity: cell subset-specific mapping reveals pathways for activation and expansion of memory T, monocytes and B cells.

PubMed

Grigoryev, Yevgeniy A; Kurian, Sunil M; Avnur, Zafi; Borie, Dominic; Deng, Jun; Campbell, Daniel; Sung, Joanna; Nikolcheva, Tania; Quinn, Anthony; Schulman, Howard; Peng, Stanford L; Schaffer, Randolph; Fisher, Jonathan; Mondala, Tony; Head, Steven; Flechner, Stuart M; Kantor, Aaron B; Marsh, Christopher; Salomon, Daniel R

2010-10-14

A major challenge for the field of transplantation is the lack of understanding of genomic and molecular drivers of early post-transplant immunity. The early immune response creates a complex milieu that determines the course of ensuing immune events and the ultimate outcome of the transplant. The objective of the current study was to mechanistically deconvolute the early immune response by purifying and profiling the constituent cell subsets of the peripheral blood. We employed genome-wide profiling of whole blood and purified CD4, CD8, B cells and monocytes in tandem with high-throughput laser-scanning cytometry in 10 kidney transplants sampled serially pre-transplant, 1, 2, 4, 8 and 12 weeks. Cytometry confirmed early cell subset depletion by antibody induction and immunosuppression. Multiple markers revealed the activation and proliferative expansion of CD45RO(+)CD62L(-) effector memory CD4/CD8 T cells as well as progressive activation of monocytes and B cells. Next, we mechanistically deconvoluted early post-transplant immunity by serial monitoring of whole blood using DNA microarrays. Parallel analysis of cell subset-specific gene expression revealed a unique spectrum of time-dependent changes and functional pathways. Gene expression profiling results were validated with 157 different probesets matching all 65 antigens detected by cytometry. Thus, serial blood cell monitoring reflects the profound changes in blood cell composition and immune activation early post-transplant. Each cell subset reveals distinct pathways and functional programs. These changes illuminate a complex, early phase of immunity and inflammation that includes activation and proliferative expansion of the memory effector and regulatory cells that may determine the phenotype and outcome of the kidney transplant.

Harnessing Functional Genomics to Reverse Chemoresistance in Breast Cancer

DTIC Science & Technology

2008-10-01

lymphoproliferative syndrome This is a rare immunodeficiency disease characterized by fatal or near-fatal Epstein–Barr virus-induced infectious ... mononucleosis in childhood, subsequent hypogammaglob- ulinaemia and a markedly increased risk of lymphoma or other lymphoproliferative diseases

Peri-operative kidney injury and long-term chronic kidney disease following orthotopic heart transplantation in children.

PubMed

Hoskote, Aparna; Burch, Michael

2015-06-01

Significant advances in cardiac intensive care including extracorporeal life support have enabled children with complex congenital heart disease and end-stage heart failure to be supported while awaiting transplantation. With an increasing number of survivors after heart transplantation in children, the complications from long-term immunosuppression, including renal insufficiency, are becoming more apparent. Severe renal dysfunction after heart transplant is defined by a serum creatinine level >2.5 mg/dL (221 μmol/L), and/or need for dialysis or renal transplant. The degree of renal dysfunction is variable and is progressive over time. About 3-10 % of heart transplant recipients will go on to develop severe renal dysfunction within the first 10 years post-transplantation. Multiple risk factors for chronic kidney disease post-transplant have been identified, which include pre-transplant worsening renal function, recipient demographics and morbidity, peri-transplant haemodynamics and long-term exposure to calcineurin inhibitors. Renal insufficiency increases the risk of post-transplant morbidity and mortality. Hence, screening for renal dysfunction pre-, peri- and post-transplantation is important. Early and timely detection of renal insufficiency may help minimize renal insults, and allow prompt implementation of renoprotective strategies. Close monitoring and pre-emptive management of renal dysfunction is an integral aspect of peri-transplant and subsequent post-transplant long-term care.

Cytomegalovirus infection and disease reduce 10-year cardiac allograft vasculopathy-free survival in heart transplant recipients.

PubMed

Johansson, Inger; Andersson, Rune; Friman, Vanda; Selimovic, Nedim; Hanzen, Lars; Nasic, Salmir; Nyström, Ulla; Sigurdardottir, Vilborg

2015-12-24

Cytomegalovirus (CMV) is associated with an increased risk of cardiac allograft vasculopathy (CAV), the major limiting factor for long-term survival after heart transplantation (HTx). The purpose of this study was to evaluate the impact of CMV infection during long-term follow-up after HTx. A retrospective, single-centre study analyzed 226 HTx recipients (mean age 45 ± 13 years, 78 % men) who underwent transplantation between January 1988 and December 2000. The incidence and risk factors for CMV infection during the first year after transplantation were studied. Risk factors for CAV were included in an analyses of CAV-free survival within 10 years post-transplant. The effect of CMV infection on the grade of CAV was analyzed. Survival to 10 years post-transplant was higher in patients with no CMV infection (69 %) compared with patients with CMV disease (55 %; p = 0.018) or asymptomatic CMV infection (54 %; p = 0.053). CAV-free survival time was higher in patients with no CMV infection (6.7 years; 95 % CI, 6.0-7.4) compared with CMV disease (4.2 years; CI, 3.2-5.2; p < 0.001) or asymptomatic CMV infection (5.4 years; CI, 4.3-6.4; p = 0.013). In univariate analysis, recipient age, donor age, coronary artery disease (CAD), asymptomatic CMV infection and CMV disease were significantly associated with CAV-free survival. In multivariate regression analysis, CMV disease, asymptomatic CMV infection, CAD and donor age remained independent predictors of CAV-free survival at 10 years post-transplant. CAV-free survival was significantly reduced in patients with CMV disease and asymptomatic CMV infection compared to patients without CMV infection. These findings highlight the importance of close monitoring of CMV viral load and appropriate therapeutic strategies for preventing asymptomatic CMV infection.

Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases.

PubMed

Nash, Richard A; Dansey, Roger; Storek, Jan; Georges, George E; Bowen, James D; Holmberg, Leona A; Kraft, George H; Mayes, Maureen D; McDonagh, Kevin T; Chen, Chien-Shing; Dipersio, John; Lemaistre, C Fred; Pavletic, Steven; Sullivan, Keith M; Sunderhaus, Julie; Furst, Daniel E; McSweeney, Peter A

2003-09-01

High-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) is currently being evaluated for the control of severe autoimmune diseases. The addition of antithymocyte globulin (ATG) to high-dose chemoradiotherapy in the high-dose immunosuppressive therapy regimen and CD34 selection of the autologous graft may induce a higher degree of immunosuppression compared with conventional autologous HSCT for malignant diseases. Patients may be at higher risk of transplant-related complications secondary to the immunosuppressed state, including Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD), but this is an unusual complication after autologous HSCT. Fifty-six patients (median age, 42 years; range, 23-61 years) with either multiple sclerosis (n = 26) or systemic sclerosis (n = 30) have been treated. The median follow-up has been 24 months (range, 2-60 months). Two patients (multiple sclerosis, n = 1; systemic sclerosis, n = 1) had significant reactivations of herpesvirus infections early after HSCT and then developed aggressive EBV-PTLD and died on days +53 and +64. Multiorgan clonal B-cell infiltrates that were EBV positive by molecular studies or immunohistology were identified at both autopsies. Both patients had positive screening skin tests for equine ATG (Atgam) and had been converted to rabbit ATG (Thymoglobulin) from the first dose. Of the other 54 patients, 2 of whom had partial courses of rabbit ATG because of a reaction to the intravenous infusion of equine ATG, only 1 patient had a significant clinical reactivation of a herpesvirus infection (herpes simplex virus 2) early after HSCT, and none developed EBV-PTLD. The T-cell count in the peripheral blood on day 28 was 0/microL in all 4 patients who received rabbit ATG; this was significantly less than in patients who received equine ATG (median, 174/microL; P =.001; Mann-Whitney ranked sum test). Although the numbers are limited

Alcoholic Liver Disease and Liver Transplantation.

PubMed

Gallegos-Orozco, Juan F; Charlton, Michael R

2016-08-01

Excessive alcohol use is a common health care problem worldwide and is associated with significant morbidity and mortality. Alcoholic liver disease represents the second most frequent indication for liver transplantation in North America and Europe. The pretransplant evaluation of patients with alcoholic liver disease should aim at identifying those at high risk for posttransplant relapse of alcohol use disorder, as return to excessive drinking can be deleterious to graft and patient survival. Carefully selected patients with alcoholic liver disease, including those with severe alcoholic hepatitis, will have similar short-term and long-term outcomes when compared with other indications for liver transplantation. Copyright © 2016 Elsevier Inc. All rights reserved.

[Clinicopathologic features of primary mucosal CD30-positive T-cell lymphoproliferative disorders in head and neck region].

PubMed

Liu, F; Li, M; Zhang, L Y; Guo, L; Hu, W W; Rao, H L

2018-06-08

Objective: To study clinicopathologic features, prognosis and differential diagnoses of primary mucosal CD30-positive T-cell lymphoproliferative disorders of the head and neck(mCD30(+) TLPD-head and neck). Methods: Three cases of mCD30(+) TLPD-head and neck were collected from January 2014 to April 2017 at Sun Yat-Sen University Foshan Hospital. A literature review of mCD30(+) TLPD of head and neck was provided. Results: All three cases presented with either bulging/exophytic nodule or mucosal ulcer/erosion. Morphologically, the tumor consisted of diffuse proliferation of uniform, large atypical mononuclear lymphoid cells that showed irregular or polymorphic nuclei with small nucleoli, and abundant pale or amphophilic cytoplasm. Hallmark cells with eccentric, horseshoe, kidney-like, or doughnut-shaped nuclei were present. While mitotic figures were present, no tumor necrosis was found. Eosinophilc infiltration was obvious in the background. The atypical large lymphoid cells had a immunophenotype of CD30(+) /CD3(+) /CD4(+) /CD56(-) along with positive cytotoxic molecule. While being negative for EBER/ALK/CD20/CD8, TCR rearrangement was found in 2 out of 3 cases. Three patients were cured after excision without relapse and metastasis.The two patients with TCR rearrangement didn't show aggressive clinical course. Conclusions: mCD30(+) TLPD-head and neck is a rare benign lymphoproliferative disorder with spontaneous regression. It should be differentiated from cutaneous CD30(+) anaplstic large cell lymphoma, lymphomatoid papulosis, and EBV-related mucocutaneous ulcer. Correct recognition of mCD30(+) TLPD of head and neck is important to avoid overtreatment.

[Recurrence of chronic active Epstein-Barr virus infection presenting with myelopathy after umbilical cord blood transplantation].

PubMed

Watanabe, Shohei; Okada, Masaya; Tokugawa, Tazuko; Sawada, Akihiro; Ogawa, Hiroyasu; Yoshikawa, Hiroo

2014-01-01

A 38-year-old man was admitted to our hospital with neck pain, dysesthesia of both hands, and weakness of the left upper limb. He had been diagnosed with a chronic active Epstein-Barr virus infection (CAEBV) at the age of 34 and had undergone umbilical cord blood transplantation at the age of 37. MRI of the spinal cord revealed an intramedullary hyperintense lesion on T₂-weighted images with gadolinium enhancement. Because his laboratory tests revealed proliferation of CD19(+) lymphocytes in the peripheral blood, and EBV DNA was detected in both peripheral blood and CSF, he was diagnosed as having post-transplant EBV associated lymphoproliferative disease. However, chemotherapy did not alleviate his symptoms. At a later time, quantitative chimerism analysis of his CSF showed a higher proportion of lymphocytes that had originated from the recipient. Finally, he was diagnosed as having a recurrence of CAEBV in the central nervous system, and his symptoms were restored by intrathecal chemotherapy (methotrexate, cytosine arabinoside, and prednisolone). Quantitative chimerism analysis of CSF was useful for diagnosing the recurrence of CAEBV in the central nervous system.

Special considerations in pediatric lung transplantation.

PubMed

Wells, Audrey; Faro, Albert

2006-10-01

More than 1300 lung or heart-lung transplants have been performed in children to date, resulting in many years of improved quality of life. Increasing experience has demonstrated that this therapy is unique and differs from adult lung transplantation in terms of indications, complications, pharmacokinetics, and monitoring. Unlike adult lung transplant recipients, cystic fibrosis and pulmonary vascular disease are very common indications. Complications such as graft dysfunction and bronchiolitis obliterans occur similarly in children as in adults, but others such as posttransplant lymphoproliferative disorders, growth retardation, respiratory tract infections, and medical nonadherence appear to be more common in pediatric lung transplant recipients. In addition, infants and adolescents are two very distinct populations that require special attention. Although the new lung allocation system grants some preference to children, donor shortage remains a limiting factor. Living donor lobar transplantation is an alternative for select candidates. Survival rates are similar between adult and pediatric transplant recipients. Support for collaborative studies is critical if we are to improve long-term outcomes for our young patients.

Current diagnosis and treatment of Castleman's disease.

PubMed

González García, A; Moreno Cobo, M Á; Patier de la Peña, J L

2016-04-01

Castleman's disease is not just a single disease but rather an uncommon, heterogeneous group of nonclonal lymphoproliferative disorders, which have a broad spectrum of clinical expression. Three histological types have been reported, along with several clinical forms according to clinical presentation, histological substrate and associated diseases. Interleukin-6, its receptor polymorphisms, the human immunodeficiency virus and the human herpes virus 8 are involved in the etiopathogenesis of Castleman's disease. The study of this disease has shed light on a syndrome whose incidence is unknown. Despite recent significant advances in our understanding of this disease and the increasing therapeutic experience with rituximab, tocilizumab and siltuximab, there are still difficult questions concerning its aetiology, prognosis and optimal treatment. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Soluble CD30 serum level--an adequate marker for allograft rejection of solid organs?

PubMed

Schlaf, G; Altermann, W W; Rothhoff, A; Seliger, B

2007-11-01

The CD30 molecule, a 120 kDa cell surface glycoprotein, is a member of the tumor necrosis factor receptor (TNF-R) superfamily and was originally identified on the surface of Reed-Sternberg cells and anaplastic large cell lymphomas in Hodgkin's disease patients. In addition to lymphoproliferative disorders the expression of CD30 was found in both activated CD8+ and CD4+ Th2 cells which lead to the activation of B-cells and consequently to the inhibition of the Th1-type cellular immunity. The membrane-bound CD30 molecule can be proteolytically cleaved, thereby generating a soluble form (sCD30) of about 85 kDa. Low serum levels of soluble CD30 were found in healthy humans, whereas increased sCD30 serum concentrations were detected under pathophysiological situations such as systemic lupus erythematosus, rheumatoid arthritis, certain viral infections and adult T cell leukaemia/lymphoma. In addition, it has recently been suggested that pre- or post-transplant levels of sCD30 represent a biomarker for graft rejection associated with an impaired outcome for transplanted patients. We here review (i) the current knowledge of the clinical significance of sCD30 serum levels for solid organ transplantations and (ii) our own novel data regarding inter- and intra-individual variations as well as time-dependent alterations of sCD30 levels in patients. (iii) Based on this information the implementation of sCD30 as predictive pre-transplant or post-transplant parameter for solid organ transplantation is critically discussed.

B cell lymphoma with lung involvement: what is it about?

PubMed

Mian, Michael; Wasle, Ines; Gritsch, Stefan; Willenbacher, Wolfgang; Fiegl, Michael

2015-01-01

Primary lymphoma of the lung or pleural is a very rare condition. Due to the outdated literature data, the approximate occurrence of primary and secondary lung and/or pleural involvement according to the most common B cell lymphoma entities is unknown. To answer this open question in Austria, we screened the Tyrolean registry for B cell non-Hodgkin's lymphomas regarding primary and secondary lung involvement. Of 854 patients affected by B cell lymphoma, 7.5% had lung/pleural disease. This organ was the primary site in only 0.7%, while a secondary involvement was registered in 6.8%. Most of them were affected by diffuse large B cell lymphoma (DLBCL; 29/368, 8%) followed by follicular lymphoma (7/188, 4%), mantle cell lymphoma (7/57, 12%), mucosa-associated tissue lymphoma (10/37, 27%), posttransplant lymphoproliferative disease (6/24, 25%), Burkitt lymphoma (3/19, 16%), other lymphomas (1/32, 3%) and Richter transformation (1/11, 9%). Moreover, primary lung/pleural lymphoma is one of the rarest neoplasias affecting the lung, accounting for only 0.4% of cases. Lung/pleural involvement is a very rare condition among B cell lymphomas since it mainly occurs in the setting of a generalized disease. A large majority of patients with secondary organ involvement are affected by DLBCL and have similar clinical features at diagnosis to others with advanced-stage disease. © 2014 S. Karger AG, Basel.

Validation of Roche LightCycler Epstein-Barr virus quantification reagents in a clinical laboratory setting.

PubMed

Gulley, Margaret L; Fan, Hongxin; Elmore, Sandra H

2006-11-01

Epstein-Barr virus (EBV) is associated with a wide range of benign and malignant diseases, including infectious mononucleosis, lymphoma, posttransplant lymphoproliferative disorder, and nasopharyngeal carcinoma. Measurement of EBV viral load in plasma is increasingly used for rapid assessment of disease status. We evaluated the performance characteristics of an EBV polymerase chain reaction assay that uses commercial reagents and instruments from Roche Diagnostics (Indianapolis, IN). DNA was extracted from plasma using a MagNaPure instrument, and viral load was measured by real-time polymerase chain reaction on a LightCycler. Analyte-specific reagents included primers and hybridization probes targeting the EBV LMP2 gene and a spiked control sequence. Accuracy and reproducibility were established using DNA from three cell lines. The assay was sensitive to approximately 750 copies of EBV DNA per milliliter of plasma and was linear across at least four orders of magnitude. The assay detected EBV DNA in three of five samples from nasopharyngeal carcinoma patients, seven of nine infectious mononucleosis samples, and 34/34 samples from immunosuppressed patients with clinically significant EBV-related disease, whereas EBV DNA was undetectable in plasma from 21 individuals without EBV-related disease. In conclusion, this LightCycler EBV assay is rapid, sensitive, and linear for quantifying EBV viral load. The assay appears to be useful for measuring clinically significant EBV levels in immunodeficient patients.

Atypical cells in a voided urine cytology specimen in a renal transplant recipient.

PubMed

Lu, Miao; Ho, Julie; Azordegan, Nazila; Perry, Anamarija M; Gibson, Ian W; Baker, Patricia

2017-01-01

Voided urine is routinely collected from renal transplant patients to screen for polyomavirus. In rare cases, atypical lymphoid cells can be detected in voided urine and raise the suspicion of post-transplant lymphoproliferative disorder (PTLD). However, further immunohistochemistry of the cell block and flow cytometry is frequently limited by the low cellularity and poor preservation of voided urine. Therefore, PTLD of the renal allograft is usually diagnosed from tissue biopsy or nephrectomy specimens. Herein, we report a rare case of atypical cells in a voided urine cytology specimen from a kidney transplant recipient. Needle core biopsy of the renal allograft showed monomorphic PTLD. Diagn. Cytopathol. 2017;45:69-72. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Genetically Modified T-cell Infusion Following Peripheral Blood Stem Cell Transplant in Treating Patients With Recurrent or High-Risk Non-Hodgkin Lymphoma

ClinicalTrials.gov

2018-01-26

Adult Grade III Lymphomatoid Granulomatosis; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

One-Year Review of the SCREEN (Skin Cancer Post-Transplant) Clinic.

PubMed

Baldwin, Sarah; Au, Sheila

The Skin Cancer Post-Transplant (SCREEN) Clinic is a skin-cancer screening clinic that is fully integrated into the renal transplantation clinic at St Paul's Hospital in Vancouver, British Columbia. The purpose of this review was to determine characteristics of patients most at risk for skin cancer, to specify types and locations of skin cancers diagnosed, and to identify areas for patient and physician education. Transplant patients (91% renal; 5% heart) screened by a dermatologist during a 12-month period were stratified into low-, medium-, and high-risk groups based on detailed history and skin examination. In total, 118 skin cancers were diagnosed. White males were found to be most at risk. Squamous cell carcinoma accounted for the majority of tumours, over 25% of which demonstrated invasion. Forty-two percent of patients used only 1 to 2 bottles of sunscreen per year, and sun-protective practices were limited. With this information, we have identified potential target areas for patient and physician education.

Heart transplant outcomes in recipients of Centers for Disease Control (CDC) high risk donors.

PubMed

Tsiouris, Athanasios; Wilson, Lynn; Sekar, Rajesh B; Mangi, Abeel A; Yun, James J

2016-12-01

A lack of donor hearts remains a major limitation of heart transplantation. Hearts from Centers for Disease Control (CDC) high-risk donors can be utilized with specific recipient consent. However, outcomes of heart transplantation with CDC high-risk donors are not well known. We sought to define outcomes, including posttransplant hepatitis and human immunodeficiency virus (HIV) status, in recipients of CDC high-risk donor hearts at our institution. All heart transplant recipients from August 2010 to December 2014 (n = 74) were reviewed. Comparison of 1) CDC high-risk donor (HRD) versus 2) standard-risk donor (SRD) groups were performed using chi-squared tests for nominal data and Wilcoxon two-sample tests for continuous variables. Survival was estimated with Kaplan-Meier curves. Of 74 heart transplant recipients reviewed, 66 (89%) received a SRD heart and eight (11%) received a CDC HRD heart. We found no significant differences in recipient age, sex, waiting list 1A status, pretransplant left ventricular assist device (LVAD) support, cytomegalovirus (CMV) status, and graft ischemia times (p = NS) between the HRD and SRD groups. All of the eight HRD were seronegative at the time of transplant. Postoperatively, there was no significant difference in rejection rates at six and 12 months posttransplant. Importantly, no HRD recipients acquired hepatitis or HIV. Survival in HRD versus SRD recipients was not significantly different by Kaplan-Meier analysis (log rank p = 0.644) at five years posttransplant. Heart transplants that were seronegative at the time of transplant had similar posttransplant graft function, rejection rates, and five-year posttransplant survival versus recipients of SRD hearts. At our institution, no cases of hepatitis or HIV occurred in HRD recipients in early follow-up. © 2016 Wiley Periodicals, Inc.

The effects of increased heme oxygenase-1 on the lymphoproliferative response in dogs with visceral leishmaniasis.

PubMed

Almeida, Breno Fernando Martins de; Silva, Kathlenn Liezbeth Oliveira; Chiku, Vanessa Marim; Leal, Aline Aparecida Correa; Venturin, Gabriela Lovizutto; Narciso, Luis Gustavo; Fink, Maria Fernanda Cereijido Bersni; Eugênio, Flavia de Rezende; Santos, Paulo Sergio Patto Dos; Ciarlini, Paulo Cesar; Lima, Valéria Marçal Felix de

2017-05-01

Canine visceral leishmaniasis (CVL) is known to affect the cellular immunity of infected dogs, through impairing lymphoproliferation and microbicidal mechanisms. This study examined heme oxygenase-1 (HO-1) and its metabolites, oxidative stress and IL-10 levels in CVL and investigated correlations between these parameters. Additionally, the effects of HO-1 inhibition on the lymphoproliferative response and cytokine production in lymph node cells (LNCs) from infected dogs were evaluated. Forty-four dogs, 24 controls and 20 dogs with CVL were selected. Plasma and splenic levels of HO-1, haptoglobin, soluble CD163 receptor, ferritin and IL-10 were determined using capture ELISA. The HO-1 levels and relative gene expression in peripheral blood and bone marrow mononuclear cells were also determined. LNCs proliferation was evaluated with an HO-1 activator and with an HO-1 inhibitor, in the presence of the Leishmania infantum soluble antigen (SAgL), using flow cytometry. HO-1, IL-2, IFN-gamma and IL-10 were also determined in these cultures using capture ELISA. Infected dogs presented oxidative stress and increased HO-1 levels and relative gene expression, with correlation between oxidative stress and HO-1. The substances from heme metabolism and IL-10 were also elevated in the plasma and spleens of infected dogs. IL-10 and HO-1 levels were positively correlated with one another. Inhibition of HO-1 increased LNCs proliferation and decreased IL-10 and IL-2 production in the presence of SAgL. The increased HO-1 metabolism observed in CVL is probably associated with oxidative stress and increased IL-10, which could be one of the mechanisms responsible for inhibition of the lymphoproliferative response in sick dogs. Copyright © 2016 Elsevier GmbH. All rights reserved.

Estimation of abbreviated mycophenolic acid area under the concentration-time curve during early posttransplant period by limited sampling strategy.

PubMed

Mohammadpour, A-H; Nazemian, F; Abtahi, B; Naghibi, M; Gholami, K; Rezaee, S; Nazari, M-R A; Rajabi, O

2008-12-01

Area under the concentration curve (AUC) of mycophenolic acid (MPA) could help to optimize therapeutic drug monitoring during the early post-renal transplant period. The aim of this study was to develop a limited sampling strategy to estimate an abbreviated MPA AUC within the first month after renal transplantation. In this study we selected 19 patients in the early posttransplant period with normal renal graft function (glomerular filtration rate > 70 mL/min). Plasma MPA concentrations were measured using reverse-phase high-performance liquid chromatography. MPA AUC(0-12h) was calculated using the linear trapezoidal rule. Multiple stepwise regression analysis was used to determine the minimal and convenient time points of MPA levels that could be used to derive model equations best fitted to MPA AUC(0-12h). The regression equation for AUC estimation that gave the best performance was AUC = 14.46 C(10) + 15.547 (r(2) = .882). The validation of the method was performed using the jackknife method. Mean prediction error of this model was not different from zero (P > .05) and had a high root mean square prediction error (8.06). In conclusion, this limited sampling strategy provided an effective approach for therapeutic drug monitoring during the early posttransplant period.

Prognostic factors of methotrexate-associated lymphoproliferative disorders associated with rheumatoid arthritis and plausible application of biological agents.

PubMed

Katsuyama, Takayuki; Sada, Ken-Ei; Yan, Minglu; Zeggar, Sonia; Hiramatsu, Sumie; Miyawaki, Yoshia; Ohashi, Keiji; Morishita, Michiko; Watanabe, Haruki; Katsuyama, Eri; Takano-Narazaki, Mariko; Toyota-Tatebe, Noriko; Sunahori-Watanabe, Katsue; Kawabata, Tomoko; Miyake, Kohei; Kiguchi, Toru; Wada, Jun

2017-09-01

To determine prognostic factors of methotrexate-associated lymphoproliferative disorder (MTX-LPD) and evaluate the efficacy and safety of biological therapy in rheumatoid arthritis (RA) complicated with MTX-LPD. Thirty RA patients who developed MTX-LPD were investigated in this study. We compared the clinical and laboratory parameters of patients who achieved regression of LPD by MTX withdrawal with those who required chemotherapy and evaluated the clinical course of RA after LPD development. Twenty-three patients (76.7%) achieved regression of LPD by MTX withdrawal. Chemotherapy-free patients had a tendency of shorter RA duration (13.1 vs. 22.0 years, p = 0.108) and higher doses of MTX at LPD diagnosis (8.0 vs. 5.3 mg/w, p = 0.067) than patients who required chemotherapy. A significantly higher positive rate of peripheral blood Epstein-Barr virus (EBV)-DNA was observed in the chemotherapy-free group (9/9 vs. 0/3, p = 0.0002). Of 15 patients that received biological agents after LPD development, 14 patients (93.3%) demonstrated an improved disease activity of RA and persistent remission of LPD, whereas only one patient experienced relapse of LPD during tocilizumab therapy. Peripheral blood EBV-DNA positivity is a potential prognostic marker of better outcome in MTX-LPD. Biological agents could be an option for the treatment of RA patients with MTX-LPD.

Castleman's disease presenting as a pleural tumor: a case report with CT findings.

PubMed

Doo, Kyung Won; Kim, Bomi

2018-02-01

Castleman's disease (CD) is an uncommon benign lymphoproliferative disorder which most commonly involves the mediastinum but rarely affects the pleura. We report a case of unicentric CD that presents as a pleural mass in a 45-year-old man, which was subsequently resected followed by an unexpected diagnosis on histologic examination. Although rare, CD should be included in the differential diagnosis of well-enhancing pleural mass.

An unusual manifestation of post-transplant lymphoproliferative disorder in the lip after pediatric heart transplantation.

PubMed

Chen, C; Akanay-Diesel, S; Schuster, F R; Klee, D; Schmidt, K G; Donner, B C

2012-11-01

PTLD is a serious and frequently observed complication after solid organ transplantation. We present a six-yr-old girl with a rapidly growing, solid tumor of the lip four yr after orthotopic heart transplantation, which was classified as monomorphic PTLD with the characteristics of a diffuse large B-cell lymphoma. Treatment with reduction in immunosuppression, ganciclovir, and anti B-cell monoclonal antibody (rituximab) resulted in full remission since 12 months. To the best of our knowledge, this report is the first description of PTLD in the lip in a pediatric patient after heart transplantation in the English literature. © 2012 John Wiley & Sons A/S.

Durable Clinical and Immunologic Advantage of Living Donor Liver Transplantation in Children.

PubMed

Przybyszewski, Eric M; Verna, Elizabeth C; Lobritto, Steven J; Martinez, Mercedes; Vittorio, Jennifer M; Fox, Alyson N; Samstein, Benjamin; Kato, Tomoaki; Griesemer, Adam D; Emond, Jean C

2018-06-01

Despite high survival in pediatric living donor liver transplantation (LDLT), only 10% of liver transplants in children in the United States are from living donors, reflecting reluctance to embrace this approach. In addition to optimal timing and graft quality, LDLT may offer immunologic benefit because most donors are haploidentical parents. We sought to quantify the benefit of LDLT compared to deceased donor liver transplantation (DDLT) using granular clinical and immunologic outcomes over the long term. A retrospective cohort of children (age <18 years) surviving 1 year or longer posttransplant was evaluated to determine the impact of donor type on graft survival and immunologic outcomes. Two hundred forty-one children (177 DDLT and 64 LDLT) were assessed. In multivariable analysis, LDLT was associated with a lower rate of acute cellular rejection (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98; P = 0.04), a lower rate of chronic rejection (HR, 0.12; 95% CI, 0.03-0.56; P = 0.007), better graft survival on monotherapy immunosuppression at 3 years posttransplant (87.7% vs 46.7%; odds ratio, 7.41; 95% CI, 2.80-19.66; P < 0.001), and a lower rate of graft loss (HR, 0.29; 95% CI, 0.10-0.88; P = 0.03). Graft type was not an independent predictor of posttransplant mortality (LDLT HR, 0.57; 95% CI, 0.16-2.01; P = 0.38). Maternal graft LDLT was associated with a lower rate of acute cellular rejection (HR, 0.13; 95% CI, 0.03-0.64; P = 0.01) and posttransplant lymphoproliferative disorder (HR, 0.04; 95% CI, 0.004-0.44; P = 0.008) compared with paternal grafts. This study demonstrates the potential benefit of LDLT, particularly with maternal grafts, for pediatric liver transplant recipients on multiple clinical parameters over long-term follow-up.

Antigen-specific T cell therapies for cancer

PubMed Central

Manzo, Teresa; Heslop, Helen E.; Rooney, Cliona M.

2015-01-01

Adoptively transferred antigen-specific T cells that recognize tumor antigens through their native receptors have many potential benefits as treatment for virus-associated diseases and malignancies, due to their ability to selectively recognize tumor antigens, expand and persist to provide long-term protection. Infusions of T cells targeting Epstein–Barr virus (EBV) antigens have shown encouraging response rates in patients with post-transplant lymphoproliferative disease as well as EBV-positive lymphomas and nasopharyngeal cancer, although a recent study also showed that human papilloma virus-reactive T cells can induce complete regression of metastatic cervical cancer. This strategy is also being evaluated to target non-viral tumor-associated antigens. Targeting these less immunogenic antigens is more challenging, as tumor antigens are generally weak, and high avidity T cells specific for self-antigens are deleted in the thymus, but tumor responses have been reported. Current research focusses on defining factors that promote in vivo persistence of transferred cells and ameliorate the immunosuppressive microenvironment. To this end, investigators are evaluating the effects of combining adoptive transfer of antigen-specific T cells with other immunotherapy moieties such as checkpoint inhibitors. Genetic modification of infused T cells may also be used to overcome tumor evasion mechanisms, and vaccines may be used to promote in vivo proliferation. PMID:26160910

Epstein-Barr Virus-Positive T/NK-Cell Lymphoproliferative Disorders Manifested as Gastrointestinal Perforations and Skin Lesions: A Case Report.

PubMed

Xiao, Hai-Juan; Li, Ji; Song, Hong-Mei; Li, Zheng-Hong; Dong, Mei; Zhou, Xiao-Ge

2016-02-01

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorders (LPDs) of childhood is a highly aggressive EBV-positive T/natural killer (NK)-cell LPD, which emerges in the background of chronic active EBV infection (CAEBV) or shortly after primary acute EBV infection. The clinical presentations of CAEBV are varied; patients with atypical manifestations are easily misdiagnosed. We described a 14-year-old boy suffering from digestive disorders and intermittent fever for 1 year and 9 months, whose conditions worsened and skin lesions occurred 2 months before hospitalization. He was diagnosed as inflammatory bowel diseases (IBD) and treated accordingly. His other clinical features, hepatosplenomegaly, lymphadenopathy, anemia, hypoalbuminemia, and elevated inflammatory marks, were found in hospitalization. The boy suffered from repeatedly spontaneous intestinal perforations shortly after hospitalization and died of intestinal hemorrhea. The pathological results of intestine and skin both showed EBV-positive T/NK-cell LPD (lymphoma stage).There are rare studies reporting gastrointestinal perforations in EBV-positive T/NK-cell LPD, let alone repeatedly spontaneous perforations. Based on the clinical features and pathological results of this patient, the disease progressed from CAEBV (T-cell type) to systemic EBV-positive T-cell LPD of childhood (lymphoma). Not all the patients with CAEBV could have unusual patterns of anti-EBV antibodies. However, the presence of high EBV loads (EBV-encoded early small ribonucleic acid (RNA) (EBER) in affected tissues and/or EBV deoxyribonucleic acid (DNA) in peripheral blood) is essential for diagnosing CAEBV. Maybe because of his less common clinical features for CAEBV and negative anti-EBV antibodies, the boy was not diagnosed correctly. We should have emphasized the test for EBER or EBV-DNA. Meanwhile, for the IBD patients whose manifestations were not typical, and whose conditions were not improved by suitable

Increasing Stem Cell Dose Promotes Posttransplant Immune Reconstitution.

PubMed

Xu, Ning; Shen, Sylvie; Dolnikov, Alla

2017-04-01

Umbilical cord blood (UCB) transplantation can provide a successful therapeutic option for patients that have no suitable related donor. UCB transplantation is often limited by the relatively small hematopoietic stem cell (HSC) numbers in UCB especially for adult recipients. Early neutrophil and platelet engraftment correlates with the stem cell numbers in UCB transplant. Compared to other HSC sources, immune reconstitution following UCB transplant is slower and complicated by increased frequency of opportunistic infections. The effect of HSC numbers in UCB transplant on immune reconstitution was not thoroughly examined. Using immunocompromised mice transplanted with purified UCB CD34+ stem cells, we have demonstrated that increasing the numbers of CD34+ cells in the transplant promotes hematopoietic and immune reconstitution. At early stages posttransplant, high stem cell dose generated relatively more B cells, while lower dose generated more myeloid and T cells. Thus, the size of the stem cell graft appears to modulate the differentiation potential of infused stem cells. In addition, increasing stem cell dose in the transplant improved CD8+ T cell development and delayed late memory T cell skewing in expense of naive T cells highlighting the importance of HSC dose to maintain the pool of naive T cells able to develop strong immune responses. Transplantation of ex vivo expanded CD34+ cells did not promote, but rather delayed immune reconstitution suggesting the loss of primitive lymphoid precursor cells during ex vivo expansion.

Hydrogen, a potential safeguard for graft-versus-host disease and graft ischemia-reperfusion injury?

PubMed Central

Yuan, Lijuan; Shen, Jianliang

2016-01-01

Post-transplant complications such as graft-versus-host disease and graft ischemia-reperfusion injury are crucial challenges in transplantation. Hydrogen can act as a potential antioxidant, playing a preventive role against post-transplant complications in animal models of multiple organ transplantation. Herein, the authors review the current literature regarding the effects of hydrogen on graft ischemia-reperfusion injury and graft-versus-host disease. Existing data on the effects of hydrogen on ischemia-reperfusion injury related to organ transplantation are specifically reviewed and coupled with further suggestions for future work. The reviewed studies showed that hydrogen (inhaled or dissolved in saline) improved the outcomes of organ transplantation by decreasing oxidative stress and inflammation at both the transplanted organ and the systemic levels. In conclusion, a substantial body of experimental evidence suggests that hydrogen can significantly alleviate transplantation-related ischemia-reperfusion injury and have a therapeutic effect on graft-versus-host disease, mainly via inhibition of inflammatory cytokine secretion and reduction of oxidative stress through several underlying mechanisms. Further animal experiments and preliminary human clinical trials will lay the foundation for hydrogen use as a drug in the clinic. PMID:27652837

Post-transplant reactions of mycorrhizal and mycorrhiza-free seedlings of Leucaena leucocephala to pH changes in an Oxisol and Ultisol of Hawaii

Treesearch

M. Habte; G. Diarra; P.G. Scowcroft

2011-01-01

The extent to which pretransplant colonization of seedlings with the arbuscular mycorrhizal fungus (AMF) Glomus aggregatum Schenck and Smith emend. Koske could enhance the post-transplant growth of two cultivars of Leucaena leucocephala (Lam.) de Wit (cv. K-8 and cv. K-636) in Al- and Mn-rich acid soils was evaluated in a...

Management Strategies for Posttransplant Diabetes Mellitus after Heart Transplantation: A Review

PubMed Central

Cehic, Matthew G.; Nundall, Nishant; Greenfield, Jerry R.

2018-01-01

Posttransplant diabetes mellitus (PTDM) is a well-recognized complication of heart transplantation and is associated with increased morbidity and mortality. Previous studies have yielded wide ranging estimates in the incidence of PTDM due in part to variable definitions applied. In addition, there is a limited published data on the management of PTDM after heart transplantation and a paucity of studies examining the effects of newer classes of hypoglycaemic drug therapies. In this review, we discuss the role of established glucose-lowering therapies and the rationale and emerging clinical evidence that supports the role of incretin-based therapies (glucagon like peptide- (GLP-) 1 agonists and dipeptidyl peptidase- (DPP-) 4 inhibitors) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in the management of PTDM after heart transplantation. Recently published Consensus Guidelines for the diagnosis of PTDM will hopefully lead to more consistent approaches to the diagnosis of PTDM and provide a platform for the larger-scale multicentre trials that will be needed to determine the role of these newer therapies in the management of PTDM. PMID:29623219

T-cell receptor gene rearrangement in Epstein-Barr virus infectious mononucleosis.

PubMed

Marbello, L; Riva, M; Veronese, S; Nosari, A M; Ravano, E; Colosimo, A; Paris, L; Morra, E

2012-09-01

This report describes the case of a previously healthy young man who presented with fever, pharyngitis, cervical lymphadenopathy, lymphocytosis, and severe thrombocytopenia. Serological tests for Epstein-Barr virus were diagnostic of a primary Epstein-Barr virus infectious mononucleosis but severe thrombocytopenia aroused the suspicion of a lymphoproliferative disease. T-cell receptor gene analysis performed on peripheral and bone marrow blood revealed a T-cell receptor γ-chain rearrangement without the evidence of malignancy using standard histologic and immunophenotype studies. Signs and symptoms of the infectious disease, blood count, and T-cell receptor gene rearrangement resolved with observation without the evidence of emergence of a lymphoproliferative disease. In the contest of a suspected lymphoproliferative disease, molecular results should be integrated with all available data for an appropriate diagnosis.

A novel homozygous Fas ligand mutation leads to early protein truncation, abrogation of death receptor and reverse signaling and a severe form of the autoimmune lymphoproliferative syndrome.

PubMed

Nabhani, Schafiq; Hönscheid, Andrea; Oommen, Prasad T; Fleckenstein, Bernhard; Schaper, Jörg; Kuhlen, Michaela; Laws, Hans-Jürgen; Borkhardt, Arndt; Fischer, Ute

2014-12-01

We report a novel type of mutation in the death ligand FasL that was associated with a severe phenotype of the autoimmune lymphoproliferative syndrome in two patients. A frameshift mutation in the intracellular domain led to complete loss of FasL expression. Cell death signaling via its receptor and reverse signaling via its intracellular domain were completely abrogated. In vitro lymphocyte proliferation induced by weak T cell receptor stimulation could be blocked and cell death was induced by engagement of FasL in T cells derived from healthy individuals and a heterozygous carrier, but not in FasL-deficient patient derived cells. Expression of genes implicated in lymphocyte proliferation and activation (CCND1, NFATc1, NF-κB1) was increased in FasL-deficient T cells and could not be downregulated by FasL engagement as in healthy cells. Our data thus suggest, that deficiency in FasL reverse signaling may contribute to the clinical lymphoproliferative phenotype of ALPS. Copyright © 2014 Elsevier Inc. All rights reserved.

Castleman's Disease: From Basic Mechanisms to Molecular Therapeutics

PubMed Central

El-Osta, Hazem E.

2011-01-01

Castleman's disease is a rare lymphoproliferative disorder in which there has been recent progress in elucidating underlying mechanisms with potential therapeutic implications. Unicentric Castleman's disease is an indolent condition that is often treated with local approaches. In contrast, patients with multicentric Castleman's disease (MCD) have a less favorable prognosis and require systemic treatment. Cytotoxic chemotherapy, with its attendant risk for toxicity, has been widely used to treat MCD, with variable efficacy. The discovery of putative etiologic factors and targets in MCD, particularly human herpes virus 8, CD20, and interleukin (IL)-6, has been translated into the use of rituximab and anti–IL-6-based therapy, as well as antiviral agents. In this article, we review the current state of the art of our understanding of Castleman's disease and its treatment and we provide insight into future treatment strategies based on disease biology. PMID:21441298

X-Linked Lymphoproliferative Disease (XLP)

MedlinePlus

... Operations Administrative Services Office of Biodefense Research & Surety Communications Government Relations Cyber Infrastructure Computational Biology Equal Employment Opportunity Ethics Global Research Office of Mission Integration and Financial ...

Primary immunodeficiencies predisposed to Epstein-Barr virus-driven haematological diseases.

PubMed

Parvaneh, Nima; Filipovich, Alexandra H; Borkhardt, Arndt

2013-09-01

Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, maintains lifelong subclinical persistent infections in humans. In the circulation, EBV primarily infects the B cells, and protective immunity is mediated by EBV-specific cytotoxic T cells (CTLs) and natural killer (NK) cells. However, EBV has been linked to several devastating diseases, such as haemophagocytic lymphohistiocytosis (HLH) and lymphoproliferative diseases in the immunocompromised host. Some types of primary immunodeficiencies (PIDs) are characterized by the development of EBV-associated complications as their predominant clinical feature. The study of such genetic diseases presents an ideal opportunity for a better understanding of the biology of the immune responses against EBV. Here, we summarize the range of PIDs that are predisposed to EBV-associated haematological diseases, describing their clinical picture and pathogenetic mechanisms. © 2013 John Wiley & Sons Ltd.

Risk Factors for and the Clinical Impact of Cytomegalovirus and Epstein-Barr Virus Infections in Pediatric Recipients of TCR-α/β- and CD19-Depleted Grafts.

PubMed

Laberko, Alexandra; Bogoyavlenskaya, Anna; Shelikhova, Larisa; Shekhovtsova, Zhanna; Balashov, Dmitriy; Voronin, Kirill; Kurnikova, Elena; Boyakova, Elena; Raykina, Elena; Brilliantova, Varvara; Pirumova, Valentina; Novichkova, Galina; Maschan, Alexei; Maschan, Michael

2017-03-01

Alpha/beta T cell and CD19 depletion are used to improve the outcomes of hematopoietic stem cell transplantation (HSCT). We evaluated the burden of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in pediatric patients after this HSCT type. A cohort of 182 patients with malignant (n = 114) or nonmalignant (n = 68) disorders was transplanted from either matched unrelated (n = 124) or haploidentical (n = 58) donors. The cumulative incidence of CMV and EBV viremia were 51% and 33%, respectively. Acute graft-versus-host disease (GVHD) grades II to IV, D-/R+ serology, and malignant HSCT indications were associated with increased risk of CMV viremia. CMV disease developed in 10 patients (6%). The occurrence of CMV viremia was not associated with inferior outcomes. Acute GVHD grade ≥ II was the only factor significantly associated with an increased risk of EBV viremia. Rituximab significantly decreased the rate of EBV reactivation in a subgroup that received a higher B cell dose in the graft. The rate of EBV-associated disease was .5%, and EBV viremia did not affect survival. TCR-α/β and CD19 depletion are associated with a significant rate of CMV viremia that does not affect survival. The hazard of EBV post-transplant lymphoproliferative disease (PTLD) is eliminated by the combination of CD19 depletion and rituximab. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations

PubMed Central

Price, Susan; Shaw, Pamela A.; Seitz, Amy; Joshi, Gyan; Davis, Joie; Niemela, Julie E.; Perkins, Katie; Hornung, Ronald L.; Folio, Les; Rosenberg, Philip S.; Puck, Jennifer M.; Hsu, Amy P.; Lo, Bernice; Pittaluga, Stefania; Jaffe, Elaine S.; Fleisher, Thomas A.; Lenardo, Michael J.

2014-01-01

Autoimmune lymphoproliferative syndrome (ALPS) presents in childhood with nonmalignant lymphadenopathy and splenomegaly associated with a characteristic expansion of mature CD4 and CD8 negative or double negative T-cell receptor αβ+ T lymphocytes. Patients often present with chronic multilineage cytopenias due to autoimmune peripheral destruction and/or splenic sequestration of blood cells and have an increased risk of B-cell lymphoma. Deleterious heterozygous mutations in the FAS gene are the most common cause of this condition, which is termed ALPS-FAS. We report the natural history and pathophysiology of 150 ALPS-FAS patients and 63 healthy mutation-positive relatives evaluated in our institution over the last 2 decades. Our principal findings are that FAS mutations have a clinical penetrance of <60%, elevated serum vitamin B12 is a reliable and accurate biomarker of ALPS-FAS, and the major causes of morbidity and mortality in these patients are the overwhelming postsplenectomy sepsis and development of lymphoma. With longer follow-up, we observed a significantly greater relative risk of lymphoma than previously reported. Avoiding splenectomy while controlling hypersplenism by using corticosteroid-sparing treatments improves the outcome in ALPS-FAS patients. This trial was registered at www.clinicaltrials.gov as #NCT00001350. PMID:24398331

Dual pathology as a cause of proteinuria in the post-transplant period; report of a case.

PubMed

Tewari, Rohit; Mendonca, Satish; Nijhawan, Vijay

2016-01-01

Proteinuria is common after renal transplantation and affects between 35%-45% of patients during the same year as their transplant. We report a case of dual pathology in the renal allograft as a cause of severe proteinuria. A 38-year-old male presented with end-stage renal disease. He underwent live related renal allograft transplant. His immediate post-transplant period was unremarkable. He developed rise in serum creatinine (2.1 mg/dl) 6 months after transplant and was biopsied. He was diagnosed as a case of acute cellular rejection type Ib with suspicion for antibody mediated rejection. He was treated with methylprednisolone to which he showed a good response with return of serum creatinine to 1.6 mg/dl. Subsequently, he developed a nephrotic range proteinuria 6 months after this episode of rejection. Repeat biopsy was performed. He was diagnosed as a case of immune complex mediated glomerulonephritis (GN) (morphologically consistent with pattern of membranoproliferative glomerulonephritis) with chronic humoral rejection in the form of transplant glomerulopathy (TG). IHC for C4d and immunofluorescence studies were instrumental making the diagnosis. He was treated with steroids and rituximab to which he showed a good response with remission of proteinuria. This case highlights the importance of picking up dual pathology in an allograft biopsy to ensure appropriate therapy. The role of C4d and its correct interpretation is further highlighted, especially with regard to pattern (granular versus linear) and location (glomerular capillaries versus peritubular capillaries).

Dual pathology as a cause of proteinuria in the post-transplant period; report of a case

PubMed Central

Tewari, Rohit; Mendonca, Satish; Nijhawan, Vijay

2016-01-01

Proteinuria is common after renal transplantation and affects between 35%-45% of patients during the same year as their transplant. We report a case of dual pathology in the renal allograft as a cause of severe proteinuria. A 38-year-old male presented with end-stage renal disease. He underwent live related renal allograft transplant. His immediate post-transplant period was unremarkable. He developed rise in serum creatinine (2.1 mg/dl) 6 months after transplant and was biopsied. He was diagnosed as a case of acute cellular rejection type Ib with suspicion for antibody mediated rejection. He was treated with methylprednisolone to which he showed a good response with return of serum creatinine to 1.6 mg/dl. Subsequently, he developed a nephrotic range proteinuria 6 months after this episode of rejection. Repeat biopsy was performed. He was diagnosed as a case of immune complex mediated glomerulonephritis (GN) (morphologically consistent with pattern of membranoproliferative glomerulonephritis) with chronic humoral rejection in the form of transplant glomerulopathy (TG). IHC for C4d and immunofluorescence studies were instrumental making the diagnosis. He was treated with steroids and rituximab to which he showed a good response with remission of proteinuria. This case highlights the importance of picking up dual pathology in an allograft biopsy to ensure appropriate therapy. The role of C4d and its correct interpretation is further highlighted, especially with regard to pattern (granular versus linear) and location (glomerular capillaries versus peritubular capillaries). PMID:28197503

Clinicopathologic Assessment of Ocular Adnexal Lymphoproliferative Lesions at a Tertiary Eye Hospital in Iran.

PubMed

Asadi-Amoli, Fahimeh; Nozarian, Zohreh; Bonaki, Hirbod Nasiri; Mehrtash, Vahid; Entezari, Samaneh

2016-01-01

The most common type of ocular lymphoma is non-Hodgkin lymphoma (NHL), categorized into two groups: indolent (slow growing) and aggressive (rapid growing). Differentiating benign reactive lymphoid hyperplasia (RLH) from malignant ocular adnexal lymphoma (OAL) is challenging. Histopathology, immunohistochemistry (IHC) and ow cytometry have been used as diagnostic tools in such cases. In this retrospective case series, from 2002 to 2013 at Farabi Eye Center, 110 patients with ocular lymphoproliferative disease were enrolled. Prevalence, anatomical locations, mean age at diagnosis and the nal diagnosis of the disease with IHC were assessed. Comparison between previous pathologic diagnoses and results of IHC was made. Immunoglobulin light chains and B-cell and T-cell markers and other immuno-phenotyping markers including CD20, CD3, CD5, CD23, CD10, CYCLIND1 and BCL2 were evaluated to determine the most accurate diagnosis. The lymphomas were categorized based on revised European-American lymphoma (REAL) classi cation. Mean age±SD (years) of the patients was 55.6 ±19.3 and 61% were male. Patients with follicular lymphoma, large B-cell lymphoma or chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL) tended to be older. Nine patients with previous diagnoses of low grade B-cell lymphoma were re-evaluated by IHC and the new diagnoses were as follows: extranodal marginal zone lymphoma(EMZL) (n=1), SLL(n=1), mantle cell lymphoma (MCL) (n=3), reactive lymphoid hyperplasia RLH (n=2). Two cases were excluded due to poor blocks. Flow cytometry reports in these seven patients revealed SLL with positive CD5 and CD23, MCL with positive CD5 and CyclinD1 and negative CD23, EMZL with negative CD5,CD23 and CD10. One RLH patient was negative for Kappa/Lambda and positive for CD3 and CD20 and the other was positive for all of the light chains, CD3 and CD20. Orbit (49.1%), conjunctiva (16.1%) and lacrimal glands (16.1%) were the most common sites of involvement. Accurate

Posttransplant sCD30 as a biomarker to predict kidney graft outcome.

PubMed

Süsal, Caner; Opelz, Gerhard

2012-09-08

In current clinical praxis, monitoring of immunosuppressive agents in organ transplantation is restricted to measurement of drug blood levels and does not consider the drug's variable effect on the individual patient's immune system. Establishment of biological markers that measure the biological effect of immunosuppressive drugs is desirable and would enable the identification of patients who are at risk of developing rejection, or patients who are suitable for minimization or weaning of immunosuppressive therapy. Several studies demonstrated that the technically simple posttransplant measurement in serum of the T cell activation marker soluble CD30 (sCD30) allows prediction of subsequent graft loss in kidney transplant recipients. sCD30 is a relatively large molecule and therefore an attractive biological marker which is resistant to repeated thawing cycles and temperature differences and easily determined using commercial ELISA. Whether sCD30-based prospective adjustment of immunosuppressive therapy can prevent irreversible graft damage and improve long-term graft outcome awaits evaluation in randomized controlled trials. Copyright © 2011 Elsevier B.V. All rights reserved.

Heart transplantation in adults with congenital heart disease.

PubMed

Stewart, Garrick C; Mayer, John E

2014-01-01

Heart transplantation has become an increasingly common and effective therapy for adults with end-stage congenital heart disease (CHD) because of advances in patient selection and surgical technique. Indications for transplantation in CHD are similar to other forms of heart failure. Pretransplant assessment of CHD patients emphasizes evaluation of cardiac anatomy, pulmonary vascular disease, allosensitization, hepatic dysfunction, and neuropsychiatric status. CHD patients experience longer waitlist times and higher waitlist mortality than other transplant candidates. Adult CHD patients undergoing transplantation carry an early hazard for mortality compared with non-CHD recipients, but by 10 years posttransplant, CHD patients have a slight actuarial survival advantage. Copyright © 2014 Elsevier Inc. All rights reserved.

Immune Disorder HSCT Protocol

ClinicalTrials.gov

2017-11-17

Immune Deficiency Disorders; Severe Combined Immunodeficiency; Chronic Granulomatous Disease; X-linked Agammaglobulinemia; Wiskott-Aldrich Syndrome; Hyper-IgM; DiGeorge Syndrome; Chediak-Higashi Syndrome; Common Variable Immune Deficiency; Immune Dysregulatory Disorders; Hemophagocytic Lymphohistiocytosis; IPEX; Autoimmune Lymphoproliferative Syndrome; X-linked Lymphoproliferative Syndrome

Epstein-Barr virus-related lymph node lesion resembling autoimmune disease-like clinicopathological findings in elderly patients. Report of three cases.

PubMed

Kojima, Masaru; Yamane, Yuko; Itoh, Hideaki; Tanaka, Hiroshi; Sugihara, Shiro; Masawa, Nobuhide; Nakamura, Shigeo

2003-12-01

Three cases of Epstein-Barr virus (EBV)-related lymphoproliferative disorders in elderly patients showing autoimmune disease-associated lymphadenopathy-like clinicopathological findings have been reported. Clinically, they were characterized by systemic lymphadenopathy, "B" symptoms, polyclonal hypergammaglobulinemia, elevated serum LDH and transient presence of various autoantibodies, and absence of atypical lymphocytosis in peripheral blood. One case was associated with idiopathic thrombocytopenic purpura. The clinical course was self-limiting. Histologically, they exhibited numerous lymphoid follicles with hyperplastic germinal centers and atypical interfollicular widening with prominent vascular proliferation. In the paracortical area, there was a mixed infiltrate comprising small to medium-sized lymphocytes and plasma cells, and variable numbers of eosinophils and T- and B-immunoblasts. In situ hybridization demonstrated a varying number of EBV-infected lymphocytes in the germinal center as well as in the interfollicular area. Polymerase chain reaction demonstrated that neither clonal rearrangement of T-cell receptor gamma-gene nor immunoglobulin heavy-chain rearrangement was detected in two of the cases examined. Although acute EBV infection rarely occurs in older adults, EBV related to reactive lymphoproliferative disorder should be added to the differential diagnosis of autoimmune disease-associated lymphadenopathy and node-based peripheral T-cell lymphoma in elderly patients.

Multiple intracranial space-occupying lesions in a renal transplant recipient from an area endemic for tuberculosis (TB): TB vs. toxoplasmosis.

PubMed

Bagchi, S; Sachdev, S S; Nalwa, A; Das, C J; Sinha, S; Suri, V; Mahajan, S; Bhowmik, D; Agarwal, S

2014-10-01

Renal transplant recipients may present with intracranial space-occupying lesions (SOLs) due to infections as well as a post-transplant lymphoproliferative disorder (PTLD). Here, we discuss a renal transplant recipient who presented with neurologic symptoms and magnetic resonance imaging (MRI) of the brain showed multiple focal SOLs. Tuberculosis (TB), toxoplasmosis, nocardiosis, fungal infections, and PTLD were considered in the differential diagnosis. MRI spectroscopy was suggestive of an infectious cause, such as toxoplasmosis or TB. Serologic tests using Toxoplasma were negative. A brain biopsy followed by immunohistochemical staining using Toxoplasma antibody demonstrated multiple intravascular cysts of toxoplasma. This case highlights the diagnostic dilemma in an immunocompromised patient with multiple focal brain lesions, especially in areas where TB is endemic. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Multicentric hyaline vascular Castleman's disease. A POEMS type variant].

PubMed

Gracia-Ramos, Abraham Edgar; Cruz-Domínguez, María del Pilar; Vera-Lastra, Olga Lidia

2013-01-01

Castleman's disease is an atypical lymphoproliferative disorder which may be compatible with paraneoplastic manifestations of POEMS syndrome. a 53 year old man with a history of type 2 diabetes, hypothyroidism and Addison's disease presented with numbness and weakness in limbs, dyspnea, skin hardening, Raynaud's phenomenon, weight loss and fatigue. A physical exam showed tachypnea, generalized cutaneous hyperpigmentation and skin hardening of extremities, muscle weakness, hypoesthesia and hyporeflexia. Laboratory showed hyperprolactinemia, low testosterone, hypothyroidism and Addison's disease. Electrophoresis of proteins showed polyclonal hypergammaglobulinemia. Somatosensory evoked potentials reported peripheral neuropathy and severe axonal polyneuropathy by electromyography. Chest X-rays showed bilateral reticular infiltrates and mediastinal widening. An echocardiogram displayed moderate pulmonary hypertension. Skin biopsy had no evidence of scleroderma. CT reported axillar, mediastinal and retroperitoneal nodes. The mediastinal lesion biopsy reported hyaline vascular Castleman's disease, multicentric variety. He was treated with rituximab. the case meet criteria for multicentric hyaline vascular Castleman's disease, POEMS variant, treated with rituximab.

Combination of immunoglobulins and natural killer cells in the context of CMV and EBV infection.

PubMed

Frenzel, K; Lehmann, J; Krüger, D H; Martin-Parras, L; Uharek, L; Hofmann, J

2014-04-01

Cytomegalovirus (CMV)-specific hyperimmunoglobulin (CMV-HIG) is used to treat and prevent CMV infection in immunocompromised patients, and anti-CD20 monoclonal antibody is successfully used in the treatment for post-transplant lymphoproliferative disease caused by Epstein-Barr virus (EBV). Two immunological approaches have been suggested to further improve the control of viral reproduction in patients with active disease: first, the use of monoclonal antibodies with specificity against viral epitopes and second, coadministration of cells with the capacity to promote antibody-dependent cell-mediated cytotoxicity. Here, we have evaluated the effectiveness of these strategies in vitro (alone and in combination) with neutralization and cytotoxicity assays. Our results indicate that monoclonal antibodies (in particular SM5-1) can be as effective as CMV-HIG in neutralizing-cell-free CMV. Moreover, our data indicate that antibody-mediated elimination (either by moAb or by HIG) of EBV-infected cells can be significantly enhanced by NK cells. Using human NK cells that have been purified, cultured and expanded under GMP conditions, we were able to demonstrate that the combination of NK cells and antibodies could represent a feasible and highly effective clinical approach to achieve control of EBV infections. Especially in leukopenic patients with low numbers of ADCC-promoting cells, the combination of adoptively transferred NK cells and antiviral antibodies offers a promising strategy that should be tested in clinical trials.

Methotrexate-associated lymphoproliferative disorder complicated by severe acute respiratory failure and ileal perforation: a case report.

PubMed

Suzuki, Eiji; Kanno, Takashi; Kimura, Satoru; Irie, Takumi; Odajima, Hajime; Migita, Kiyoshi

2018-06-19

Lymphoproliferative disorder (LPD) is a potentially severe adverse effect of methotrexate (MTX) administration in patients with rheumatoid arthritis (RA). We report a case of MTX-associated LPD (MTX-LPD) in a patient with RA who developed severe pulmonary failure complicated by perforation of the terminal ileum. A 61-year-old woman with RA receiving MTX complained of dyspnea and abdominal pain. She was diagnosed with intestinal perforation and peritonitis, and underwent immediate abdominal surgery. Pathological examinations of the specimen obtained from the resected ileum and a bone marrow aspirate revealed diffuse large B-cell lymphoma. Steroid therapy failed to improve her respiratory failure, but her condition improved after abdominal surgery and suspension of MTX. MTX-LPD can result in multiple life-threatening conditions; however, the symptoms are highly variable. RA patients receiving MTX should thus be monitored carefully, and MTX administration should be stopped immediately on suspicion of MTX-LPD.

Serum Uric Acid and Renal Transplantation Outcomes: At Least 3-Year Post-transplant Retrospective Multivariate Analysis

PubMed Central

Zhang, Kun; Gao, Baoshan; Wang, Yuantao; Wang, Gang; Wang, Weigang; Zhu, Yaxiang; Yao, Liyu; Gu, Yiming; Chen, Mo; Zhou, Honglan; Fu, Yaowen

2015-01-01

Since the association of serum uric acid and kidney transplant graft outcome remains disputable, we sought to evaluate the predictive value of uric acid level for graft survival/function and the factors could affect uric acid as time varies. A consecutive cohort of five hundred and seventy three recipients transplanted during January 2008 to December 2011 were recruited. Data and laboratory values of our interest were collected at 1, 3, 6, 12, 24 and 36 months post-transplant for analysis. Cox proportional hazard model, and multiple regression equation were built to adjust for the possible confounding variables and meet our goals as appropriate. The current cohort study lasts for 41.86 ± 15.49 months. Uric acid level is proven to be negatively associated with eGFR at different time point after adjustment for age, body mass index and male gender (standardized β ranges from -0.15 to -0.30 with all P<0.001).Males with low eGFR but high level of TG were on CSA, diuretics and RAS inhibitors and experienced at least one episode of acute rejection and diabetic issue were associated with a higher mean uric acid level. Hyperuricemia was significantly an independent predictor of pure graft failure (hazard ratio=4.01, 95% CI: 1.25-12.91, P=0.02) after adjustment. But it was no longer an independent risk factor for graft loss after adjustment. Interestingly, higher triglyceride level can make incidence of graft loss (hazard ratio=1.442, for each unit increase millimoles per liter 95% CI: 1.008-2.061, P=0.045) and death (hazard ratio=1.717, 95% CI: 1.105-2.665, P=0.016) more likely. The results of our study suggest that post-transplant elevated serum uric acid level is an independent predictor of long-term graft survival and graft function. Together with the high TG level impact on poor outcomes, further investigations for therapeutic effect are needed. PMID:26208103

Posttransplant Intramuscular Injection of PLX-R18 Mesenchymal-Like Adherent Stromal Cells Improves Human Hematopoietic Engraftment in A Murine Transplant Model

PubMed Central

Metheny, Leland; Eid, Saada; Lingas, Karen; Ofir, Racheli; Pinzur, Lena; Meyerson, Howard; Lazarus, Hillard M.; Huang, Alex Y.

2018-01-01

Late-term complications of hematopoietic cell transplantation (HCT) are numerous and include incomplete engraftment. One possible mechanism of incomplete engraftment after HCT is cytokine-mediated suppression or dysfunction of the bone marrow microenvironment. Mesenchymal stromal cells (MSCs) elaborate cytokines that nurture or stimulate the marrow microenvironment by several mechanisms. We hypothesize that the administration of exogenous MSCs may modulate the bone marrow milieu and improve peripheral blood count recovery in the setting of incomplete engraftment. In the current study, we demonstrated that posttransplant intramuscular administration of human placental derived mesenchymal-like adherent stromal cells [PLacental eXpanded (PLX)-R18] harvested from a three-dimensional in vitro culture system improved posttransplant engraftment of human immune compartment in an immune-deficient murine transplantation model. As measured by the percentage of CD45+ cell recovery, we observed improvement in the peripheral blood counts at weeks 6 (8.4 vs. 24.1%, p < 0.001) and 8 (7.3 vs. 13.1%, p < 0.05) and in the bone marrow at week 8 (28 vs. 40.0%, p < 0.01) in the PLX-R18 cohort. As measured by percentage of CD19+ cell recovery, there was improvement at weeks 6 (12.6 vs. 3.8%) and 8 (10.1 vs. 4.1%). These results suggest that PLX-R18 may have a therapeutic role in improving incomplete engraftment after HCT. PMID:29520362

Posttransplant Intramuscular Injection of PLX-R18 Mesenchymal-Like Adherent Stromal Cells Improves Human Hematopoietic Engraftment in A Murine Transplant Model.

PubMed

Metheny, Leland; Eid, Saada; Lingas, Karen; Ofir, Racheli; Pinzur, Lena; Meyerson, Howard; Lazarus, Hillard M; Huang, Alex Y

2018-01-01

Late-term complications of hematopoietic cell transplantation (HCT) are numerous and include incomplete engraftment. One possible mechanism of incomplete engraftment after HCT is cytokine-mediated suppression or dysfunction of the bone marrow microenvironment. Mesenchymal stromal cells (MSCs) elaborate cytokines that nurture or stimulate the marrow microenvironment by several mechanisms. We hypothesize that the administration of exogenous MSCs may modulate the bone marrow milieu and improve peripheral blood count recovery in the setting of incomplete engraftment. In the current study, we demonstrated that posttransplant intramuscular administration of human placental derived mesenchymal-like adherent stromal cells [PLacental eXpanded (PLX)-R18] harvested from a three-dimensional in vitro culture system improved posttransplant engraftment of human immune compartment in an immune-deficient murine transplantation model. As measured by the percentage of CD45 + cell recovery, we observed improvement in the peripheral blood counts at weeks 6 (8.4 vs. 24.1%, p  < 0.001) and 8 (7.3 vs. 13.1%, p  < 0.05) and in the bone marrow at week 8 (28 vs. 40.0%, p  < 0.01) in the PLX-R18 cohort. As measured by percentage of CD19 + cell recovery, there was improvement at weeks 6 (12.6 vs. 3.8%) and 8 (10.1 vs. 4.1%). These results suggest that PLX-R18 may have a therapeutic role in improving incomplete engraftment after HCT.

Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies.

PubMed

García-Suárez, Julio; de Miguel, Dunia; Krsnik, Isabel; Bañas, Helena; Arribas, Ignacio; Burgaleta, Carmen

2005-12-01

The aims of this study were to evaluate the clinical characteristics of HIV-negative patients affected by lymphoproliferative disorders (LPD) who developed progressive multifocal leukoencephalopathy (PML), to delineate the risk factors, and to analyze whether the new antineoplastic therapies are changing the natural history of this infectious disease. We retrospectively analyzed 46 cases with confirmed LPD-associated PML published from 1958 to 2004. Patients were stratified according to two different time periods: group A included patients diagnosed before 1989, and group B included patients diagnosed since 1990, after introduction of purine analogues. Group A patients (n = 22) had received alkylating agents and/or radiotherapy, and the majority (63.6%) had advanced Hodgkin disease. At univariate analysis, uncontrolled Hodgkin disease was the only risk factor for PML. In group B patients (n = 24), the most frequent treatments received were purine analogues (58.3%) and high-dose therapy with hematopoietic stem cell transplantation (33.3%; HDT/HSCT). B-cell chronic lymphocytic leukemia (45.8%) and aggressive non-Hodgkin lymphoma (24.9%) were the most frequent underlying LPDs. Patients treated with purine analogues were more likely to have active LPD, lower CD4 cell counts, and to be older and male than were HSCT recipients. The median interval from purine analogues or HDT/HSCT to PML was 11 months. In HDT/HSCT recipients, this interval was delayed for 10 months when peri-transplantation rituximab was used. Univariate analysis identified age >55 years, male sex, and CD4 cell counts

Use of Sirolimus (Rapamycin) for Treatment of Cytopenias and Lymphoproliferation Linked to Autoimmune Lymphoproliferative Syndrome (ALPS). Two Case Reports.

PubMed

Cayrol, Julie; Garrido Colino, Carmen

2017-05-01

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte apoptosis. Children present with chronic nonmalignant lymphadenopathy, hepatosplenomegaly, and autoimmune cytopenias. Recent advances show efficacy of treatment with immunosuppressive drugs. Sirolimus, an mammalian target of rapamycin inhibitor, improves autoimmune cytopenias and lymphoproliferation, with a safe profile. We present 2 patients, a 5-year-old girl and 15-year-old boy, diagnosed with ALPS with initial partial response to steroid treatment. Autoimmune cytopenias and lymphoproliferation then became refractory to treatment, with recurrence of symptoms. In both cases, treatment with sirolimus was started, with a rapid response, complete remission of cytopenias, and resolution of lymphoproliferation, with no significant adverse effects. sirolimus is an effective and safe drug for controlling children with cytopenias and lymphoproliferation linked to ALPS.

Clinicopathological analysis of the age-related differences in patients with Epstein-Barr virus (EBV)-associated extranasal natural killer (NK)/T-cell lymphoma with reference to the relationship with aggressive NK cell leukaemia and chronic active EBV infection-associated lymphoproliferative disorders.

PubMed

Takahashi, Emiko; Ohshima, Koichi; Kimura, Hiroshi; Hara, Kazuo; Suzuki, Ritsuro; Kawa, Keisei; Eimoto, Tadaaki; Nakamura, Shigeo

2011-10-01

Extranodal natural killer (NK)/T-cell lymphoma (NKTL), comprising nasal NKTL and extranasal NKTL (ENKTL), is associated with Epstein-Barr virus (EBV). A bimodal age distribution was noted in NKTL patients. We examined the clinicopathological differences between two age groups of ENKTL patients (n = 23) and compared the findings with those of aggressive NK cell leukaemia (ANKL; n = 10) and monoclonal chronic active EBV infection-associated T/NK-cell lymphoproliferative disorders [chronic active EBV infection/TNK-lymphoproliferative disorders (CAEBV/TNK-LPD)] of NK-cell type (n = 45). Distinct differences existed between elderly (> 50 years; n = 13) and younger (≤ 50 years; n = 10) ENKTL patients; the latter showed a higher disease stage (P = 0.0286), worse performance status (P = 0.0244), more frequent B symptoms (P = 0.0286) and more frequent liver, spleen and bone marrow involvement (P = 0.0222, 0.0005 and 0.0259, respectively). Few clinicopathological differences existed between younger ENKTL and ANKL patients. Patients with monoclonal CAEBV/TNK-LPD of NK-cell type (n = 45) showed features similar to those in younger ENKTL/ANKL patients, except a more juvenile onset of CAEBV-related symptoms and better prognosis. However, the onset age of overt leukaemia/lymphoma in CAEBV/TNK-LPD patients and overall survival thereafter were similar to those in younger ENKTL/ANKL patients. ENKTL (≤ 50 years) is distinct from that in elderly patients and may encompass ANKL and overlap in the clinicopathological profile with NK-cell type CAEBV/TNK-LPD. 2011 Blackwell Publishing Limited.

Nonmyeloablative allogeneic stem cell transplantation for chronic lymphocytic leukaemia offers the possibility of disease control with minimal morbidity and mortality--a single institution experience.

PubMed

Chakupurakal, G; Leitzke, S; Langerbeins, P; Schiller, J; Schneider, P M; Holtick, U; Shimabukuro-Vornhagen, A; Theurich, S; Chemnitz, J; Hallek, M; von Bergwelt-Baildon, M; Scheid, C

2015-10-01

Allogeneic stem cell transplantation is a treatment option for patients with poor risk CLL. We conducted a retrospective analysis of all CLL patients allografted at our institution, the University Hospital of Cologne, Germany. Data was collected on 40 patients from 2004 to 2012. The mean age was 54, and the majority were male (75 %). On average, the patients were diagnosed 6 years (range 2-12) prior to transplant with an average of 4 years (range 1-8) from time of first-line therapy to transplant. The remission states at the time of transplant were complete remission (CR) (n = 4), stable disease (n = 10), partial remission (n = 20) and progressive disease (n = 6). Only reduced intensity conditioning regimens were employed. The average CD34(+) cell dose was 4.16 × 10(6)/kg. Neutrophil engraftment was seen by day +17 (range 10-23) post-transplant, and 88 % achieved 95-100 % donor chimerism by day 100. Overall survival, progression-free survival and non-relapse mortality at 2 years post-transplant were 65, 52.5 and 27.5 %, respectively. A total of 51 % of patients were found to be minimal residual disease (MRD)-negative at 1 year post-transplant. Our single-centre experience confirms the valuable role of allogeneic stem cell transplantation (allo-SCT) in the treatment of poor risk CLL patients with promising long-term survival and acceptable transplant-related mortality. The advent of newer therapeutic agents should not hinder the consideration of allo-SCT for this patient cohort as it remains the only curative option for these patients.

Rabbit model for human EBV-associated hemophagocytic syndrome (HPS): sequential autopsy analysis and characterization of IL-2-dependent cell lines established from herpesvirus papio-induced fatal rabbit lymphoproliferative diseases with HPS.

PubMed

Hayashi, Kazuhiko; Jin, Zaishun; Onoda, Sachiyo; Joko, Hiromasa; Teramoto, Norihiro; Ohara, Nobuya; Oda, Wakako; Tanaka, Takehiro; Liu, Yi-Xuan; Koirala, Tirtha Raj; Oka, Takashi; Kondo, Eisaku; Yoshino, Tadashi; Takahashi, Kiyoshi; Akagi, Tadaatsu

2003-05-01

Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS) is often associated with fatal infectious mononucleosis or T-cell lymphoproliferative diseases (LPD). To elucidate the true nature of fatal LPD observed in Herpesvirus papio (HVP)-induced rabbit hemophagocytosis, reactive or neoplastic, we analyzed sequential development of HVP-induced rabbit LPD and their cell lines. All of the seven Japanese White rabbits inoculated intravenously with HVP died of fatal LPD 18 to 27 days after inoculation. LPD was also accompanied by hemophagocytic syndrome (HPS) in five of these seven rabbits. Sequential autopsy revealed splenomegaly and swollen lymph nodes, often accompanied by bleeding, which developed in the last week. Atypical lymphoid cells infiltrated many organs with a "starry sky" pattern, frequently involving the spleen, lymph nodes, and liver. HVP-small RNA-1 expression in these lymphoid cells was clearly demonstrated by a newly developed in situ hybridization (ISH) system. HVP-ISH of immunomagnetically purified lymphoid cells from spleen or lymph nodes revealed HVP-EBER1+ cells in each CD4+, CD8+, or CD79a+ fraction. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus. HVP-DNA was detected in the tissues and peripheral blood from the infected rabbits by PCR or Southern blot analysis. Clonality analysis of HVP-induced LPD by Southern blotting with TCR gene probe revealed polyclonal bands, suggesting polyclonal proliferation. Six IL-2-dependent rabbit T-cell lines were established from transplanted scid mouse tumors from LPD. These showed latency type I/II HVP infection and had normal karyotypes except for one line, and three of them showed tumorigenicity in nude mice. These data suggest that HVP-induced fatal LPD in rabbits is reactive polyclonally in nature.

Differential chemokine, chemokine receptor and cytokine expression in Epstein-Barr virus-associated lymphoproliferative diseases.

PubMed

Ohshima, Koichi; Karube, Kennosuke; Hamasaki, Makoto; Tutiya, Takeshi; Yamaguchi, Takahiro; Suefuji, Hiroaki; Suzuki, Keiko; Suzumiya, Junji; Ohga, Shouichi; Kikuchi, Masahiro

2003-08-01

T cell immunity plays an important role in the clinicopathology of Epstein-Barr virus (EBV)-associated diseases. Acute EBV-induced infectious mononucleosis (IM) is a common self-limiting disease, however, other EBV-associated diseases, including chronic active EBV infection (CAEBV), NK cell lymphoma (NKL), and Hodgkin's lymphoma (HL), exhibit distinct clinical features. Chemokines are members of a family of small-secreted proteins. The relationships between chemokines and the chemokine receptor (R) are thought to be important for selectivity of local immunity. Some chemokines, chemokine R and cytokines closely associate with the T cell subtypes, Th1 and Th2 T cells and cytotoxic cells. To clarify the role of T cell immunity in EBV-associated diseases, we conducted gene expression profiling, using chemokine, chemokine R and cytokine DNA chips. Compared to EBV negative non-specific lymphadenitis, CAEBV and NKL exhibited diffuse down- and up-regulation, respectively, of these gene profiles. IM had a predominantly Th1-type profile, whereas HL had a mixed Th1/Th2-type profile. Reduction of the Th1-type cytokine interferon gamma (IFN-gamma) in CAEBV was confirmed by Reverse transcriptase-polymerase chain reaction, whereas IFN-gamma expression was markedly enhanced in NKL, and moderately enhanced in IM. Compared to IM, CAEBV showed slight elevation of "regulated upon activation, normal T expressed and secreted" (RANTES), but almost all other genes assayed were down-regulated. NKL exhibited elevated expression of numerous genes, particularly IFN-gamma-inducible-10 (IP-10) and monokine induced by IFN-gamma (MIG). HL showed variable elevated and reduced expression of various genes, with increased expression of IL-13 receptor and MIG. Our study demonstrated the enormous potential of gene expression profiling for clarifying the pathogenesis of EBV-associated diseases.

Higher Bilirubin Levels of Healthy Living Liver Donors Are Associated With Lower Posttransplant Hepatocellular Carcinoma Recurrence.

PubMed

Han, Sangbin; Yang, Ju Dong; Sinn, Dong Hyun; Ko, Justin Sangwook; Kim, Jong Man; Shin, Jun Chul; Son, Hee Jeong; Gwak, Mi Sook; Joh, Jae-Won; Kim, Gaab Soo

2016-09-01

Serum bilirubin level, which may reflect the host defense against increased oxidative stress, is inversely associated with the risk of cancer development. In liver transplantation, the intrinsic bilirubin metabolism of donor liver is subsequently translated into recipient. Thus, we hypothesized that liver transplantation conducted with living donors with higher serum bilirubin reduces hepatocellular carcinoma (HCC) recurrence. Two hundred fifty recipients who underwent liver transplantation for treating HCC within the Milan criteria were included in the study. The association between donor preoperative total bilirubin concentration and the risk of HCC recurrence was analyzed using the Fine and Gray regression model with posttransplant death as a competing risk event with adjustment for tumor biology including α-fetoprotein, histological differentiation, and microvascular invasion. All donors were confirmed to have no underlying hepatobiliary diseases or hematological disorders. Donor preoperative total bilirubin concentration was 0.7 mg/dL in median and ranged from 0.2 to 2.7 mg/dL. Thirty-five (14.0%) recipients developed HCC recurrence. Multivariable analysis demonstrated that donor preoperative total bilirubin concentration was inversely associated with the recurrence risk (hazard ratio, 0.22; 95% confidence interval, 0.07-0.72; P = 0.013). The highest (≥1.0 mg/dL) versus lowest (≤0.6 mg/dL) tertile of donor preoperative total bilirubin showed a significant reduction of the recurrence risk (hazard ratio, 0.28; 95% confidence interval, 0.11-0.70; P = 0.006). Hepatocellular carcinoma recurrence risk decreases in relation to the increase in total serum bilirubin level of healthy living donors without underlying hepatobiliary or hematological disorders. Further validation of bilirubin as a potent anticancer substance against HCC is warranted.

KU HAPLOINSUFFIENCY CAUSES A LYMPHOPROLIFERATIVE DISORDER OF IMMATURE T-CELL PRECURSORS DUE TO IKAROS MALFUNCTION

PubMed Central

Ozer, Zahide; Qazi, Sanjive; Ishkhanian, Rita; Hasty, Paul; Ma, Hong; Uckun, Fatih M.

2013-01-01

Ikaros (IK) malfunction has been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL), the most common form of childhood cancer. Therefore, a stringent regulation of IK activity is very important. Here we provide unique genetic and biochemical evidence that the Ku protein components Ku70 and Ku80 act as positive regulators of IK function via formation of IK-Ku70 and IK-Ku80 heterodimers with augmented sequence-specific DNA binding activity. siRNA-mediated depletion of Ku70 or Ku80 reduced the sequence-specific DNA binding activity of IK in EMSA as well as the RT-PCR measured IK target gene expression levels in human cells. The interaction of Ku components with IK likely contributes to the anti-leukemic effects of IK as a tumor suppressor, because Ku70 as well as Ku80 haploinsuffiency in mice caused development of a lymphoproliferative disorder (LPD) involving CD2+CD4+CD8+CD1+IL7R+ thymic T-cell precursors with functional IK deficiency. PMID:24478815

[Premature immunosenescence in triple-transgenic mice for Alzheimer's disease].

PubMed

Mate, Ianire; Cruces, Julia; Vida, Carmen; Sanfeliu, Coral; Manassra, Rashed; Giménez-Llort, Lydia; De la Fuente, Mónica

2014-01-01

A deterioration of the neuroimmunoendocrine network has been observed in Alzheimer's disease (AD). However, the peripheral immune response has hardly been investigated in this pathology. Since some immune function parameters have been established as good markers of the rate of ageing, and can predict longevity, the aim of the present work was to study some of these functions in splenic leucocytes in transgenic mice for AD of different ages. Young female (4 ± 1 months), adult (9 ± 1 months), and mature (12 ± 1 months) triple-transgenic mice for AD (3 xTgAD) and non-transgenic (NTg) control mice of the same ages were used. The chemotaxis, the anti-tumour activity of « natural killer » (NK) cells and the lymphoproliferative response in the presence of the mitogens concanavalin A and lipopolysaccharide, functions that decrease with age, were determined in splenic leucocytes. In addition, the differences in lifespan between 3 xTgAD and NTg were studied in parallel using other animals, until their death through natural causes. In 3 xTgAD, with respect to NTg, chemotaxis decreased at all ages studied, whereas in lymphoproliferative response this reduction was shown at 4 months and 9 months. NK activity was diminished only in young 3 xTgAD with respect to NTg. The 3 xTgAD showed a shorter lifespan than the NTg control group. The 3 xTgAD mice show a premature immunosenescence, which could explain their early mortality. The determination of these immune functions at peripheral level could serve as a marker of the progression of the Alzheimer's disease. Copyright © 2013 SEGG. Published by Elsevier Espana. All rights reserved.

Metastatic Neuroendocrine Tumour in a Renal Transplant Recipient: Dual-Tracer PET-CT with (18)F-FDG and (68)Ga-DOTANOC in This Rare Setting.

PubMed

Karunanithi, Sellam; Roy, Shambo Guha; Sharma, Punit; Yadav, Rajni; Bal, Chandrasekhar; Kumar, Rakesh

2015-03-01

Recipients of renal transplant are at increased risk of developing various malignancies, especially post-transplant lymphoproliferative disorder (PTLD) and skin cancers. Neuroendocrine tumours (NET) of the gastrointestinal tract have not been reported in this setting. Here we describe the case of a 75-year-old male who had undergone renal transplant 8 years back and now presented with significant weight loss and backache, clinically suspected as PTLD. (18)F-Fluordeoxyglucose ((18)F-FDG) positron emission tomography-computed tomography (PET-CT) showed hypermetabolic lesions in the liver and rectum, raising the suspicion of PTLD. However, biopsy from the liver lesion showed poorly differentiated NET. (68)Ga-labelled [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI(3)-octreotide ((68)Ga-DOTANOC) PET-CT was then done, which confirmed the primary lesion in the rectum with liver metastases.

Panobinostat and Everolimus in Treating Patients With Recurrent Multiple Myeloma, Non-Hodgkin Lymphoma, or Hodgkin Lymphoma

ClinicalTrials.gov

2018-04-19

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; B-cell Adult Acute Lymphoblastic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia; Waldenström Macroglobulinemia

Persistent Legionnaire's disease in an adult with hairy cell leukemia successfully treated with prolonged levofloxacin therapy.

PubMed

Cunha, Burke A; Munoz-Gomez, Sigridh; Gran, Arthur; Raza, Muhammad; Irshad, Nadia

2015-01-01

Legionnaire's disease (LD) manifests most commonly as an atypical community acquired pneumonia (CAP) with systemic extrapulmonary manifestations. Disorders associated with impaired cell mediated immunity (CMI) are particularly predisposed to LD. Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative leukemia associated with decreased CMI. LD has only rarely been reported in HCL. We present a most interesting case of persistent LD in a elderly male with HCL who required prolonged antibiotic therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

A review of the evidence for use of thymoglobulin induction in renal transplantation.

PubMed

Gaber, A Osama; Knight, R J; Patel, S; Gaber, L W

2010-06-01

Depleting antilymphocyte, or antithymocyte antibodies, have long been an integral part of induction regimens and continue today to be used in the management of patients at risk of early rejection or those in whom the introduction of calcineurins or other immune suppressants must be delayed. Registry data demonstrate that the most commonly used depleting antibody, rabbit anti-human thymocyte globulin (rATG), is associated with improved outcomes following renal transplantation in high-risk patients, particularly in conjunction with steroid-avoidance regimens. Two prospective randomized trials in high-risk renal allograft patients have also demonstrated an advantage of r-ATG induction compared to the nondepleting interleukin receptor (IL2RA) antibodies. In low-immunologic-risk patients, however, r-ATG induction and IL2RA induction appear to be equivalent in terms of rejection prophylaxis and long-term function. Other studies have shown that sequential rATG-containing regimens were superior to no induction and allowed for successful late introduction of calcineurin inhibitors. The side effect profile of the depleting antibody included increased incidence of fever, hematologic abnormalities, cytomegalovirus infections when prophylaxis was not employed, and in some studies, increased incidence of posttransplant lymphoproliferative disease. This review describes the evidence supporting the use of depleting ATGs in kidney transplantation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lindner, I.; Ehlers, B.; Noack, S.

The porcine lymphotropic herpesviruses (PLHV) are discussed as possible risk factors in xenotransplantation because of the high prevalence of PLHV-1, PLHV-2 and PLHV-3 in pig populations world-wide and the fact that PLHV-1 has been found to be associated with porcine post-transplant lymphoproliferative disease. To provide structural and functional knowledge on the PLHV immediate-early (IE) transactivator genes, the central regions of the PLHV genomes were characterized by genome walking, sequence and splicing analysis. Three spliced genes were identified (ORF50, ORFA6/BZLF1{sub h}, ORF57) encoding putative IE transactivators, homologous to (i) ORF50 and BRLF1/Rta (ii) K8/K-bZIP and BZLF1/Zta and (iii) ORF57 and BMLF1more » of HHV-8 and EBV, respectively. Expressed as myc-tag or HA-tag fusion proteins, they were located to the cellular nucleus. In reporter gene assays, several PLHV-promoters were mainly activated by PLHV-1 ORF50, to a lower level by PLHV-1 ORFA6/BZLF1{sub h} and not by PLHV-1 ORF57. However, the ORF57-encoded protein acted synergistically on ORF50-mediated activation.« less

Regulatory T-Cells in Chronic Lymphocytic Leukemia and Autoimmune Diseases

PubMed Central

D’Arena, Giovanni; Rossi, Giovanni; Vannata, Barbara; Deaglio, Silvia; Mansueto, Giovanna; D’Auria, Fiorella; Statuto, Teodora; Simeon, Vittorio; De Martino, Laura; Marandino, Aurelio; Del Poeta8, Giovanni; De Feo, Vincenzo; Musto, Pellegrino

2012-01-01

Regulatory T-cells (Tregs) constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL). Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosus, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis. Efforts are made aiming to develop approaches to deplete Tregs or inhibit their function in cancer and autoimmune disorders, as well. PMID:22973497

Acute or chronic life-threatening diseases associated with Epstein-Barr virus infection.

PubMed

Okano, Motohiko; Gross, Thomas G

2012-06-01

Infectious mononucleosis (IM) is one of the representative, usually benign, acute diseases associated with primary Epstein-Barr virus (EBV) infection. IM is generally self-limiting and is characterized mostly by transient fever, lymphadenopathy and hepatosplenomegaly. However, very rarely primary EBV infection results in severe or fatal conditions such as hemophagocytic lymphohistiocytosis together with fulminant hepatitis designated as severe or fatal IM or EBV-associated hemophagocytic lymphohistiocytosis alone. In addition, chronic EBV-associated diseases include Burkitt's lymphoma, undifferentiated nasopharyngeal carcinoma, Hodgkin lymphoma, T-cell lymphoproliferative disorder (LPD)/lymphoma, natural killer-cell LPD including leukemia or lymphoma, gastric carcinoma, pyothorax-associated lymphoma and senile B-cell LPD as well as chronic active EBV infection and LPD/lymphoma in patients with immunodeficiency. The number of chronic life-threatening diseases linked to the EBV infection is increasingly reported and many of these diseases have a poor prognosis. This review will focus on the historical, pathogenetic, diagnostic, therapeutic and prophylactic issues of EBV-associated life-threatening diseases.

Adverse effects of meglumine diatrizoate on renal function in the early post-transplant period.

PubMed

Light, J A; Perloff, L J; Etheredge, E E; Hill, G; Spees, E K

1975-11-01

Thirty-four renal transplant recipients received drip infusion urograms from 2-24 days post-transplantation. Twenty-two patients exhibited changes in renal function within 1-4 days of the urogram that were indistinguishable from allograft rejection: a tender, swollen kidney, elevation of serum creatinine, oliguria, decreased urine sodium concentration, weight gain, and hypertension. Two patients developed acute tubular necrosis and required hemodialysis, but renal function in the remaining 20 patients improved after therapy for "graft rejection" with i.v. methyprednisolone sodium succinnate. Kidneys from older-age donors that were functioning suboptimally and kidneys which exhibited subsequent clinical allograft rejection were more at risk for contrast media toxicity. This suggests that occult vascular lesions may have been present in the allograft which were exacerbated when exposed to the irritant vascular effects of contrast media, producing a mild, reversible toxic nephritis. However, several kidneys with normal function and several kidneys which never exhibited rejection activity were also adversely affected by exposure to contrast media. It appears these agents should be used cautiously, if at all, in the early post-transplant period.

Lymphoproliferative disorders in patients with chronic myeloproliferative neoplasms: A systematic review.

PubMed

Marchetti, Monia; Carobbio, Alessandra; Capitoni, Enrica; Barbui, Tiziano

2018-05-01

Patients with a Ph-negative myeloproliferative neoplasm (MPN) may harbor or develop lymphoproliferative disorders (LPD), however, the clinical and molecular determinants of MPN and LPD co-occurrence are still uncertain. To systematically pool the available knowledge, we conducted a scoping review of literature published since January 2005 and analyzed single-patient clinical data from 50 papers reporting 214 individuals harboring both MPN and LPD. Patients had been diagnosed essential thrombocythemia (44%), polycythemia vera (29%), or myelofibrosis (23%) at a median age of 67 years (26-94): half of them incurred a LPD after a median of 72 months from MPN diagnosis, while in 20% the LPD diagnosis was antecedent or synchronous. Patients mainly incurred indolent LPD, particularly chronic lymphocytic leukemia (CLL), while aggressive lymphomas and multiple myeloma were a relevant portion of the LPDs occurring in the follow-up of MPN. CLL was preferentially diagnosed in PV patients and was associated with a very high male-to-female ratio, as well as an older age at MPN diagnosis. On converse, multiple myeloma was rarely reported in PV patients and was preferentially diagnosed in female patients not harboring the JAK2 V617F mutation. Based on the 46 cases reporting follow-up data, median survival after MPN diagnosis was 96 months. This thorough review of published evidence confirms that LPD are relevant clinical events in the history of MPN patients. Controlled studies are needed to better refine individuals at higher risk of developing LPD, to support surveillance programs and to avoid therapies possibly favoring LPD. © 2018 Wiley Periodicals, Inc.

Post-transplant sCD30 and neopterin as predictors of chronic allograft nephropathy: impact of different immunosuppressive regimens.

PubMed

Weimer, R; Süsal, C; Yildiz, S; Staak, A; Pelzl, S; Renner, F; Dietrich, H; Daniel, V; Kamali-Ernst, S; Ernst, W; Padberg, W; Opelz, G

2006-08-01

Immunological monitoring for chronic allograft nephropathy (CAN) is of great potential interest. We assessed serum soluble CD30 (sCD30) together with in vitro Th2-type responses (IL-4, IL-10, CD4 helper activity) and neopterin in a prospective study of 84 renal transplant recipients with 2-year follow-up. Patients were randomized to CsA/Aza, CsA/MMF and Tacr/Aza, respectively, to analyze the effect of immunosuppression on posttransplant sCD30 and neopterin. ATG induction and acute rejections did not alter sCD30 levels whereas CMV disease was associated with transient upregulation of sCD30 (p = 0.003 at 4 months) and sustained upregulation of neopterin (corrected for graft function (Neo/CR) p = 0.005 at 2 years). Tacr versus CsA treatment proved to be an independent variable associated with downregulation of 1-year sCD30, which was positively related to Neo/CR (p = 0.007 and 0.01, respectively; logistic regression). Importantly, increased 1-year sCD30 and Neo/CR were associated with decreased glomerular filtration rate at 2 years (p = 0.02 and p < 0.0005, respectively) and evidence of CAN (p < 0.0005). High 1-year sCD30 could not be attributed to enhanced Th2-type responses and was not associated with HLA antibody formation. Our data suggest that elevated sCD30 and neopterin predict graft deterioration by CAN. Tacr effectively downregulates these responses and might be of advantage in patients with elevated sCD30 or neopterin.

Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease.

PubMed

Dudakov, Jarrod A; Mertelsmann, Anna M; O'Connor, Margaret H; Jenq, Robert R; Velardi, Enrico; Young, Lauren F; Smith, Odette M; Boyd, Richard L; van den Brink, Marcel R M; Hanash, Alan M

2017-08-17

Graft-versus-host disease (GVHD) and posttransplant immunodeficiency are frequently related complications of allogeneic hematopoietic transplantation. Alloreactive donor T cells can damage thymic epithelium, thus limiting new T-cell development. Although the thymus has a remarkable capacity to regenerate after injury, endogenous thymic regeneration is impaired in GVHD. The mechanisms leading to this regenerative failure are largely unknown. Here we demonstrate in experimental mouse models that GVHD results in depletion of intrathymic group 3 innate lymphoid cells (ILC3s) necessary for thymic regeneration. Loss of thymic ILC3s resulted in deficiency of intrathymic interleukin-22 (IL-22) compared with transplant recipients without GVHD, thereby inhibiting IL-22-mediated protection of thymic epithelial cells (TECs) and impairing recovery of thymopoiesis. Conversely, abrogating IL-21 receptor signaling in donor T cells and inhibiting the elimination of thymic ILCs improved thymopoiesis in an IL-22-dependent fashion. We found that the thymopoietic impairment in GVHD associated with loss of ILCs could be improved by restoration of IL-22 signaling. Despite uninhibited alloreactivity, exogenous IL-22 administration posttransplant resulted in increased recovery of thymopoiesis and development of new thymus-derived peripheral T cells. Our study highlights the role of innate immune function in thymic regeneration and restoration of adaptive immunity posttransplant. Manipulation of the ILC-IL-22-TEC axis may be useful for augmenting immune reconstitution after clinical hematopoietic transplantation and other settings of T-cell deficiency. © 2017 by The American Society of Hematology.

Challenges in transplantation for alcoholic liver disease.

PubMed

Berlakovich, Gabriela A

2014-07-07

Transplantation for the treatment of alcoholic cirrhosis is more controversially discussed than it is for any other indication. The crucial aspect in this setting is abstinence before and after liver transplantation. We established pre-transplant selection criteria for potential transplant candidates. Provided that the underlying disease can be treated, there is no reason to withhold liver transplantation in a patient suffering from alcoholic cirrhosis. Evaluation of the patient by a multidisciplinary team, including an addiction specialist, is considered to be the gold standard. However, several centers demand a specified period of abstinence - usually 6 mo- irrespective of the specialist's assessment. The 6-mo rule is viewed critically because liver transplantation was found to clearly benefit selected patients with acute alcoholic hepatitis; the benefit was similar to that achieved for other acute indications. However, the discussion may well be an academic one because the waiting time for liver transplantation exceeds six months at the majority of centers. The actual challenge in liver transplantation for alcoholic cirrhosis may well be the need for lifelong post-transplant follow-up rather than the patient's pre-transplant evaluation. A small number of recipients experience a relapse of alcoholism; these patients are at risk for organ damage and graft-related death. Post-transplant surveillance protocols should demonstrate alcohol relapse at an early stage, thus permitting the initiation of adequate treatment. Patients with alcoholic cirrhosis are at high risk of developing head and neck, esophageal, or lung cancer. The higher risk of malignancies should be considered in the routine assessment of patients suffering from alcoholic cirrhosis. Tumor surveillance protocols for liver transplant recipients, currently being developed, should become a part of standard care; these will improve survival by permitting diagnosis at an early stage. In conclusion, the key

Epstein-Barr virus and human diseases: recent advances in diagnosis.

PubMed Central

Okano, M; Thiele, G M; Davis, J R; Grierson, H L; Purtilo, D T

1988-01-01

Since the discovery of Epstein-Barr virus (EBV) from a cultured Burkitt's lymphoma cell line in 1964, the virus has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and infectious mononucleosis. During the recent decade, EBV has been etiologically implicated in a broad spectrum of human diseases. The precise role of this virus in these diseases is not well understood, but clearly, defective immunosurveillance against the virus may permit an uncontrolled proliferation of EBV-infected cells. As a result, a growing number of cases of EBV-associated B-cell proliferative diseases or lymphoma have been noted in patients with primary and acquired immunodeficiencies. These lymphoproliferative diseases and others, such as chronic mononucleosis syndrome, are leading to new areas of investigation which are providing information regarding the pathogenetic mechanisms of EBV-induced diseases. The early accurate diagnosis of EBV infection can be achieved by performing EBV-specific serology, detecting for EBV-determined nuclear antigen in tissues, establishing spontaneous lymphoid cell lines, and using molecular hybridization techniques for demonstrating the presence of viral genome in affected lesions. Images PMID:2848624

Disruptive technological advances in vascular access for dialysis: an overview.

PubMed

Yeo, Wee-Song; Ng, Qin Xiang

2017-11-29

End-stage kidney disease (ESKD), one of the most prevalent diseases in the world and with increasing incidence, is associated with significant morbidity and mortality. Current available modes of renal replacement therapy (RRT) include dialysis and renal transplantation. Though renal transplantation is the preferred and ideal mode of RRT, this modality may not be available to all patients with ESKD. Moreover, renal transplant recipients are constantly at risk of complications associated with immunosuppression and immunosuppressant use, and posttransplant lymphoproliferative disorder. Dialysis may be the only available modality in certain patients. However, dialysis has its limitations, which include issues associated with lack of vascular access, risks of infections and vascular thrombosis, decreased quality of life, and absence of biosynthetic functions of the kidney. In particular, the creation and maintenance of hemodialysis vascular access in children poses a unique set of challenges to the pediatric nephrologist owing to the smaller vessel diameters and vascular hyperreactivity compared with adult patients. Vascular access issues continue to be one of the major limiting factors prohibiting the delivery of adequate dialysis in ESKD patients and is the Achilles' heel of hemodialysis. This review aims to provide a critical overview of disruptive technological advances and innovations for vascular access. Novel strategies in preventing neointimal hyperplasia, novel bioengineered products, grafts and devices for vascular access will be discussed. The potential impact of these solutions on improving the morbidity encountered by dialysis patients will also be examined.

Systemic type Epstein-Barr virus-related lymphoproliferative diseases in children and young adults: challenges for pediatric hemato-oncologists and infectious disease specialists.

PubMed

Imashuku, Shinsaku

2007-12-01

Involvement of Epstein-Barr virus (EBV) has long been known in the development of various tumor-forming proliferating diseases, such as nasopharyngeal carcinoma in adults. However, in children and young adults more attention should be focused on systemic, severe type EBV-related diseases, such as fatal infectious mononucleosis, hemophagocytic syndrome, or chronic active EBV infection (CAEBV). These disorders show the typical clinical features of hemophagocytic lymphohistiocytosis (HLH). Although viral infectious diseases are mostly taken care of by infectious disease specialists, pediatric hemato-oncologists need to intervene in the treatment of this kind of disease because of their clonal and neoplastic disease characteristics and of their hematologically problematic, rapid, and life-threatening clinical courses.

Case Report: Successful Lung Transplantation from a Donor Seropositive for Trypanosoma cruzi Infection (Chagas Disease) to a Seronegative Recipient.

PubMed

Salvador, Fernando; Sánchez-Montalvá, Adrián; Sulleiro, Elena; Berastegui, Cristina; Jauregui, Alberto; Pont, Teresa; Los-Arcos, Ibai; Len, Óscar; Gavaldà, Joan; Molina, Israel

2017-10-01

The increasing shortage of organs for transplantation has prompted transplant programs to investigate the use of extended criteria donors, such as those with transmissible infectious diseases. Successful cases of organ transplantation (mostly kidney and liver) from Trypanosoma cruzi seropositive donors to seronegative recipients have been reported. We present a case of lung transplantation from a donor serologically positive for Chagas disease to a seronegative recipient, and provide a review of the literature. Left single lung transplantation was performed in a 44-year-old Spanish woman presenting with interstitial lung disease in February 2016. The deceased donor was a Colombian immigrant living in Spain who was serologically positive for Chagas disease. Oral administration of 5 mg/kg/day benznidazole divided in three doses for 60 days was given for specific Chagas disease prophylaxis after transplantation. Periodic follow-up with serological reverse transcription polymerase chain reaction to detect T. cruzi DNA were performed until 6 months after the end of treatment. All results were negative, indicating that transmission of T. cruzi had not occurred. In a review of the literature, two similar cases were identified in Argentina and the United States. In both cases T. cruzi infection was detected posttransplant in the recipients, after which they were treated with benznidazole. The course of the patient described herein confirms that lungs from donors with chronic T. cruzi infection can be used successfully as allografts, and that posttransplant prophylaxis with benznidazole may reduce the probability of transmission of T. cruzi to the recipient.

Phase II Study Evaluating Busulfan and Fludarabine as Preparative Therapy in Adults With Hematopoietic Disorders Undergoing MUD SCT

ClinicalTrials.gov

2009-01-22

Chronic Myeloid Leukemia; Acute Myelogenous Leukemia; Myelodysplasia; Acute Lymphocytic Leukemia; Severe Aplastic Anemia; Non-Hodgkin's Lymphoma; Lymphoproliferative Disease; Multiple Myeloma; Advanced Myeloproliferative Disease

What is the impact of immunosuppressive treatment on the post-transplant renal osteopathy?

PubMed

Blaslov, Kristina; Katalinic, Lea; Kes, Petar; Spasovski, Goce; Smalcelj, Ruzica; Basic-Jukic, Nikolina

2014-05-01

Although glucocorticoid therapy is considered to be the main pathogenic factor, a consistent body of evidence suggests that other immunosuppressants might also play an important role in the development of the post-transplant renal osteopathy (PRO) through their pleiotropic pharmacological effects. Glucocorticoids seem to induce osteoclasts' activity suppressing the osteoblasts while data regarding other immunosuppressive drugs are still controversial. Mycophenolate mofetil and azathioprine appear to be neutral regarding the bone metabolism. However, the study analyzing any independent effect of antimetabolites on bone turnover has not been conducted yet. Calcineurin inhibitors (CNIs) induce trabecular bone loss in rodent, with contradictory results in renal transplant recipients. Suppression of vitamin D receptor is probably the underlying mechanism of renal calcium wasting in renal transplant recipients receiving CNI. In spite of an increased 1,25(OH)2 vitamin D level, the kidney is not able to reserve calcium, suggesting a role of vitamin D resistance that may be related to bone loss. More efforts should be invested to determine the role of CNI in PRO. In particular, data regarding the role of mammalian target of rapamycin inhibitors (mTORi), such as sirolimus and everolimus, in the PRO development are still controversial. Rapamycin markedly decreases bone longitudinal growth as well as callus formation in experimental models, but also lowers the rate of bone resorption markers and glomerular filtration in clinical studies. Everolimus potently inhibits primary mouse and human osteoclast activity as well as the osteoclast differentiation. It also prevents the ovariectomy-induced loss of cancellous bone by 60 %, an effect predominantly associated with a decreased osteoclast-mediated bone resorption, resulting in a partial preservation of the cancellous bone. At present, there is no clinical study analyzing the effect of everolimus on bone turnover in renal

Higher Mortality in registrants with sudden model for end-stage liver disease increase: Disadvantaged by the current allocation policy.

PubMed

Massie, Allan B; Luo, Xun; Alejo, Jennifer L; Poon, Anna K; Cameron, Andrew M; Segev, Dorry L

2015-05-01

Liver allocation is based on current Model for End-Stage Liver Disease (MELD) scores, with priority in the case of a tie being given to those waiting the longest with a given MELD score. We hypothesized that this priority might not reflect risk: registrants whose MELD score has recently increased receive lower priority but might have higher wait-list mortality. We studied wait-list and posttransplant mortality in 69,643 adult registrants from 2002 to 2013. By likelihood maximization, we empirically defined a MELD spike as a MELD increase ≥ 30% over the previous 7 days. At any given time, only 0.6% of wait-list patients experienced a spike; however, these patients accounted for 25% of all wait-list deaths. Registrants who reached a given MELD score after a spike had higher wait-list mortality in the ensuing 7 days than those with the same resulting MELD score who did not spike, but they had no difference in posttransplant mortality. The spike-associated wait-list mortality increase was highest for registrants with medium MELD scores: specifically, 2.3-fold higher (spike versus no spike) for a MELD score of 10, 4.0-fold higher for a MELD score of 20, and 2.5-fold higher for a MELD score of 30. A model incorporating the MELD score and spikes predicted wait-list mortality risk much better than a model incorporating only the MELD score. Registrants with a sudden MELD increase have a higher risk of short-term wait-list mortality than is indicated by their current MELD score but have no increased risk of posttransplant mortality; allocation policy should be adjusted accordingly. © 2015 American Association for the Study of Liver Diseases.

The role of heat shock proteins in kidney disease

PubMed Central

2016-01-01

Abstract Heat Shock Proteins (HSP) belong to the family of intracellular proteins that are constitutively expressed and are upregulated by various stressors including heat, oxidative and chemical stress. HSP helps in reparative processes, including the refolding of damaged proteins and the removal of irreparably damaged proteins that would initiate cellular death or apoptosis. A growing body of evidence has expanded the role of HSP and defined their role in diseases such as neurodegenerative disorders, cancer, ischemic heart disease and kidney diseases. The protective role of HSP in ischemic renal injury has been described and HSP impairment has been noted in other forms of kidney injuries including post-transplant situation. Further research into the role of HSP in prevention of kidney injury is crucial if translation from the laboratory to patient bedside has to occur. This article aims to be a review of heat shock protein, and its relevance to kidney diseases. PMID:28191532

Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Human C1q Deficiency: The Karolinska Experience.

PubMed

Olsson, Richard F; Hagelberg, Stefan; Schiller, Bodil; Ringdén, Olle; Truedsson, Lennart; Åhlin, Anders

2016-06-01

Human C1q deficiency is associated with systemic lupus erythematosus (SLE) and increased susceptibility to severe bacterial infections. These patients require extensive medical therapy and some develop treatment-resistant disease. Because C1q is produced by monocytes, it has been speculated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) may cure this disorder. We have so far treated 5 patients with C1q deficiency. In 3 cases, SLE symptoms remained relatively mild after the start of medical therapy, but 2 patients developed treatment-resistant SLE, and we decided to pursue treatment with allo-HSCT. For this purpose, we chose a conditioning regimen composed of treosulfan (14 g/m) and fludarabine (30 mg/m) started on day -6 and given for 3 and 5 consecutive days, respectively. Thymoglobulin was given at a cumulative dose of 8 mg/kg, and graft-versus-host disease prophylaxis was composed of cyclosporine and methotrexate. A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms. The boy developed posttransplant lymphoproliferative disease, which resolved after treatment with rituximab and donor lymphocyte infusion. Unfortunately, donor lymphocyte infusion induced severe cortisone-resistant gastrointestinal graft-versus-host disease, and the patient died from multiple organ failure 4 months after transplantation. The girl is doing well 33 months after transplantation, and clinically, all signs of SLE have resolved. Allo-HSCT can cure SLE in human C1q deficiency and should be considered early in subjects resistant to medical therapy.

Non-canonical WNT6/WNT10A signal factor expression in EBV+ post-transplant smooth muscle tumors.

PubMed

Teiken, Kristin; Kuehnel, Mark; Rehkaemper, Jan; Kreipe, Hans; Laenger, Florian; Hussein, Kais; Jonigk, Danny

2018-01-01

Post-transplant smooth muscle tumors (PTSMTs) are rare mesenchymal neoplasms which occur after solid organ or haematopoietic stem cell transplantation. PTSMT typically consist of Epstein-Barr-virus (EBV)+ smooth muscle-like cells and show an intermediate malignancy. Their main occurrences are visceral organs, especially the liver, but intracranial appearances are described and associated with a poor prognosis. EBV drives the growth of PTSMT; however, the underlying molecular mechanisms still remain unclear. Gene expression analysis of a set of morphologically similar tumors (leiomyomas, leiomyosarcomas, angioleiomyomas and endothelial haemangiomas) from patients without immunosuppression or EBV-association was performed. Our findings indicate that PTSMT's growth is driven by two factors of the wingless-type protein family: WNT6 and WNT10A. We are first to report that in PTSMTs, a non-canonical activation of WNT, independent of beta-catenin, drives tumor cell proliferation via MTOR/AKT1, MYC and Cyclin D2.

Posttransplant complications in adult recipients of intestine grafts without bowel decontamination.

PubMed

Clouse, Jared W; Kubal, Chandrashekhar A; Fridell, Jonathan A; Mangus, Richard S

2018-05-01

Selective digestive decontamination is commonly used to decrease lumenal bacterial flora. Preoperative bowel decontamination may be associated with a lower wound infection rate but has not been shown to decrease risk of intra-abdominal abscess or lower leak rate for enteric anastomoses. Alternatively, the decontamination disrupts the normal flora of the gastrointestinal tract and may affect normal physiology, including immunologic function. This study reports complication rates of an intestine transplant program that has never used bowel decontamination. All adult patients who underwent intestine transplant from 2003 to 2015 at a single center were reviewed. Posttransplant complications included intra-abdominal abscess, enteric fistula, and leak from the enteric anastomosis. Viral, fungal, and bacterial infections in the first year after transplant are reported. There were 184 adult patients who underwent deceased donor intestine transplant during the study period. Among these patients, 30% developed an infected postoperative fluid collection, 4 developed an enteric fistula (2%), and 16 had an enteric or anastomotic leak (8%). The rate of any bacterial infection was 91% in the first year, with a wound infection rate of 25%. Fungal infection occurred in 47% of patients. Rejection rates were 55% at 1 y for isolated intestine patients and 17% for multivisceral (liver inclusive) patients. Among this population of intestine transplant patients in which no bowel decontamination was used, rates of surgical complications, infections, and rejection were similar to those reported by other centers. Bowel decontamination provides no identifiable benefit in intestine transplantation. Copyright © 2018 Elsevier Inc. All rights reserved.

Lymphoproliferation in captive wild ruminants affected with malignant catarrhal fever: 25 cases (1977-1985).

PubMed

Blake, J E; Nielsen, N O; Heuschele, W P

1990-04-01

The severity of lymphoproliferative disease associated with malignant catarrhal fever was extremely variable among 25 animals at the San Diego Wild Animal Park. Severe lymphoproliferative disease was seen in 3 of 10 Formosan Sika deer (Cervus nippon taiouanus), 3 of 6 Indian Axis deer (Cervus a axis), 3 of 6 Barasingha deer (Cervus d duvauceli), and 1 of 3 Nilgai (Boselaphus tragocamelus). Two Sika deer and 2 Barasingha deer had lesions morphologically indistinguishable from lymphosarcoma. Our findings were consistent with the hypothesis that alcelaphine herpesvirus-1 has oncogenic potential.

[Sinus histiocytosis (Destombes-Rosai-Dorfman disease) revealed by extranodal spinal involvement].

PubMed

Bernard, F; Sarran, N; Serre, I; Baldet, P; Callamand, P; Margueritte, G; Astruc, J

1999-02-01

Sinus histiocytosis with massive cervical lymphadenopathy (Rosai-Dorfman disease) is a non-neoplastic lymphoproliferative disorder. Extranodal involvement, especially of the nervous system, is unusual. We report a case revealed by neurological symptoms. A 10-year-old girl presented with paraparesis due to a dural extramedullary mass on magnetic resonance imaging. Massive cervical lymphadenopathy appeared secondarily. Radiological investigations showed mediastinal, paranasal sinus and lower eyelid involvement. The diagnosis of Rosai-Dorfman disease was established histologically and by immunohistochemical studies of nodal lesions by the demonstration of characteristic sinus histiocytosis with sheets of S-100 protein and CD-68 positive large histiocytes displaying lymphocyte phagocytosis. A dramatic response occurred with complete resolution of all clinical findings after treatment with corticosteroids and etoposide, although neurological lesions were unchanged on magnetic resonance imaging. Despite its rarity, this case underlines the unknown pathogenesis of this disease (immune dysfunction?) and the difficulties of treatment (choice of chemotherapeutic agents, duration).

Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.

PubMed

Vukotic, R; Conti, F; Fagiuoli, S; Morelli, M C; Pasulo, L; Colpani, M; Foschi, F G; Berardi, S; Pianta, P; Mangano, M; Donato, M F; Malinverno, F; Monico, S; Tamè, M; Mazzella, G; Belli, L S; Viganò, R; Carrai, P; Burra, P; Russo, F P; Lenci, I; Toniutto, P; Merli, M; Loiacono, L; Iemmolo, R; Degli Antoni, A M; Romano, A; Picciotto, A; Rendina, M; Andreone, P

2017-10-01

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments. © 2017 John Wiley & Sons Ltd.

The lymphoproliferative response to enzymatically digested gelatin in subjects with gelatin hypersensitivity.

PubMed

Kumagai, T; Nakayama, T; Kamada, M; Igarashi, C; Yuri, K; Furukawa, H; Wagatuma, K; Tsutsumi, H; Chiba, S; Kojima, H; Saito, A; Okui, T; Yano, S

2000-10-01

This study was designed to evaluate the immunogenic characteristics of enzymatically digested gelatin, 'FreAlagin', employing the lymphoproliferative response in subjects with gelatin hypersensitivity. Our purpose was to assess the response of primed lymphocytes to the newly developed FreAlagin and compare it to the response to conventional gelatin. A gelatin-specific lymphocyte proliferation test (LPT) was performed in 110 children with adverse reactions to gelatin-containing vaccines, who showed positive gelatin-specific cell-mediated immunity and were thus diagnosed as having gelatin hypersensitivity. Gelatin-specific IgE was measured in all subjects. The antigenic activity of FreAlagin to lymphocytes was compared with that of conventional bovine gelatin. Positive and negative control specimens were obtained from the patients with anaphylaxis and from subjects inoculated with gelatin-free vaccine who showed no adverse reactions in order to establish the fluorometric ELISA system to determine IgE antibody to gelatin and LPT. The lymphocyte activity against FreAlagin was much less than that to Wako gelatin and more than half of the subjects who reacted positively to Wako gelatin had a negative LPT to FreAlagin. Although 47% of the subjects had positive LPTs to FreAlagin, all but two still had lower SIs to FreAlagin compared with Wako gelatin. We conclude that the antigenic activity of FreAlagin as measured by the cell-mediated immune response is significantly less than that of conventional bovine gelatin. However, it is still necessary to perform clinical trials to show a reduced or absent clinical reactivity to FreAlagin in sensitized patients to conventional gelatin.

Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States.

PubMed

Cohen, Jeffrey I; Jaffe, Elaine S; Dale, Janet K; Pittaluga, Stefania; Heslop, Helen E; Rooney, Cliona M; Gottschalk, Stephen; Bollard, Catherine M; Rao, V Koneti; Marques, Adriana; Burbelo, Peter D; Turk, Siu-Ping; Fulton, Rachael; Wayne, Alan S; Little, Richard F; Cairo, Mitchell S; El-Mallawany, Nader K; Fowler, Daniel; Sportes, Claude; Bishop, Michael R; Wilson, Wyndham; Straus, Stephen E

2011-06-02

Chronic active EBV disease (CAEBV) is a lymphoproliferative disorder characterized by markedly elevated levels of antibody to EBV or EBV DNA in the blood and EBV RNA or protein in lymphocytes in tissues. We present our experience with CAEBV during the last 28 years, including the first 8 cases treated with hematopoietic stem cell transplantation in the United States. Most cases of CAEBV have been reported from Japan. Unlike CAEBV in Japan, where EBV is nearly always found in T or natural killer (NK) cells in tissues, EBV was usually detected in B cells in tissues from our patients. Most patients presented with lymphadenopathy and splenomegaly; fever, hepatitis, and pancytopenia were common. Most patients died of infection or progressive lymphoproliferation. Unlike cases reported from Japan, our patients often showed a progressive loss of B cells and hypogammaglobulinemia. Although patients with CAEBV from Japan have normal or increased numbers of NK cells, many of our patients had reduced NK-cell numbers. Although immunosuppressive agents, rituximab, autologous cytotoxic T cells, or cytotoxic chemotherapy often resulted in short-term remissions, they were not curative. Hematopoietic stem cell transplantation was often curative for CAEBV, even in patients with active lymphoproliferative disease that was unresponsive to chemotherapy. These studies are registered at http://www.clinicaltrials.gov as NCT00032513 for CAEBV, NCT00062868 and NCT00058812 for EBV-specific T-cell studies, and NCT00578539 for the hematopoietic stem cell transplantation protocol.

Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States

PubMed Central

Jaffe, Elaine S.; Dale, Janet K.; Pittaluga, Stefania; Heslop, Helen E.; Rooney, Cliona M.; Gottschalk, Stephen; Bollard, Catherine M.; Rao, V. Koneti; Marques, Adriana; Burbelo, Peter D.; Turk, Siu-Ping; Fulton, Rachael; Wayne, Alan S.; Little, Richard F.; Cairo, Mitchell S.; El-Mallawany, Nader K.; Fowler, Daniel; Sportes, Claude; Bishop, Michael R.; Wilson, Wyndham; Straus, Stephen E.

2011-01-01

Chronic active EBV disease (CAEBV) is a lymphoproliferative disorder characterized by markedly elevated levels of antibody to EBV or EBV DNA in the blood and EBV RNA or protein in lymphocytes in tissues. We present our experience with CAEBV during the last 28 years, including the first 8 cases treated with hematopoietic stem cell transplantation in the United States. Most cases of CAEBV have been reported from Japan. Unlike CAEBV in Japan, where EBV is nearly always found in T or natural killer (NK) cells in tissues, EBV was usually detected in B cells in tissues from our patients. Most patients presented with lymphadenopathy and splenomegaly; fever, hepatitis, and pancytopenia were common. Most patients died of infection or progressive lymphoproliferation. Unlike cases reported from Japan, our patients often showed a progressive loss of B cells and hypogammaglobulinemia. Although patients with CAEBV from Japan have normal or increased numbers of NK cells, many of our patients had reduced NK-cell numbers. Although immunosuppressive agents, rituximab, autologous cytotoxic T cells, or cytotoxic chemotherapy often resulted in short-term remissions, they were not curative. Hematopoietic stem cell transplantation was often curative for CAEBV, even in patients with active lymphoproliferative disease that was unresponsive to chemotherapy. These studies are registered at http://www.clinicaltrials.gov as NCT00032513 for CAEBV, NCT00062868 and NCT00058812 for EBV-specific T-cell studies, and NCT00578539 for the hematopoietic stem cell transplantation protocol. PMID:21454450

Perceptions of post-transplant recidivism in liver transplantation for alcoholic liver disease.

PubMed

Kawaguchi, Yoshikuni; Sugawara, Yasuhiko; Akamatsu, Nobuhisa; Kaneko, Junichi; Tanaka, Tomohiro; Tamura, Sumihito; Aoki, Taku; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Kokudo, Norihiro

2014-11-27

Although alcoholic liver disease (ALD) is regarded as a common indication for liver transplantation (LT), debatable issues exist on the requirement for preceding alcoholic abstinence, appropriate indication criteria, predictive factors for alcoholic recidivism, and outcomes following living-donor LT. In most institutions, an abstinence period of six months before LT has been adopted as a mandatory selection criterion. Data indicating that pre-transplant abstinence is an associated predictive factor for alcoholic recidivism supports the reasoning behind this. However, conclusive evidence about the benefit of adopting an abstinence period is yet to be established. On the other hand, a limited number of reports available on living-donor LT experiences for ALD patients suggest that organ donations from relatives have no suppressive effect on alcoholic recidivism. Prevention of alcoholic recidivism has proved to be the most important treatment after LT based on the resultant inferior long-term outcome of patients. Further evaluations are still needed to establish strategies before and after LT for ALD.

Intrathoracic tumor of the chest wall: A case of Castleman's disease mimicking myositis of the lower extremities.

PubMed

Tampakis, Athanasios; Tampaki, Ekaterini Christina; Daikeler, Thomas; Lardinois, Didier

2017-11-01

Castleman's disease refers to a group of uncommon lymphoproliferative disorders which exhibit common lymph-node histological features. A 72-year-old male patient presented with signs of lower limb myositis. Detailed work-up focused initially on evaluating hematological malignancies, the presence of a solid tumor, autoimmune diseases and degenerative disorders of the peripheral nerves. Finally, a PET-CT scan was performed to exclude paraneoplastic manifestations of a primary tumor, revealing  however a tumor of the thoracic wall. The definite histological diagnosis confirmed the presence of unicentric Castleman's disease of the chest wall. The manifestations of the present case suggest that a systemic inflammation might occur in the unicentric form of the disease possibly due to cytokine hypersecretion. The unicentric manifestation of the disease should be well distinguished from the multicentric appearance. Unicentric disease is a surgical condition and warrants a follow-up based on the systemic inflammation that might occur.

Impact of antiviral prophylaxis in adults Epstein-Barr Virus-seronegative kidney recipients on early and late post-transplantation lymphoproliferative disorder onset: a retrospective cohort study.

PubMed

Ville, Simon; Imbert-Marcille, Berthe-Marie; Coste-Burel, Marianne; Garandeau, Claire; Meurette, Aurélie; Cantarovitch, Diego; Giral, Magali; Hourmant, Maryvonne; Blancho, Gilles; Dantal, Jacques

2018-05-01

Post-transplantation lymphoproliferative disorder (PTLD) pathogenesis is related to EBV infection. Mismatch with the donor (EBV D+/R-) is the main risk factor for both early PTLD (<1 year post-transplantation) and late (>1 year). In these at-risk patients, the role of antiviral prophylaxis for preventing PTLD remains controversial. We analyzed the impact of antiviral drugs given to prevent CMV disease in a monocentric retrospective cohort of 73 adult kidney or kidney-pancreas EBV-seronegative recipients, transplanted between 01/01/2000 and 01/01/2016. Thirty-seven (50.7%, prophylaxis group) received (val-)aciclovir or (val-)ganciclovir for 3-6 months and 36 (49.3%, no-prophylaxis group) received no-prophylaxis. Mean follow-up was 69 ± 7.2 months in the prophylaxis group and 91 ± 10.3 months in the no-prophylaxis group. Monitoring of EBV PCR revealed that prophylaxis delayed primary infection at 100 days (43% vs. 84%, P = 0.02). Early PTLD incidence was not different between groups (4/37 vs. 4/36, P = 0.99). Concerning late events, EBV-related neoplasia incidence was significantly lower in treated patients among whom no cases were observed, while in the no-prophylaxis group 6 cases were reported (P = 0.02). Despite a weak level of evidence our study suggests that antiviral prophylaxis could prevent late onset PTLD. © 2017 Steunstichting ESOT.

Orbital Epstein-Barr Virus-Positive Polymorphic B-Cell Lymphoproliferative Disorder in an Apparently Immunocompetent Woman.

PubMed

Abendroth, Michael D; Bayerl, Michael G; Wilkinson, Michael J; Claxton, David F; Specht, Charles S

2017-12-01

We report a rare case of Epstein-Barr virus (EBV)-positive polymorphic B-cell lymphoproliferative disorder (LPD) involving the lacrimal gland of a 28-year-old, apparently immunocompetent woman. She presented with a chief complaint of orbital swelling and tenderness and was found to have a lesion involving the right lacrimal gland and distal superior and lateral rectus muscles. Histology of the lesion revealed histiocytes with pleomorphic nuclei, reactive lymphocytes, and scattered cells that resembled the Reed-Sternberg (R-S) cells of classical Hodgkin lymphoma. The R-S-like cells were positive for PAX5 and CD30 and negative for CD15, supporting a diagnosis of polymorphic B-cell LPD. In situ hybridization for EBV-encoded RNA demonstrated the presence of EBV. Most EBV-positive polymorphic B-cell LPDs are associated with immunodeficiency. However, the patient described is HIV-negative and has no identifiable defects in immunoglobulin levels or cell-mediated immunity. This raises the question of whether she has an underlying immunodeficiency resulting from subtle changes in T-cell physiology, or whether chronic EBV infection contributed to her immune dysfunction through an unclear mechanism. The orbital mass partially regressed with chemotherapy, and the patient has done well clinically with no recurrence of this EBV-LPD for over 2 years.

Nodular pulmonary amyloidosis with primary pulmonary MALT lymphoma masquerading as metastatic lung disease

PubMed Central

Upadhaya, Sunil; Baig, Mohd; Towfiq, Basim; Al Hadidi, Samer

2017-01-01

ABSTRACT Nodular pulmonary amyloidosis is a very rare form of localized amyloidosis involving the lung, with very little known about its nature. It is usually associated with indolent B cell lymphoproliferative disorder and also connective tissue disorders. No definite treatment guideline exists. Many patients respond to chemotherapy with low risk of progression and a ‘wait and watch’ strategy is also considered a valid treatment option. In this report the authors present a case of nodular pulmonary amyloidosis with pulmonary mucosa associated lymphoid tissue (MALT) lymphoma that presented with features of metastatic malignant disease and after definitive diagnosis decided not to undergo treatment. PMID:28808514

Subclinical pulmonary function defects following autologous and allogeneic bone marrow transplantation: relationship to total body irradiation and graft-versus-host disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tait, R.C.; Burnett, A.K.; Robertson, A.G.

1991-06-01

Pulmonary function results pre- and post-transplant, to a maximum of 4 years, were analyzed in 98 patients with haematological disorders undergoing allogeneic (N = 53) or autologous bone marrow transplantation (N = 45) between 1982 and 1988. All received similar total body irradiation based regimens ranging from 9.5 Gy as a single fraction to 14.4 Gy fractionated. FEV1/FVC as a measure of airway obstruction showed little deterioration except in patients experiencing graft-versus-host disease in whom statistically significant obstructive ventilatory defects were evident by 6 months post-transplant (p less than 0.01). These defects appeared to be permanent. Restrictive ventilatory defects, asmore » measured by reduction in TLC, and defects in diffusing capacity (DLCO and KCO) were also maximal at 6 months post-transplant (p less than 0.01). Both were related, at least in part, to the presence of GVHD (p less than 0.01) or use of single fraction TBI with absorbed lung dose of 8.0 Gy (p less than 0.05). Fractionated TBI resulted in less marked restricted ventilation and impaired gas exchange, which reverted to normal by 2 years, even when the lung dose was increased from 11.0 Gy to between 12.0 and 13.5 Gy. After exclusion of patients with GVHD (30% allografts) there was no significant difference in pulmonary function abnormalities between autograft and allograft recipients.« less

Predictors of Cardiovascular Events After Liver Transplantation.

PubMed

Gallegos-Orozco, Juan F; Charlton, Michael R

2017-05-01

Indications for liver transplant have been extended, and older and sicker patients are undergoing transplantation. Infectious, malignant, and cardiovascular diseases account for the most posttransplant deaths. Cirrhotic patients can develop heart disease through systemic diseases affecting the heart and the liver, cirrhosis-specific heart disease, or common cardiovascular. No single factor can predict posttransplant cardiovascular complications. Patients with history of cardiovascular disease, and specific abnormalities on echocardiography, electrocardiography, or serum markers of heart disease seem to be at increased risk of complications. Pretransplant cardiovascular evaluation is essential to detecting these risk factors so their effects can be mitigated through appropriate intervention. Copyright © 2016 Elsevier Inc. All rights reserved.

Alcohol abuse in deceased liver donors: impact on post-transplant outcomes.

PubMed

Mangus, Richard S; Kubal, Chandrashekhar A; Fridell, Jonathan A; Pena, Jose M; Frost, Evan M; Joseph Tector, A

2015-01-01

Many deceased liver donors with a history of alcohol abuse are excluded based upon medical history alone. This paper summarizes the transplant outcomes for a large number of deceased liver donors with a documented history of alcohol abuse. The records for 1478 consecutive deceased liver donors were reviewed (2001-2012). As per the United Network for Organ Sharing criteria, heavy alcohol use by an organ donor is defined as chronic intake of two or more drinks per day. Donors with a documented history of alcohol abuse were divided into three groups according to duration of abuse (<10 years, 10-24 years and 25 + years). Reperfusion biopsies are reported. Outcomes include biopsy appearance, early graft function and early and late graft survival. There were 161 donors with alcohol abuse: <10 years (29%); 10-24 years (42%); and ≥25 years (29%). Risk of 90-day graft loss for these three groups was: 0%, 3% and 2%, compared to 3% for all other donors (P = 0.62). Graft survival at 1 year for donor grafts with and without alcohol abuse was 89% and 87% (P = 0.52). There was no difference in early graft function. Cox proportional hazards modelling for graft survival demonstrates no statistically significant difference in survival up to 10 years post-transplant. This study demonstrates successful transplantation of a large number of deceased donor liver grafts from donors with a documented history of alcohol abuse (n = 161; 11% of all grafts). These extended criteria donor allografts may, therefore, be utilized successfully with similar outcomes. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Donor PNPLA3 rs738409 genotype is a risk factor for graft steatosis. A post-transplant biopsy-based study.

PubMed

Trunečka, Pavel; Míková, Irena; Dlouhá, Dana; Hubáček, Jaroslav A; Honsová, Eva; Kolesár, Libor; Lánská, Věra; Fraňková, Soňa; Šperl, Jan; Jirsa, Milan; Poledne, Rudolf

2018-05-01

The rs738409 c.444C > G (p.I148M) polymorphism in PNPLA3 is a major factor predisposing to non-alcoholic fatty liver disease. The aim of the study was to clarify the impact of liver and extrahepatic expression of the PNPLA3 p.148M variant on liver graft steatosis after liver transplantation. Fat content was assessed in liver biopsies from 176 transplant recipients. During a period of 4 ± 1 years after transplantation, 17 patients developed grade 3 steatosis, 14 patients grade 2 steatosis, 56 patients grade 1 steatosis, and 89 patients grade 0 steatosis. The influence of the recipient and donor rs738409 genotype and clinical and laboratory data on liver fat content were analyzed using ordinal logistic regression. The PNPLA3 rs738409 CC/CG/GG genotype frequencies, respectively, were 0.494/0.449/0.057 in the graft donors and 0.545/0.330/0.125 in the graft recipients. In the multivariate analysis, the presence of the PNPLA3 c.444G allele in donor (OR 1.62; 95%CI 1.12-2.33), post-transplant BMI (OR 1.14; 95%CI 1.07-1.22), diabetes mellitus (OR 1.99; 95%CI 1.22-3.22), and serum triglycerides (OR 1.40; 95%CI 1.11-1.76) were independent risk factors for increased liver graft fat content. These data indicate that the liver expression of the PNPLA3 p.148M variant confers a genetic predisposition to liver graft steatosis along with nutritional status and diabetes. Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study.

PubMed

Klintmalm, G B; Feng, S; Lake, J R; Vargas, H E; Wekerle, T; Agnes, S; Brown, K A; Nashan, B; Rostaing, L; Meadows-Shropshire, S; Agarwal, M; Harler, M B; Garcia-Valdecasas, J-C

2014-08-01

This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N = 260) to one of the following immunosuppressive regimens: (i) basiliximab + belatacept high dose [HD] + mycophenolate mofetil (MMF), (ii) belatacept HD + MMF, (iii) belatacept low dose [LD] + MMF, (iv) tacrolimus + MMF, or (v) tacrolimus alone. All received corticosteroids. Demographic characteristics were similar among groups. The proportion of patients who met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (42–48%) versus tacrolimus groups (15–38%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus + MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab + belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15–34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated.

Infection Rates in Tacrolimus versus Cyclosporine Treated Pediatric Kidney Transplant Recipients on a Rapid Discontinuation of Prednisone Protocol: 1-year Analysis

PubMed Central

Kizilbash, Sarah J; Rheault, Michelle N; Bangdiwala, Ananta; Matas, Arthur; Chinnakotla, Srinath; Chavers, Blanche M

2017-01-01

Introduction Acute rejection (AR) is lower in pediatric kidney transplant (pKTx) recipients on tacrolimus (Tac) versus cyclosporine (CsA). Data comparing infection outcomes for children treated with these agents are limited. Methods We retrospectively studied infection outcomes in 96 pKTx recipients on a rapid discontinuation of prednisone protocol (RDP). Patient survival (PS), death-censored graft survival (DCGS), AR and infection free survival were assessed using Kaplan-Meier/log-rank tests and proportional hazards models. Results There were no differences in 1-year PS, DCGS, or AR between Tac and CsA recipients. After adjusting for AR, the hazard of CMV viremia was 4.0 times higher (95%CI: 1.04, 15.5; p=0.044) and that of BK viremia was 3.8 times higher (95%CI: 1.5, 10.2; p=0.007) in Tac recipients. The incidence of EBV viremia was similar between the groups (p=0.56). Posttransplant lymphoproliferative disease was only observed in Tac recipients (3%). There was no difference in the incidence of pneumonia, urinary tract or clostridium difficile infections between Tac and CsA recipients. Conclusion Among KTx recipients on RDP, the hazards of CMV and BK viremia within 1-year post-KTx were significantly higher in Tac recipients compared to CsA. Regular assessment for infections and lower Tac trough levels may be warranted in Tac recipients. PMID:28371243

Therapeutic trials for a rabbit model of EBV-associated Hemophagocytic Syndrome (HPS): effects of vidarabine or CHOP, and development of Herpesvirus papio (HVP)-negative lymphomas surrounded by HVP-infected lymphoproliferative disease.

PubMed

Hayashi, K; Joko, H; Koirala, T R; Onoda, S; Jin, Z-S; Munemasa, M; Ohara, N; Oda, W; Tanaka, T; Oka, T; Kondo, E; Yoshino, T; Takahashi, K; Yamada, M; Akagi, T

2003-10-01

Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS), which is often associated with fatal infectious mononucleosis or T-cell lymphoproliferative diseases (LPD), is a distinct disease characterized by high mortality. Treatment of patients with EBV-AHS has proved challenging. To develop some therapeutic interventions for EBV-AHS, we examined the effectiveness of an antiviral agent (vidarabine) or chemotherapy (CHOP), using a rabbit model for EBV-AHS. Fourteen untreated rabbits were inoculated intravenously with cell-free virions of the EBV-like virus Herpesvirus papio (HVP). All of the rabbits died of HVP-associated (LPD) and hemophagocytic syndrome (HPS) between 21 and 31 days after inoculation. Furthermore, three HVP-infected rabbits treated with vidarabine died between days 23 and 28 after inoculation, and their clinicopathological features were no different from those of untreated rabbits, indicating that this drug is not effective at all to treat HVP-induced rabbit LPD and HPS. Three of the infected rabbits that were treated with one course, with an incomplete set of three courses, or with three full courses of CHOP treatment died of HVP-induced LPD and HPS with a bleeding tendency and/or with opportunistic infections. They died on the 26th, 62nd and 105th day after virus inoculation, respectively. CHOP treatment transiently suppressed the HVP-induced LPD and contributed to the prolonged survival time of two infected rabbits. However, it did not remove all of the HVP-infected cells from the infected rabbits, and residual HVP-infected lymphocytes caused recurrences of rabbit LPD and HPS. The most interesting finding of this experiment was observed in the infected rabbit with the longest survival time of 105 days: HVP-negative lymphomas surrounded by HVP-induced LPD developed in the larynx and ileum of this rabbit, causing an obstruction of the lumen. We concluded that these were not secondary lymphomas caused by CHOP treatment, because no suspicious

Impaired Control of Epstein-Barr Virus Infection in B-Cell Expansion with NF-κB and T-Cell Anergy Disease.

PubMed

Arjunaraja, Swadhinya; Angelus, Pamela; Su, Helen C; Snow, Andrew L

2018-01-01

B -cell e xpansion with N F-κB and T -cell a nergy (BENTA) disease is a B-cell-specific lymphoproliferative disorder caused by germline gain-of-function mutations in CARD11 . These mutations force the CARD11 scaffold into an open conformation capable of stimulating constitutive NF-κB activation in lymphocytes, without requiring antigen receptor engagement. Many BENTA patients also suffer from recurrent infections, with 7 out of 16 patients exhibiting chronic, low-grade Epstein-Barr virus (EBV) viremia. In this mini-review, we discuss EBV infection in the pathogenesis and clinical management of BENTA disease, and speculate on mechanisms that could explain inadequate control of viral infection in BENTA patients.

Epstein-Barr virus-associated peripheral T-Cell lymphoma involving spleen in a renal transplant patient.

PubMed Central

Lee, Hye Kyung; Kim, Hee Jung; Lee, Eun Hee; Kim, Suk Young; Park, Tae In; Kang, Chang Suk; Yang, Woo Ick

2003-01-01

The incidence of posttransplantation lymphoproliferative disorders (PTLDs) has increased in recent years. Although rare, various types of T-cell lymphoma have been reported and their association with Epstein-Barr virus (EBV) has been compared with B-cell PTLDs. We report a case of splenic peripheral T-cell lymphoma occurring in a 47-yr-old male patient 7 yr after renal allograft transplantation. The spleen showed sinusoidal proliferation of focal CD30 positive, large, atypical lymphoid cells. Positivity for CD3 and cytolytic granule-associated proteins was also demonstrated in the tumor cells, while anaplastic large cell lymphoma kinase (ALK) and CD8 were not expressed. Strong nuclear signals for EBV mRNA were noted by EBER1 in situ hybridization. A molecular genetic study demonstrated a rearrangement of the gamma T-cell receptor gene. To our knowledge, this case is unique in terms of a posttransplant T-cell lymphoma that shows focal CD30, cytolytic granule-associated proteins, and EBV positivity. PMID:12692428

Superior outcome using cyclosporin A alone versus cyclosporin A plus methotrexate for post-transplant immunosuppression in children with acute leukemia undergoing sibling hematopoietic stem cell transplantation.

PubMed

Weiss, Melissa; Steinbach, Daniel; Zintl, Felix; Beck, James; Gruhn, Bernd

2015-06-01

The outcome of cyclosporin A (CSA) alone (n = 19) as graft-versus-host disease (GVHD) prophylaxis was compared to that of CSA combined with methotrexate (MTX) (n = 43) in children with acute leukemia who underwent hematopoietic stem cell transplantation. All respective donors were HLA-identical siblings. All patients received CSA at a dose of 3 mg/kg/day starting on day -1. A CSA level of 80-130 ng/ml was aimed for. The 43 patients in the historical control were given an additional 10 mg/m(2) dosage of MTX on days 1, 3, 6, and 11. Patients who received CSA alone had a significantly reduced cumulative incidence of relapse (5 vs. 40 %; p = 0.002), a significantly increased 5-year event-free survival (84 vs. 35 %; p = 0.001), and a significantly increased 5-year overall survival (84 vs. 42 %; p = 0.004). The incidence of acute GVHD grade II-IV and chronic GVHD in patients in the CSA group was equivalent to the CSA+MTX group (26 vs. 19 %; p = 0.440, and 32 vs. 23 %; p = 0.428). In conclusion, post-transplant immunosuppression consisting of CSA alone is well tolerated and may contribute to a superior outcome.

Pretransplant urinary proteome analysis does not predict development of chronic kidney disease after liver transplantation.

PubMed

Milongo, David; Bascands, Jean-Loup; Huart, Antoine; Esposito, Laure; Breuil, Benjamin; Moulos, Panagiotis; Siwy, Justyna; Ramírez-Torres, Adela; Ribes, David; Lavayssière, Laurence; Del Bello, Arnaud; Muscari, Fabrice; Alric, Laurent; Bureau, Christophe; Rostaing, Lionel; Schanstra, Joost P; Kamar, Nassim

2015-07-01

Chronic kidney disease (CKD) is a common complication after liver transplantation. Kidney biopsies cannot be easily performed before liver transplantation to predict patients at high risk for CKD. The aim of our study was to determine whether pre-, peri- and post-transplant factors, as well as peptides present in preliver transplant urine samples were associated with loss in kidney function at 6 months post-transplantation using proteome analysis. Eighty patients who underwent a liver transplantation and that had pretransplant glomerular filtration rate (GFR) value of ≥60 mL/min/1.73 m² (MDRD) were included in the study. GFR decreased significantly after transplantation. At month 6 post-transplantation, 40 patients displayed a CKD, i.e. eGFR of <60 mL/min/1.73 m², while the other 40 patients did not. Although thousands of peptides were identified, none was significantly associated with the development of CKD at 6 months after liver transplantation. Moreover, using a urinary peptidome classifier to detect preexisting CKD, no difference was found in CKD scores between the 2 groups. After analysis of a large number of pre-, peri- and post-transplant parameters, viral hepatitis as a cause for liver transplantation was the sole independent predictive factor for CKD. No difference in peptides with differential urinary abundance between patients who received a graft for virus related liver disease vs. all other causes of liver disease was observed. Urinary peptidome analysis before liver transplantation failed to identify a peptide pattern associated with the development of CKD at 6 months after liver transplantation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chidamide Combined With R-GDP in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)

ClinicalTrials.gov

2017-12-12

Chidamide; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Neoplasm by Histology; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Cyclophosphamide; Rituximab; Gemcitabine; Cisplatin; Dexamethasone; HDAC Inhibitor

Pilot Study of Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients With Life Threatening Hemophagocytic Disorders

ClinicalTrials.gov

2005-06-23

Chediak-Higashi Syndrome; Graft Versus Host Disease; X-Linked Lymphoproliferative Syndrome; Familial Erythrophagocytic Lymphohistiocytosis; Hemophagocytic Lymphohistiocytosis; Virus-Associated Hemophagocytic Syndrome

Hemophagocytic lymphohistiocytosis caused by primary Epstein-Barr virus in patient with Crohn's disease.

PubMed

Virdis, Francesco; Tacci, Sara; Messina, Federico; Varcada, Massimo

2013-11-27

We present a case of a 19-year-old man with a 6-year history of Crohn's disease (CD), previously treated with 6-mercaptopurine, who was admitted to our department for Epstein-Barr virus (EBV) infection and subsequently developed a hemophagocytic lymphohistiocytosis (HLH). HLH is a rare disease which causes phagocytosis of all bone marrow derived cells. It can be a primary form as a autosomic recessive disease, or a secondary form associated with a variety of infections; EBV is the most common, the one with poorer prognosis. The incidence of lymphoproliferative disorders was increased in patients with inflammatory bowel disease (IBD) treated with thiopurines. Specific EBV-related clinical and virological management should be considered when treating a patient with IBD with immunosuppressive therapy. Moreover EBV infection in immunosuppressed patient can occur with more aggressive forms such as encephalitis and diffuse large B cell lymphoma. Our case confirms what is described in the literature; patients with IBD, particularly patients with CD receiving thiopurine therapy, who present 5 d of fever and cervical lymphadenopathy or previous evidence of lymphopenia should be screened for HLH.

CD8-positive T-cell lymphoproliferative disorder associated with Epstein-Barr virus-infected B-cells in a rheumatoid arthritis patient under methotrexate treatment.

PubMed

Koji, Hitoshi; Yazawa, Takuya; Nakabayashi, Kimimasa; Fujioka, Yasunori; Kamma, Hiroshi; Yamada, Akira

2016-01-01

We report a 48-year-old female who developed lymphoproliferative disorder (LPD) during treatment of rheumatoid arthritis (RA) with methotrexate (MTX). She presented with multiple tumors in the cervical lymph nodes (LNs), multiple lung shadows and round shadows in both kidneys with pancytopenia and a high CRP level. The LN showed CD8-positive T-cell LPD associated with Epstein-Barr (EB) virus-infected B-cells. Clonality assays for immunoglobulin (Ig) heavy chain and T-cell receptor gamma (TCRγ) were negative. The cessation of MTX without chemotherapy resulted in the complete disappearance of the tumors and abnormal clinical features. We compared this case with previously published ones and discuss the pathological findings, presuming that the proliferation of CD8 T-cells was a reactive manifestation to reactivated EB virus-infected B-cells.

Live Donor Renal Anatomic Asymmetry and Post-Transplant Renal Function

PubMed Central

Tanriover, Bekir; Fernandez, Sonalis; Campenot, Eric S.; Newhouse, Jeffrey H.; Oyfe, Irina; Mohan, Prince; Sandikci, Burhaneddin; Radhakrishnan, Jai; Wexler, Jennifer J.; Carroll, Maureen A.; Sharif, Sairah; Cohen, David J.; Ratner, Lloyd E.; Hardy, Mark A.

2014-01-01

Background Relationship between live donor renal anatomic asymmetry and post-transplant recipient function has not been studied extensively. Methods We analyzed 96 live-kidney donors, who had anatomical asymmetry (>10% renal length and/or volume difference calculated from CT angiograms) and their matching recipients. Split function differences (SFD) were quantified with 99mTc-DMSA renography. Implantation biopsies at time-zero were semi-quantitatively scored. A comprehensive model utilizing donor renal volume adjusted to recipient weight (Vol/Wgt), SFD, and biopsy score was used to predict recipient estimated glomerular filtration rate (eGFR) at one-year. Primary analysis consisted of a logistic regression model of outcome (odds of developing eGFR>60ml/min/1.73 m2 at one-year), a linear regression model of outcome (predicting recipient eGFR at one-year, using the CKD-EPI formula), and a Monte Carlo simulation based on the linear regression model (N=10,000 iterations). Results In the study cohort, the mean Vol/Wgt and eGFR at one-year were 2.04 ml/kg and 60.4 ml/min/1.73m2, respectively. Volume and split ratios between two donor kidneys were strongly correlated (r=0.79, p-value<0.001). The biopsy scores among SFD categories (<5%, 5–10%, >10%) were not different (p=0.190). On multivariate models, only Vol/Wgt was significantly associated with higher odds of having eGFR>60ml/min/1.73 m2 (OR=8.94, 95% CI 2.47–32.25, p=0.001) and had a strong discriminatory power in predicting the risk of eGFR<60ml/min/1.73m2 at one-year (ROC curve=0.78, 95% CI 0.68–0.89). Conclusion In the presence of donor renal anatomic asymmetry, Vol/Wgt appears to be a major determinant of recipient renal function at one-year post-transplantation. Renography can be replaced with CT volume calculation in estimating split renal function. PMID:25719258

Hepatitis C infection in the transplant recipient.

PubMed

Terrault, N A; Wright, T L; Pereira, B J

1995-12-01

This article highlights the increasing role of HCV in the transplant setting. Its importance in the liver transplant setting is clear. It produces end-stage liver disease and represents a common indication for transplant referral. Recurrent infection is nearly universal posttransplant in those with viremia pretransplant. Acquired disease is uncommon. The natural history of posttransplant disease suggests there is no significant impact of graft or patient survival, at least in the short-term. Long-term follow-up is needed, as well as more detailed study of the factors contributing to posttransplant disease. Kidney transplant patients commonly are infected with HCV prior to transplantation. Acquisition of infection through infected donors also serves as a source of HCV infection. HCV infection after transplantation is associated with an increased risk of liver disease but has no significant effect on short-term patient survival. The issues of organ allocation from anti-HCV-positive donors are particularly relevant to this patient population because maintenance dialysis always is a treatment alternative to transplantation. Much less information is available on other transplant groups, such as heart, lung, and bone marrow transplant recipients. There are many unanswered questions, especially with respect to the natural history of disease after 5 to 10 years of infection. The pathogenesis of infection in the transplant setting is emerging slowly but requires further investigation. Both direct viral cytopathicity and host-mediated immunity appear to play a role in liver injury. An increased understanding of pathogenicity will lead to improved management of patients with HCV infection both pre- and posttransplant.

Reduced Intensity Preparative Regimen Followed by Stem Cell Transplant (FAB)

ClinicalTrials.gov

2016-03-29

Myelodysplastic and Myeloproliferative Disorders; Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Chronic Myelogenous Leukemia; Multiple Myeloma; Plasma Cell Dyscrasia; Lymphoproliferative Disorders; Hematologic Diseases

Very virulent plus strains of MDV induce acute form of transient paralysis in both susceptible and resistant chicken lines

USDA-ARS?s Scientific Manuscript database

Marek’s Disease (MD) is a lymphoproliferative disease of domestic chickens caused by a highly cell-associated alpha herpesvirus, Marek’s disease virus (MDV). Clinical signs of MD include depression, crippling, weight loss, and transient paralysis (TP). TP is a disease of the central nervous system...

Genome-wide histone modification profile induced by MDV in MD-resistant and -susceptible chickens

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a lymphoproliferative disease in chicken caused by oncogenic Marek’s disease virus (MDV). MD is characterized by infiltration of proliferating lymphoid cells in organs, such as peripheral nerve, skin, muscle, liver, spleen, heart, kidney, gonads and proventriculus. Epigenetic...

Inhibitors of apoptosis (IAPs) regulate intestinal immunity and inflammatory bowel disease (IBD) inflammation.

PubMed

Pedersen, Jannie; LaCasse, Eric C; Seidelin, Jakob B; Coskun, Mehmet; Nielsen, Ole H

2014-11-01

The inhibitor of apoptosis (IAP) family members, notably cIAP1, cIAP2, and XIAP, are critical and universal regulators of tumor necrosis factor (TNF) mediated survival, inflammatory, and death signaling pathways. Furthermore, IAPs mediate the signaling of nucleotide-binding oligomerization domain (NOD)1/NOD2 and other intracellular NOD-like receptors in response to bacterial pathogens. These pathways are important to the pathogenesis and treatment of inflammatory bowel disease (IBD). Inactivating mutations in the X-chromosome-linked IAP (XIAP) gene causes an immunodeficiency syndrome, X-linked lymphoproliferative disease type 2 (XLP2), in which 20% of patients develop severe intestinal inflammation. In addition, 4% of males with early-onset IBD also have inactivating mutations in XIAP. Therefore, the IAPs play a greater role in gut homeostasis, immunity and IBD development than previously suspected, and may have therapeutic potential. Copyright © 2014 Elsevier Ltd. All rights reserved.

Clinicopathological states of Epstein-Barr virus-associated T/NK-cell lymphoproliferative disorders (severe chronic active EBV infection) of children and young adults.

PubMed

Suzuki, Keiko; Ohshima, Koichi; Karube, Kennosuke; Suzumiya, Junji; Ohga, Shouichi; Ishihara, Shigehiko; Tamura, Kazuo; Kikuchi, Masahiro

2004-05-01

Epstein-Barr virus (EBV)-associated T/NK-cell lymphoproliferative disorders (LPD) of children and young adults are sometimes termed as severe chronic active EBV infection (CAEBV), and are associated with an aggressive clinical course. However, these clinicopathological states and the role of EBV have not been clarified. A retrospective study was performed on 43 children and adult patients, who manifested EBV-associated T/NK-cell lymphoproliferative disorders (EBV-T/NK-LPD) and most of whom had experienced general illness with CAEBV for several months or years. Clinicopathologically, 43 patients were classified into four groups: group A (smoldering state) (n=7), morphological non-neoplastic LPD with chronic clinical course (several years); group B (chronic state) (n=10), non-neoplastic LPD with clonal EBV-infected cells and a chronic course; group C (leukemia/lymphoma state) (n=22), neoplastic LPD with a subacute course (years to months); group D (fulminant state) (n=4), neoplastic LPD with a fulminant course (weeks to days). The 43 patients comprised 21 males and 22 females. The median age of group A was 14 years, group B 12 years, group C 17 years, and group D 1 year. Four of 7 patients in group A, 3 of 10 in group B, 12 of 22 in group C, and all 4 in group D have died. Causes of death included hemophagocytic syndrome and/or tumor death. Genotypically and phenotypically, group C was composed of peripheral T-cell lymphoma (PTCL), and NK-cell leukemia/lymphoma (NKLL), and group D comprised cases of PTCL. Groups A and B exhibited increased NK- or T-cells (CD8>CD4), and rare B-cells. Serologic titers of EBV were only modestly elevated or not elevated in almost all cases. EBV early RNA-1 (EBER-1)-expressing EBV-infected cells were frequently encountered in each group, but the number of infected cells varied between the cases. The EBV genotype did not differ between the groups. Our findings support an important pathogenic role for EBV-infected T/NK-cell infection

Diagnosis and treatment of viral diseases in recipients of allogeneic hematopoietic stem cell transplantation

PubMed Central

2013-01-01

Viral infections are important causes of morbidity and mortality after allogeneic stem cell hematopoietic transplantation (allo-HSCT). Although most viral infections present with asymptomatic or subclinical manifestations, viruses may result in fatal complications in severe immunocompromised recipients. Reactivation of latent viruses, such as herpesviruses, is frequent during the immunosuppression that occurs with allo-HSCT. Viruses acquired from community, such as the respiratory and gastrointestinal viruses, are also important pathogens of post-transplant viral diseases. Currently, molecular diagnostic methods have replaced or supplemented traditional methods, such as viral culture and antigen detection, in diagnosis of viral infections. The utilization of polymerase chain reaction facilitates the early diagnosis. In view of lacking efficacious agents for treatment of viral diseases, prevention of viral infections is extremely valuable. Application of prophylactic strategies including preemptive therapy reduces viral infections and diseases. Adoptive cellular therapy for restoring virus-specific immunity is a promising method in the treatment of viral diseases. PMID:24341630

Studies of EBV-lymphoid cell interactions in two patients with the X-linked lymphoproliferative syndrome: normal EBV-specific HLA-restricted cytotoxicity.

PubMed

Rousset, F; Souillet, G; Roncarolo, M G; Lamelin, J P

1986-02-01

Two X-linked lymphoproliferative syndrome (XLP) patients with the hypogammaglobulinemia phenotype were investigated at a time remote from their primary infection with the Epstein-Barr virus (EBV). The lymphoblastoid cell lines derived from these patients expressed the phenotypic markers characteristic of normal mature B lymphocytes and produced normal levels of immunoglobulins (Ig). These observations imply that at least some of their B cells are phenotypically normal. The natural killer (NK) activity of the two patients was low. In one patient, activated lymphocyte killer (ALK) activity was inefficient. These two XLP patients expressed a normal EBV-specific, HLA-restricted cytotoxic activity. It thus appears, from the present findings and those in cases published previously (6/11 patients expressing normal EBV-specific cytotoxic activity), that the notion of poor specific T cell memory for EBV may not be as pivotal ass suggested or, alternatively, that this defect may not be common in hypogammaglobulinemic survivors.

Frequency of a FAS ligand gene variant associated with inherited feline autoimmune lymphoproliferative syndrome in British shorthair cats in New Zealand.

PubMed

Aberdein, D; Munday, J S; Dittmer, K E; Heathcott, R W; Lyons, L A

2017-11-01

AIMS To determine the frequency of the FAS-ligand gene (FASLG) variant associated with feline autoimmune lymphoproliferative syndrome (FALPS) and the proportion of carriers of the variant in three British shorthair (BSH) breeding catteries in New Zealand. METHODS Buccal swabs were collected from all cats in two BSH breeding catteries from the South Island and one from the North Island of New Zealand. DNA was extracted and was tested for the presence of the FASLG variant using PCR. Cats with the FASLG variant were identified and the frequency of the FASLG variant allele calculated. Pedigree analysis was performed and inbreeding coefficients were calculated for cats with the FASLG variant. RESULTS Of 32 BSH cats successfully tested for the presence of the FASLG variant, one kitten (3%) was homozygous (FALPS-affected), and seven (22%) cats were heterozygous (carriers) for the FASLG variant allele, and 24 (75%) cats were homozygous for the wild type allele. The overall frequency of the FASLG variant allele in these 32 cats was 0.14. Cats carrying the FASLG variant were from all three breeding catteries sampled, including two catteries that had not previously reported cases of FALPS. Pedigree analysis revealed common ancestry of FALPS-affected and carrier cats within six generations, as well as frequent inbreeding, with inbreeding coefficients >0.12 for five cats with the FASLG variant. CONCLUSIONS AND CLINICAL RELEVANCE There was a high frequency of the FASLG variant allele (0.14) in this small sample of BSH cats, with 22% of healthy cats identified as carriers of the FASLG variant. For an inherited disease, lethal at a young age, in a small population in which inbreeding is common, these results are significant. To prevent future cases of disease and stop further spread of the FASLG variant allele within the BSH population in New Zealand, it is recommended that all BSH and BSH-cross cats be tested for the presence of the FASLG variant before mating. Cats identified as

Immunohistochemical assessment of the diagnostic utility of PD-L1: a preliminary analysis of anti-PD-L1 antibody (SP142) for lymphoproliferative diseases with tumour and non-malignant Hodgkin-Reed-Sternberg (HRS)-like cells.

PubMed

Sakakibara, Ayako; Kohno, Kei; Eladl, Ahmed E; Klaisuwan, Teerada; Ishikawa, Eri; Suzuki, Yuka; Shimada, Satoko; Nakaguro, Masato; Shimoyama, Yoshie; Takahara, Taishi; Kato, Seiichi; Asano, Naoko; Nakamura, Shigeo; Satou, Akira

2018-06-01

The programmed death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in tumour cells escape from immune control. PD-L1 immunohistochemistry is a useful predictor of immunotherapy response, but is still not used widely in the diagnostic setting. Here we describe results using PD-L1 immunohistochemistry during routine diagnostics in lymphoma. Ninety-one lymphoproliferative disease cases sharing tumour and non-malignant Hodgkin-Reed-Sternberg (HRS)-like cells with and without Epstein-Barr virus (EBV) association were investigated by immunohistochemistry for PD-L1 (clone SP142). PD-L1 expression was present in more than 5% of tumour or non-malignant HRS-like cells in 100% of EBV + classical (C) Hodgkin lymphoma (HL) (n = 10) and EBV-negative nodular sclerosis CHL (n = 8); 40% of EBV + diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS) (n = 20); and 4% of nodal peripheral T cell lymphoma of follicular helper T cell type (PTCL-TFH) (n = 22). In contrast, nodular lymphocyte-predominant HL (n = 4), lymphocyte-rich CHL (n = 6), EBV + hyperplasia (n = 8), plasmablastic lymphoma (n = 3) and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (n = 5) seldom exhibited PD-L1 in their large cells. Assessing PD-L1 positivity in tumour and non-malignant large cells was helpful in differentiating between CHL versus nodal PTCL-TFH (P < 0.0001) or EBV + DLBCL-NOS (P = 0.0052) and between EBV + DLBCL-NOS versus nodal PTCL-TFH (P = 0.0052), with PD-L1 expression indicating the first diagnosis in each of those sets. Immunohistochemical evaluation of PD-L1 expression in tumour and non-malignant HRS-like large cells may be useful for assessing either immune escape or immunodeficiency in their pathogenesis. © 2018 John Wiley & Sons Ltd.

Successful treatment of post-transplant relapsed acute myeloid leukemia with FLT3 internal tandem duplication using the combination of induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Report of three cases

PubMed Central

Campregher, Paulo Vidal; de Mattos, Vinicius Renan Pinto; Salvino, Marco Aurélio; Santos, Fabio Pires de Souza; Hamerschlak, Nelson

2017-01-01

ABSTRACT Acute myeloid leukemia is a hematopoietic stem cell neoplastic disease associated with high morbidity and mortality. The presence of FLT3 internal tandem duplication mutations leads to high rates of relapse and decreased overall survival. Patients with FLT3 internal tandem duplication are normally treated with hematopoietic stem cell transplantation in first complete remission. Nevertheless, the incidence of post-transplant relapse is considerable in this group of patients, and the management of this clinical condition is challenging. The report describes the outcomes of patients with FLT3 internal tandem duplication positive acute myeloid leukemia who relapsed after allogeneic hematopoietic stem cell transplantation and were treated with the combination of re-induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Three cases are described and all patients achieved prolonged complete remission with the combined therapy. The combination of induction chemotherapy followed by donor lymphocyte infusion, and the maintenance with azacitidine and sorafenib can be effective approaches in the treatment of post-hematopoietic stem cell transplant and relapsed FLT3 internal tandem duplication positive acute myeloid leukemia patients. This strategy should be further explored in the context of clinical trials. PMID:28746590

Epstein Barr virus-positive mucocutaneous ulcer of the colon associated Hodgkin lymphoma in Crohn's disease.

PubMed

Moran, Neil R; Webster, Bradley; Lee, Kenneth M; Trotman, Judith; Kwan, Yiu-Lam; Napoli, John; Leong, Rupert W

2015-05-21

Epstein Barr virus (EBV) positive mucocutaneous ulcers (EBVMCU) form part of a spectrum of EBV-associated lymphoproliferative disease. They have been reported in the setting of immunosenescence and iatrogenic immunosuppression, affecting the oropharyngeal mucosa, skin and gastrointestinal tract (GIT). Case reports and series to date suggest a benign natural history responding to conservative management, particularly in the GIT. We report an unusual case of EBVMCU in the colon, arising in the setting of immunosuppression in the treatment of Crohn's disease, with progression to Hodgkin lymphoma 18 mo after cessation of infliximab. The patient presented with multiple areas of segmental colonic ulceration, histologically showing a polymorphous infiltrate with EBV positive Reed-Sternberg-like cells. A diagnosis of EBVMCU was made. The ulcers failed to regress upon cessation of infliximab and methotrexate for 18 mo. Following commencement of prednisolone for her Crohn's disease, the patient developed widespread Hodgkin lymphoma which ultimately presented as a life-threatening lower GIT bleed requiring emergency colectomy. This is the first report of progression of EBVMCU to Hodgkin lymphoma, in the setting of ongoing iatrogenic immunosuppression and inflammatory bowel disease.

Peritoneal Dialysis Catheter Removal Post-Transplant - A Rare Case of Delayed Bowel Perforation.

PubMed

Maxted, Andrew P; Davies, Brian; Colliver, Daniel; Williams, Alun; Lunn, Andrew

2017-01-01

Peritoneal dialysis (PD) is a well-established form of renal replacement therapy and the practice of leaving catheters in situ post-transplantation widely accepted. We present a rare complication: a child presenting with anal protrusion of the PD catheter.The patient is an 11-year-old boy with a background of renal dysplasia and congenital cutis laxa. Twenty-three weeks after dialysis was commenced, the patient underwent a renal transplant. Thirteen weeks post-transplant, the patient felt an unusual sensation after defecation. The curled end of the catheter was seen protruding from the anus. He was admitted, and investigations showed stable graft function, with abdominal X ray showing no free air.Intraoperative findings showed a small perforation of the sigmoid colon sealed off by adherence of several small intestinal loops. This was repaired laparoscopically after removal of the distal part of the catheter per rectum. No peritoneal contamination was seen. He was treated with 5 days of intravenous antibiotics and gradual introduction of enteral feeds. His graft function remained stable throughout.Timing of catheter removal varies, from the time of transplantation to over 3 months post-transplantation. Bowel perforation due to PD catheter insertion is rare and tends to occur at the time of insertion. Anal protrusion of a PD catheter in childhood is extremely rare and unrecorded in a pediatric patient with a connective tissue disorder. Our case highlights that serious complications can occur in the period between transplantation and elective PD catheter removal and that, in the immunocompromised patient, signs can be subtle. Copyright © 2017 International Society for Peritoneal Dialysis.

Disappearance of diffuse calcinosis following autologous stem cell transplantation in a child with autoimmune disease.

PubMed

Elhasid, R; Rowe, J M; Berkowitz, D; Ben-Arush, M; Bar-Shalom, R; Brik, R

2004-06-01

A 12-year-old girl presented with arthritis, myalgia, anemia and positive ANA. Subsequently, she developed recurrent episodes of pulmonary hemorrhage, thrombocytopenia, CNS abnormalities, skin ulcers and diffuse calcinosis. This was followed by secondary antiphospholipid syndrome. Despite vigorous immunosuppression, the patient became bedridden. A peripheral blood stem cell autograft was offered when she developed pulmonary hypertension and digital ischemia at the age of 16 years. The post-transplantation course was uneventful. Liquefaction of calcinosis nodules with improvement of mobility occurred gradually. She is now 24 months post-transplant with no sign of disease activity and total disappearance of calcinosis nodules.

Esophageal motor disease and reflux patterns in patients with advanced pulmonary disease undergoing lung transplant evaluation.

PubMed

Seccombe, J; Mirza, F; Hachem, R; Gyawali, C P

2013-08-01

Advanced pulmonary disorders are linked to esophageal hypomotility and reflux disease. However, characterization of esophageal function using high resolution manometry (HRM) and ambulatory pH monitoring, segregation by pulmonary pathology, and comparison to traditional reflux disease are all limited in the literature. Over a 4 year period, 73 patients (55.2 ± 1.3 years, 44F) were identified who underwent esophageal function testing as part of lung transplant evaluation for advanced pulmonary disease (interstitial lung disease, ILD = 47, obstructive lung disease, OLD = 24, other = 2). Proportions of patients with motor dysfunction (≥ 80% failed sequences = severe hypomotility) and/or abnormal reflux parameters (acid exposure time, AET ≥ 4%) were determined, and compared to a cohort of 1081 patients (48.4 ± 0.4 years, 613F) referred for esophageal function testing prior to antireflux surgery (ARS). The proportion of esophageal body hypomotility was significantly higher within advanced pulmonary disease categories (35.6%), particularly ILD (44.7%), compared to ARS patients (12.1%, P < 0.0001). Abnormal AET was noted in 56.5%, and was similar between ILD and OLD, but less frequent than in the ARS group (P = 0.04). Post-transplant chronic rejection trended towards association with pretransplant elevated AET in OLD (P = 0.08) but not ILD. Mortality was not predicted by esophageal motor pattern or reflux evidence. Interstitial lung disease has a highly significant association with esophageal body hypomotility. Consequently, prevalence of abnormal esophageal acid exposure is high, but implications for post lung transplant chronic rejection remain unclear. © 2013 John Wiley & Sons Ltd.

Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies

ClinicalTrials.gov

2018-04-24

SCID; Omenn's Syndrome; Reticular Dysgenesis; Wiskott-Aldrich Syndrome; Bare Lymphocyte Syndrome; Common Variable Immunodeficiency; Chronic Granulomatous Disease; CD40 Ligand Deficiency; Hyper IgM Syndrome; X-linked Lymphoproliferative Disease; Hemophagocytic Lymphohistiocytosis; Griscelli Syndrome; Chediak-Higashi Syndrome; Langerhan's Cell Histiocytosis

Immune responses in cecal tonsils of MDV-infected chickens

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a lymphoproliferative disease of domestic chickens that is caused by a highly cell-associated oncogenic '-herpesvirus, Marek’s disease virus (MDV). MDV replicates in chicken lymphocytes and establishes a latent infection within CD4+ T cells. Clinical signs of MD include dep...

Human NF-κB1 Haploinsufficiency and Epstein-Barr Virus-Induced Disease-Molecular Mechanisms and Consequences.

PubMed

Hoeger, Birgit; Serwas, Nina Kathrin; Boztug, Kaan

2017-01-01

Nuclear factor kappa-light-chain-enhancer of activated B cells 1 (NF-κB1)-related human primary immune deficiencies have initially been characterized as defining a subgroup of common variable immunodeficiencies (CVIDs), representing intrinsic B-cell disorders with antibody deficiency and recurrent infections of various kind. Recent evidence indicates that NF-κB1 haploinsufficiency underlies a variable type of combined immunodeficiency (CID) affecting both B and T lymphocyte compartments, with a broadened spectrum of disease manifestations, including Epstein-Barr virus (EBV)-induced lymphoproliferative disease and immediate life-threatening consequences. As part of this review series focused on EBV-related primary immunodeficiencies, we discuss the current clinical and molecular understanding of monoallelic NFKB1 germline mutations with special focus on the emerging context of EBV-associated disease. We outline mechanistic implications of dysfunctional NF-κB1 in B and T cells and discuss the fatal relation of impaired T-cell function with the inability to clear EBV infections. Finally, we compare common and suggested treatment angles in the context of this complex disease.

De novo glomerular diseases after renal transplantation: How is it different from recurrent glomerular diseases?

PubMed Central

Abbas, Fedaey; El Kossi, Mohsen; Jin, Jon Kim; Sharma, Ajay; Halawa, Ahmed

2017-01-01

The glomerular diseases after renal transplantation can occur de novo, i.e., with no relation to the native kidney disease, or more frequently occur as a recurrence of the original disease in the native kidney. There may not be any difference in clinical features and histological pattern between de novo glomerular disease and recurrence of original glomerular disease. However, structural alterations in transplanted kidney add to dilemma in diagnosis. These changes in architecture of histopathology can happen due to: (1) exposure to the immunosuppression specifically the calcineurin inhibitors (CNI); (2) in vascular and tubulointerstitial alterations as a result of antibody mediated or cell-mediated immunological onslaught; (3) post-transplant viral infections; (4) ischemia-reperfusion injury; and (5) hyperfiltration injury. The pathogenesis of the de novo glomerular diseases differs with each type. Stimulation of B-cell clones with subsequent production of the monoclonal IgG, particularly IgG3 subtype that has higher affinity to the negatively charged glomerular tissue, is suggested to be included in PGNMID pathogenesis. De novo membranous nephropathy can be seen after exposure to the cryptogenic podocyte antigens. The role of the toxic effects of CNI including tissue fibrosis and the hemodynamic alterations may be involved in the de novo FSGS pathophysiology. The well-known deleterious effects of HCV infection and its relation to MPGN disease are frequently reported. The new concepts have emerged that demonstrate the role of dysregulation of alternative complement pathway in evolution of MPGN that led to classifying into two subgroups, immune complex mediated MPGN and complement-mediated MPGN. The latter comprises of the dense deposit disease and the C3 GN disease. De novo C3 disease is rather rare. Prognosis of de novo diseases varies with each type and their management continues to be empirical to a large extent. PMID:29312858

Patterns of kidney injury in pediatric nonkidney solid organ transplant recipients.

PubMed

Williams, C; Borges, K; Banh, T; Vasilevska-Ristovska, J; Chanchlani, R; Ng, V L; Dipchand, A I; Solomon, M; Hebert, D; Kim, S J; Astor, B C; Parekh, R S

2018-06-01

The incidence of acute kidney injury (AKI) and its impact on chronic kidney disease (CKD) following pediatric nonkidney solid organ transplantation is unknown. We aimed to determine the incidence of AKI and CKD and examine their relationship among children who received a heart, lung, liver, or multiorgan transplant at the Hospital for Sick Children between 2002 and 2011. AKI was assessed in the first year posttransplant. Among 303 children, perioperative AKI (within the first week) occurred in 67% of children, and AKI after the first week occurred in 36%, with the highest incidence among lung and multiorgan recipients. Twenty-three children (8%) developed CKD after a median follow-up of 3.4 years. Less than 5 children developed end-stage renal disease, all within 65 days posttransplant. Those with 1 AKI episode by 3 months posttransplant had significantly greater risk for developing CKD after adjusting for age, sex, and estimated glomerular filtration rate at transplant (hazard ratio: 2.77, 95% confidence interval, 1.13-6.80, P trend = .008). AKI is common in the first year posttransplant and associated with significantly greater risk of developing CKD. Close monitoring for kidney disease may allow for earlier implementation of kidney-sparing strategies to decrease risk for progression to CKD. © 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.

Immune reconstitution after allogeneic hematopoietic stem cell transplantation in children: a single institution study of 59 patients.

PubMed

Kim, Hyun O; Oh, Hyun Jin; Lee, Jae Wook; Jang, Pil-Sang; Chung, Nack-Gyun; Cho, Bin; Kim, Hack-Ki

2013-01-01

Lymphocyte subset recovery is an important factor that determines the success of hematopoietic stem cell transplantation (HSCT). Temporal differences in the recovery of lymphocyte subsets and the factors influencing this recovery are important variables that affect a patient's post-transplant immune reconstitution, and therefore require investigation. The time taken to achieve lymphocyte subset recovery and the factors influencing this recovery were investigated in 59 children who had undergone HSCT at the Department of Pediatrics, The Catholic University of Korea Seoul St. Mary's Hospital, and who had an uneventful follow-up period of at least 1 year. Analyses were carried out at 3 and 12 months post-transplant. An additional study was performed 1 month post-transplant to evaluate natural killer (NK) cell recovery. The impact of pre- and post-transplant variables, including diagnosis of Epstein-Barr virus (EBV) DNAemia posttransplant, on lymphocyte recovery was evaluated. THE LYMPHOCYTE SUBSETS RECOVERED IN THE FOLLOWING ORDER: NK cells, cytotoxic T cells, B cells, and helper T cells. At 1 month post-transplant, acute graft-versus-host disease was found to contribute significantly to the delay of CD16(+)/56(+) cell recovery. Younger patients showed delayed recovery of both CD3(+)/CD8(+) and CD19(+) cells. EBV DNAemia had a deleterious impact on the recovery of both CD3(+) and CD3(+)/CD4(+) lymphocytes at 1 year post-transplant. In our pediatric allogeneic HSCT cohort, helper T cells were the last subset to recover. Younger age and EBV DNAemia had a negative impact on the post-transplant recovery of T cells and B cells.

Proposed categorization of pathological states of EBV-associated T/natural killer-cell lymphoproliferative disorder (LPD) in children and young adults: overlap with chronic active EBV infection and infantile fulminant EBV T-LPD.

PubMed

Ohshima, Koichi; Kimura, Hiroshi; Yoshino, Tadashi; Kim, Chul Woo; Ko, Young H; Lee, Seung-Suk; Peh, Suat-Cheng; Chan, John K C

2008-04-01

EBV-associated T/natural killer (NK)-cell lymphoproliferative disorder (EBV-T/NK LPD) of children and young adults is generally referred to with the blanket nosological term of severe chronic active EBV infection (CAEBV). This disease is rare, associated with high morbidity and mortality, and appears to be more prevalent in East Asian countries. But because there is no grading or categorization system for CAEBV, pathologists and clinicians often disagree regarding diagnosis and therapy. EBV-T/NK LPD includes polyclonal, oligoclonal, and monoclonal proliferation of cytotoxic T and/or NK cells. Moreover, a unique disease previously described as infantile fulminant EBV-associated T-LPD has been identified and overlaps with EBV-T/NK LPD. In the present review a clinicopathological categorization of EBV-T/NK LPD is proposed, based on pathological evaluation and molecular data, as follows: (i) category A1, polymorphic LPD without clonal proliferation of EBV-infected cells; (ii) category A2, polymorphic LPD with clonality; (iii) category A3, monomorphic LPD (T-cell or NK cell lymphoma/leukemia) with clonality; and (iv) category B, monomorphic LPD (T-cell lymphoma) with clonality and fulminant course. Categories A1, A2, and A3 possibly constitute a continuous spectrum and together are equivalent to CAEBV. Category B is the exact equivalent of infantile fulminant EBV-associated T-LPD. It is expected that this categorization system will provide a guide for the better understanding of this disorder. This proposal was approved at the third meeting of the Asian Hematopathology Association (Nagoya, 2006).

PD-1 /PD-L1 checkpoint in hematological malignancies.

PubMed

Annibali, O; Crescenzi, A; Tomarchio, V; Pagano, A; Bianchi, A; Grifoni, A; Avvisati, G

2018-04-01

Programmed cell death protein 1 (PD-1), is a cell surface receptor with an important role in down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. PD-1/PDL1 axis represents a checkpoint to control immune responses and it is often used as a mechanism of immune escaping by cancers and infectious diseases. Many data demonstrate its important role in solid tumors and report emerging evidences in lymphoproliferative disorders. In this review, we summarized the available data on the role of PD-1/PD-L1 checkpoint in lymphoproliferative diseases and the therapeutics use of monoclonal blocking antibodies. Copyright © 2018 Elsevier Ltd. All rights reserved.

A new data-driven model for post-transplant antibody dynamics in high risk kidney transplantation.

PubMed

Zhang, Yan; Briggs, David; Lowe, David; Mitchell, Daniel; Daga, Sunil; Krishnan, Nithya; Higgins, Robert; Khovanova, Natasha

2017-02-01

The dynamics of donor specific human leukocyte antigen antibodies during early stage after kidney transplantation are of great clinical interest as these antibodies are considered to be associated with short and long term clinical outcomes. The limited number of antibody time series and their diverse patterns have made the task of modelling difficult. Focusing on one typical post-transplant dynamic pattern with rapid falls and stable settling levels, a novel data-driven model has been developed for the first time. A variational Bayesian inference method has been applied to select the best model and learn its parameters for 39 time series from two groups of graft recipients, i.e. patients with and without acute antibody-mediated rejection (AMR) episodes. Linear and nonlinear dynamic models of different order were attempted to fit the time series, and the third order linear model provided the best description of the common features in both groups. Both deterministic and stochastic parameters are found to be significantly different in the AMR and no-AMR groups showing that the time series in the AMR group have significantly higher frequency of oscillations and faster dissipation rates. This research may potentially lead to better understanding of the immunological mechanisms involved in kidney transplantation. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

A novel risk score for mortality in renal transplant recipients beyond the first posttransplant year.

PubMed

Hernández, Domingo; Sánchez-Fructuoso, Ana; González-Posada, José Manuel; Arias, Manuel; Campistol, Josep María; Rufino, Margarita; Morales, José María; Moreso, Francesc; Pérez, Germán; Torres, Armando; Serón, Daniel

2009-09-27

All-cause mortality is high after kidney transplantation (KT), but no prognostic index has focused on predicting mortality in KT using baseline and emergent comorbidity after KT. A total of 4928 KT recipients were used to derive a risk score predicting mortality. Patients were randomly assigned to two groups: a modeling population (n=2452), used to create a new index, and a testing population (n=2476), used to test this index. Multivariate Cox regression model coefficients of baseline (age, weight, time on dialysis, diabetes, hepatitis C, and delayed graft function) and emergent comorbidity within the first posttransplant year (diabetes, proteinuria, renal function, and immunosuppressants) were used to weigh each variable in the calculation of the score and allocated into risk quartiles. The probability of death at 3 years, estimated by baseline cumulative hazard function from the Cox model [P (death)=1-0.993592764 (exp(score/100)], increased from 0.9% in the lowest-risk quartile (score=40) to 4.7% in the highest risk-quartile (score=200). The observed incidence of death increased with increasing risk quartiles in testing population (log-rank analysis, P<0.0001). The overall C-index was 0.75 (95% confidence interval: 0.72-0.78) and 0.74 (95% confidence interval: 0.70-0.77) in both populations, respectively. This new index is an accurate tool to identify high-risk patients for mortality after KT.

Donor-Specific Anti-HLA Antibodies in Huntington's Disease Recipients of Human Fetal Striatal Grafts.

PubMed

Porfirio, Berardino; Paganini, Marco; Mazzanti, Benedetta; Bagnoli, Silvia; Bucciantini, Sandra; Ghelli, Elena; Nacmias, Benedetta; Putignano, Anna Laura; Rombolà, Giovanni; Saccardi, Riccardo; Lombardini, Letizia; Di Lorenzo, Nicola; Vannelli, Gabriella B; Gallina, Pasquale

2015-01-01

Fetal grafting in a human diseased brain was thought to be less immunogenic than other solid organ transplants, hence the minor impact on the efficacy of the transplant. How much prophylactic immune protection is required for neural allotransplantation is also debated. High-sensitive anti-HLA antibody screening in this field has never been reported. Sixteen patients with Huntington's disease underwent human fetal striatal transplantation in the frame of an open-label observational trial, which is being carried out at Florence University. All patients had both brain hemispheres grafted in two separate robotic-stereotactic procedures. The trial started in February 2006 with the first graft to the first patient (R1). R16 was given his second graft on March 2011. All patients received triple immunosuppressive treatment. Pre- and posttransplant sera were analyzed for the presence of anti-HLA antibodies using the multiplexed microsphere-based suspension array Luminex xMAP technology. Median follow-up was 38.5 months (range 13-85). Six patients developed anti-HLA antibodies, which turned out to be donor specific. Alloimmunization occurred in a time window of 0-49 months after the first neurosurgical procedure. The immunogenic determinants were non-self-epitopes from mismatched HLA antigens. These determinants were both public epitopes shared by two or more HLA molecules and private epitopes unique to individual HLA molecules. One patient had non-donor-specific anti-HLA antibodies in her pretransplant serum sample, possibly due to previous sensitization events. Although the clinical significance of donor-specific antibodies is far from being established, particularly in the setting of neuronal transplantation, these findings underline the need of careful pre- and posttransplant immunogenetic evaluation of patients with intracerebral grafts.

Multicentric Castleman's disease in human immunodeficiency virus infection: two case reports.

PubMed

Caroline Ribeiro Sales, Amanda; Romão de Souza Junior, Valter; Iglis de Oliveira, Marta; Azevedo Braga Albuquerque, Claudia; de Barros Campelo Júnior, Evônio; Sérgio Ramos de Araújo, Paulo

2018-05-05

Castleman's Disease is a rare B-cell lymphoproliferative disease. It is mostly benign and is characterized by non-neoplastic lymph node hypertrophy, associated with infection by human herpesvirus-8 in people with the human immunodeficiency virus/acquired immunodeficiency syndrome. Although the unicentric or localized form presents as benign, the multifocal form can manifest severe systemic symptoms. We report two unusual cases of men presenting cervical enlarged lymph nodes that were believed to be infectious. The first case is a 41-year-old feoderm man who presented to the Department of Infectious Diseases of the Hospital das Clínicas in May 2015, with irregular fever history (38-39 °C), dyspnea, weight loss (8 kg/1 year), and asthenia with increased cervical lymph nodes of 1-year duration. His immunohistochemical diagnosis presented Castleman's disease in plasmacytic/diffuse form. In the second case, a 35-year-old feoderm man presented at the same hospital with multiple cervical enlarged lymph nodes and histopathological evidence of Castleman's disease associated with human herpesvirus-8. Considering the importance of differential diagnosis of lymphoid disorders, Castleman's disease is a challenging diagnosis in people living with human immunodeficiency virus/acquired immunodeficiency syndrome and can be easily misdiagnosed when lymphoid disorders are present in the human immunodeficiency virus/acquired immunodeficiency syndrome population due to nonspecific symptoms and signs.

Belatacept-based, ATG-Fresenius-induction regimen for kidney transplant recipients: a proof-of-concept study.

PubMed

Cicora, Federico; Mos, Fernando; Petroni, Jorgelina; Casanova, Matías; Reniero, Liliana; Roberti, Javier

2015-01-01

Belatacept provides effective immunosuppression while avoiding the nephrotoxicities associated with calcineurin inhibitors (CNIs). However, existing belatacept-based regimens still have high rates of acute rejection. We hypothesized that therapy with belatacept, mycophenolic acid (MMA), steroids and induction therapy with rabbit anti-thymocyte globulin Fresenius (ATGF), rejection rate could be reduced. Prospective, single center, proof-of-concept study including males and females aged ≥18years, Epstein-Barr virus (EBV)-seropositive recipients of a first, HLA non-identical, live or deceased donor kidney allograft. Only patients with a calculated panel reactive antibody score of 0% were included. Three donors were positive for Chagas disease. Six of twelve patients had at least one infection and five were readmitted to the hospital for treatment. One patient had a Trypanosoma cruzi infection via the graft treated successfully. Median cold ischemia time for the transplant patients with a deceased donor was 21.5h. Mean serum creatinine levels at 1, 3 and 6months were 1.76±0.59, 1.55±0.60 and 1.49±0.60mg/dl, respectively. Two of twelve patients experienced clinical, biopsy-proven rejection, successfully treated with methylprednisolone. No patient developed post-transplant lymphoproliferative disorder (PTLD) or any other malignancy and no patient lost their graft or died during follow-up. The potential of this approach makes it worthy of further investigation. Copyright © 2014 Elsevier B.V. All rights reserved.

Advantage of Rapamycin Over Mycophenolate Mofetil When Used With Tacrolimus for Simultaneous Pancreas Kidney Transplants: Randomized, Single-Center Trial at 10 Years

PubMed Central

Ciancio, G.; Sageshima, J.; Chen, L.; Gaynor, J. J.; Hanson, L.; Tueros, L.; Montenora-Velarde, E.; Gomez, C.; Kupin, W.; Guerra, G.; Mattiazzi, A.; Fornoni, A.; Pugliese, A.; Roth, D.; Wolf, M.; Burke, G. W.

2015-01-01

Simultaneous pancreas kidney transplantation (SPKT) is the treatment of choice for patients with type 1 diabetes and end-stage renal disease. Rapamycin and mycophenolate mofetil (MMF) have been used for maintenance immunosuppression with tacrolimus in SPKT; however, long-term outcomes are lacking. From September 2000 through December 2009, 170 SPKT recipients were enrolled in a randomized, prospective trial receiving Rapamycin (n = 84) or MMF (n = 86). All patients received dual induction therapy with thymoglobulin and daclizumab, and low-dose maintenance tacrolimus and corticosteroids. Compared to MMF, rates of freedom from first biopsy-proven acute kidney or pancreas rejection were superior for Rapamycin at year 1 (kidney: 100% vs. 88%; P = 0.001; pancreas: 99% vs. 92%; P = 0.04) and at year 10 (kidney: 88% vs. 71%, P = 0.01; pancreas: 99% vs. 89%, P = 0.01). The higher rates of rejection were associated with withholding MMF (vs. Rapamycin, p = 0.009), generally for gastrointestinal or bone marrow toxicity. There was no significant difference in creatinine, proteinuria, c-peptide, viral infections, lymphoproliferative disorders or posttransplant diabetes. HbA1C and lipid levels were normal in both groups, although higher in the Rapamycin arm. There were no significant differences in patient or allograft survival. In this 10-year SPKT study, Rapamycin in combination with tacrolimus was better tolerated and more effective than MMF. Overall, the patient and allograft survival were equivalent. PMID:22946986

End-stage kidney disease due to Alport syndrome: outcomes in 296 consecutive Australia and New Zealand Dialysis and Transplant Registry cases.

PubMed

Mallett, Andrew; Tang, Wen; Clayton, Philip A; Stevenson, Sarah; McDonald, Stephen P; Hawley, Carmel M; Badve, Sunil V; Boudville, Neil; Brown, Fiona G; Campbell, Scott B; Johnson, David W

2014-12-01

Alport syndrome is a rare inheritable renal disease. Clinical outcomes for patients progressing to end-stage kidney disease (ESKD) are not well described. This study aimed to investigate the characteristics and clinical outcomes of patients from Australia and New Zealand commencing renal replacement therapy (RRT) for ESKD due to Alport syndrome between 1965 and 1995 (early cohort) and between 1996 and 2010 (contemporary cohort) compared with propensity score-matched, RRT-treated, non-Alport ESKD controls. A total of 58 422 patients started RRT during this period of which 296 (0.5%) patients had Alport ESKD. In the early cohort, Alport ESKD was associated with superior dialysis patient survival [adjusted hazard ratio (HR): 0.41, 95% confidence interval (CI): 0.20-0.83, P = 0.01], renal allograft survival (HR: 0.74, 95% CI: 0.54-1.01, P = 0.05) and renal transplant patient survival (HR: 0.43, 95% CI: 0.28-0.66, P < 0.001) compared with controls. In the contemporary cohort, no differences were observed between the two groups for dialysis patient survival (HR: 1.42, 95% CI: 0.65-3.11, P = 0.38), renal allograft survival (HR: 1.01, 95% CI: 0.57-1.79, P = 0.98) or renal transplant patient survival (HR: 0.67, 95% CI: 0.26-1.73, P = 0.41). One Alport patient (0.4%) had post-transplant anti-glomerular basement membrane (anti-GBM) disease. Four female and 41 male Alport patients became parents on RRT with generally good neonatal outcomes. Alport syndrome patients experienced comparable dialysis and renal transplant outcomes to matched non-Alport ESKD controls in the contemporary cohort due to relatively greater improvements in outcomes for non-Alport ESKD patients over time. Post-transplant anti-GBM disease was rare. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Risk of intestinal lymphoma in undiagnosed coeliac disease: results from a registered population with different coeliac disease prevalence.

PubMed

Elli, Luca; Contiero, Paolo; Tagliabue, Giovanna; Tomba, Carolina; Bardella, Maria Teresa

2012-09-01

Coeliac disease is often undiagnosed, early diagnosis and treatment could be relevant to avoid fearful complications as intestinal lymphoma. Our aim is to estimate the risk of intestinal lymphoma in undiagnosed coeliac patients, evaluating the real incidences and applying different theoretical settings of coeliac prevalence. We collected cases of intestinal lymphomas from the Lombardy Cancer Registry and coeliac patients through computerized search of all Pathology Departments; duodenal pathological reports compatible with a Marsh 3 grade were included. The lymphoproliferative risk was calculated for theoretical different settings of coeliac prevalence (from 1:50 to 1:200), relative risks for intestinal lymphomas and compared to the real incidence of the lymphomas in this population. Population consisted in 815,362 inhabitants; during the investigated period of time, 237 intestinal lymphomas and 326 coeliac patients were diagnosed. None of the coeliac patients had lymphoma. In the different scenarios calculated and compared with the real lymphoma incidence the relative risks of undiagnosed celiac disease for gastrointestinal B- and T-cell lymphomas ranges from 1.0 to 2.0 for 1:100 coeliac disease prevalence. Undiagnosed coeliac patients have no increased risk of developing intestinal lymphoma; population screening programmes, aimed at early diagnosis of lymphoma may not be useful in this setting. Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Ex vivo administration of trimetazidine improves post-transplant lung function in pig model.

PubMed

Cosgun, Tugba; Iskender, Ilker; Yamada, Yoshito; Arni, Stephan; Lipiski, Miriam; van Tilburg, Koen; Weder, Walter; Inci, Ilhan

2017-07-01

Ex vivo lung perfusion (EVLP) is not only used to assess marginal donor lungs but is also used as a platform to deliver therapeutic agents outside the body. We previously showed the beneficial effects of trimetazidine (TMZ) on ischaemia reperfusion (IR) injury in a rat model. This study evaluated the effects of TMZ in a pig EVLP transplant model. Pig lungs were retrieved and stored for 24 h at 4°C, followed by 4 h of EVLP. Allografts were randomly allocated to 2 groups ( n  = 5 each). TMZ (5 mg/kg) was added to the prime solution prior to EVLP. After EVLP, left lungs were transplanted and recipients were observed for 4 h. Allograft gas exchange function and lung mechanics were recorded hourly throughout reperfusion. Microscopic lung injury and inflammatory and biochemical parameters were assessed. There was a trend towards better oxygenation during EVLP in the TMZ group ( P  = 0.06). After transplantation, pulmonary gas exchange was significantly better during the 4-h reperfusion period and after isolation of the allografts for 10 min ( P  < 0.05). Tissue thiobarbituric acid levels, myeloperoxidase activity and protein concentrations in bronchoalveolar lavage samples were significantly lower in the TMZ group at the end of EVLP ( P  < 0.05). Ex vivo treatment of donor lungs with TMZ significantly improved immediate post-transplant lung function. Further studies are warranted to understand the effect of this strategy on long-term lung function. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Usefullness of IGH/TCR PCR studies in lymphoproliferative disorders with inconclusive clonality by flow cytometry.

PubMed

Ribera, Jordi; Zamora, Lurdes; Juncà, Jordi; Rodríguez, Inés; Marcé, Silvia; Cabezón, Marta; Millá, Fuensanta

2013-07-25

In up to 5-15% of studies of lymphoproliferative disorders (LPD) flow cytometry (FCM) or immunomorphologic methods cannot discriminate malignant from reactive processes. The aim of this work was to determine the usefulness of PCR for solving these diagnostic uncertainties. We analyzed IGH and TCRγ genes by PCR in 106 samples with inconclusive FCM results. A clonal result was registered in 36/106 studies, with a LPD being confirmed in 27 (75%) of these cases. Specifically, 9/9 IGH clonal and 16/25 TCRγ clonal results were finally diagnosed with LPD. Additionally, 2 clonal TCRγ samples with suspicion of undefined LPD were finally diagnosed with T LPD. Although polyclonal results were obtained in 47 of the cases studied (38 IGH and 9 TCRγ), hematologic neoplasms were diagnosed in 4/38 IGH polyclonal and in 1/9 TCRγ polyclonal studies. There were also 14 PCR polyclonal results (4 IGH, 10 TCRγ), albeit non-conclusive. Of these, 2/4 were eventually diagnosed with B-cell lymphoma and 3/10 with T-cell LPD. In 8 IGH samples the results of PCR techniques were non-informative but in 3/8 cases a B lymphoma was finally confirmed. We concluded that PCR is a useful technique to identify LPD when FCM is inconclusive. A PCR clonal B result is indicative of malignancy but IGH polyclonal and non-conclusive results do not exclude lymphoid neoplasms. Interpretation of T-cell clonality should be based on all the available clinical and analytical data. © 2013 Clinical Cytometry Society. Copyright © 2013 Clinical Cytometry Society.

Administration of Donor T Cells With the Caspase-9 Suicide Gene

ClinicalTrials.gov

2017-10-02

Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome; Acute Myeloid Leukemia; Chronic Myelogenous Leukemia; Non Hodgkin Lymphoma; Hemophagocytic Lymphohistiocytosis; Familial Hemophagocytic Lymphohistiocytosis; Hemophagocytic Syndrome; Epstein Barr Virus Infection; X-linked Lymphoproliferative Disease

Current Expectations for Cardiac Transplantation in Patients With Congenital Heart Disease.

PubMed

Kirklin, James K; Carlo, Waldemar F; Pearce, F Bennett

2016-11-01

Congenital heart disease accounts for 40% of pediatric heart transplants and presents unique challenges to the transplant team. Suitability for transplantation is defined in part by degree of sensitization, pulmonary vascular resistance, and hepatic reserves. The incremental transplant risk for patients with congenital heart disease occurs within the first 3 months, after which survival is equivalent to transplantation for cardiomyopathy. Single ventricle with prior palliation, and especially the failing Fontan, carry the highest risk for transplantation and are least amenable to bridging with mechanical circulatory support. More effective bridging to transplant with mechanical circulatory support will require improvements in the adverse event profile of available pumps and the introduction of miniaturized continuous flow technology. The major barriers to routine long-term survival are chronic allograft failure and allograft vasculopathy. Despite these many challenges, continuing improvements in the care of pediatric heart transplant patients have pushed the median posttransplant survival past 15 years for children and to 20 years for infants. © The Author(s) 2016.

Microbiota Manipulation With Prebiotics and Probiotics in Patients Undergoing Stem Cell Transplantation

PubMed Central

Andermann, Tessa M.; Rezvani, Andrew; Bhatt, Ami S.

2016-01-01

Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy that often comes at the cost of complications such as graft-versus-host disease and post-transplant infections. With improved technology to under-stand the ecosystem of microorganisms (viruses, bacteria, fungi, and microeukaryotes) that make up the gut microbiota, there is increasing evidence of the microbiota’s contribution to the development of post-transplant complications. Antibiotics have traditionally been the mainstay of microbiota-altering therapies available to physicians. Recently, interest is increasing in the use of prebiotics and probiotics to support the development and sustainability of a healthier microbiota. In this review, we will describe the evidence for the use of prebiotics and probiotics in combating microbiota dysbiosis and explore the ways in which they may be used in future research to potentially improve clinical outcomes and decrease rates of graft-versus-host disease (GVHD) and post-transplant infection. PMID:26780719

Impact of the pretransplant dialysis modality on kidney transplantation outcomes: a nationwide cohort study.

PubMed

Lin, Huan-Tang; Liu, Fu-Chao; Lin, Jr-Rung; Pang, See-Tong; Yu, Huang-Ping

2018-06-04

Most patients with uraemia must undergo chronic dialysis while awaiting kidney transplantation; however, the role of the pretransplant dialysis modality on the outcomes of kidney transplantation remains obscure. The objective of this study was to clarify the associations between the pretransplant dialysis modality, namely haemodialysis (HD) or peritoneal dialysis (PD), and the development of post-transplant de novo diseases, allograft failure and all-cause mortality for kidney-transplant recipients. Retrospective nationwide cohort study. Data retrieved from the Taiwan National Health Insurance Research Database. The National Health Insurance database was explored for patients who received kidney transplantation in Taiwan during 1998-2011 and underwent dialysis >90 days before transplantation. The pretransplant characteristics, complications during kidney transplantation and post-transplant outcomes were statistically analysed and compared between the HD and PD groups. Cox regression analysis was used to evaluate the HR of the dialysis modality on graft failure and all-cause mortality. The primary outcomes were long-term post-transplant death-censored allograft failure and all-cause mortality started after 90 days of kidney transplantation until the end of follow-up. The secondary outcomes were events during kidney transplantation and post-transplant de novo diseases adjusted by propensity score in log-binomial model. There were 1812 patients included in our cohort, among which 1209 (66.7%) and 603 (33.3%) recipients received pretransplant HD and PD, respectively. Recipients with chronic HD were generally older and male, had higher risks of developing post-transplant de novo ischaemic heart disease, tuberculosis and hepatitis C after adjustment. Pretransplant HD contributed to higher graft failure in the multivariate analysis (HR 1.38, p<0.05) after adjustment for the recipient age, sex, duration of dialysis and pretransplant diseases. There was no significant

Feasibility and Outcome of Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant High-Dose Cyclophosphamide for Children and Adolescents with Hematologic Malignancies: An AIEOP-GITMO Retrospective Multicenter Study.

PubMed

Berger, Massimo; Lanino, Edoardo; Cesaro, Simone; Zecca, Marco; Vassallo, Elena; Faraci, Maura; De Bortoli, Massimiliano; Barat, Veronica; Prete, Arcangelo; Fagioli, Franca

2016-05-01

Post-transplant high-dose cyclophosphamide (PTCy) is a novel approach to prevent graft-versus-host disease (GVHD) and rejection in patients given haploidentical hematopoietic stem cell transplantation (HSCT). Thirty-three patients with high-risk hematologic malignancies and lacking a match-related or -unrelated donor were treated with PTCy haploidentical HSCT in 5 Italian AIEOP centers. Nineteen patients had a nonmyeloablative preparative regimen (57%), and 14 patients received a full myeloablative conditioning regimen (43%). No patients received serotherapy; GVHD prophylaxis was based on PTCy (50 mg/kg on days +3 and +4) combined with mycophenolate plus tacrolimus or cyclosporine A. Neutrophil and platelet engraftment was achieved on days +17 (range, 14 to 37) and +27 (range, 16 to 71). One patient had autologous reconstitution for anti-HLA antibodies. Acute GVHD grades II to IV and III to IV and chronic GVHD developed in 22% (95% CI, 11 to 42), 3% (95% CI, 0 to 21), and 4% (95% CI, 0 to 27) of cases, respectively. The 1-year overall survival rate was 72% (95% CI, 56 to 88), progression-free survival rate was 61% (95% CI, 43 to 80), cumulative incidence of relapse was 24% (95% CI, 13 to 44), and transplant-related mortality was 9% (95% CI, 3 to 26). The univariate analysis for risk of relapse incidence showed how 3 significant variables, mother as donor (P = .02), donor gender as female (P = .04), and patient gender as female (P = .02), were significantly associated with a lower risk of relapse. Disease progression was the main cause of death. PTCy is a safe procedure also for children and adolescents who have already received several lines of chemotherapy. Among the different diseases, a trend for better 1-year rates of overall survival was obtained for nonacute leukemia patients. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

T Cell Depletion for Recipients of HLA Haploidentical Related Donor Stem Cell Grafts

ClinicalTrials.gov

2017-08-29

Acute Lymphoblastic Leukemia; Non Hodgkins Lymphoma; Myelodysplastic Syndrome; Acute Myeloid Leukemia; Chronic Myelogenous Leukemia; Hemophagocytic Lymphohistiocytosis (HLH); Familial Hemophagocytic Lymphohistiocytosis (FLH); Viral-associated Hemophagocytic Syndrome (VAHS); X-linked Lymphoproliferative Disease (XLP)

Reconstruction of the immune system after unrelated or partially matched T-cell-depleted bone marrow transplantation in children: immunophenotypic analysis and factors affecting the speed of recovery.

PubMed

Kook, H; Goldman, F; Padley, D; Giller, R; Rumelhart, S; Holida, M; Lee, N; Peters, C; Comito, M; Huling, D; Trigg, M

1996-08-01

We prospectively studied immune reconstitution in 102 children who underwent T-lymphocyte depleted bone marrow transplants using either closely matched unrelated donors or partially matched familial donors by assaying total lymphocyte counts (TLC), T-cell subsets, B cells, and natural killer cells. TLC, CD3+, and CD4+ T-cell counts remained depressed until 2 to 3 years posttransplant, whereas CD8+ T-cell counts normalized by 18 months, resulting in an inverted CD4:CD8 ratio until 12 months posttransplant. Although the percentage of NK cells was elevated early posttransplant, their absolute numbers remained normal. CD20+ B cells were depressed until 12 to 18 months posttransplant. Factors affecting immunophenotypic recovery were analyzed by nonparametric statistics. Younger patients tended to have higher TLC posttransplant. Higher marrow cell doses were not associated with hastened immunophenotypic recovery. Graft-versus-host disease (GVHD) and/or its treatment significantly delayed the immune reconstitution of CD3+, CD4+, and CD20+ cells. The presence of cytomegalovirus was associated with increased CD8+ counts and a decrease in the percentages of CD4+ and CD20+ cells.

Cytogenetics in the management of lymphomas and lymphoproliferative disorders in adults and children: an update by the Groupe francophone de cytogénétique hématologique (GFCH).

PubMed

Lefebvre, Christine; Callet-Bauchu, Evelyne; Chapiro, Elise; Nadal, Nathalie; Penther, Dominique; Poirel, Hélène-Antoine

2016-10-01

Non-Hodgkin's lymphomas and lymphoproliferative disorders include a high number of heterogeneous entities, described in the 2008 WHO classification. This classification reflects the crucial role of a multidisciplinary approach which integrates cytogenetic results both for the notion of clonality and for differential diagnosis between these entities. The prognostic impact of some cytogenetic abnormalities or genome complexity is also confirmed for many of these entities. Novel provisional entities have been described, such as BCLU (B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma) for which karyotype is critical to distinguish BCLU from Burkitt's lymphoma. The karyotype can be established from any tumour or liquid infiltrated by lymphoma cells. Recent adaptations of technics for cellular cultures according to the subtype of known (or suspected) lymphoma have significantly improved the percentage of informative karyotypes. Conventional karyotypes remain the best technical approach recommended for most of these subtypes. Interphase and/or metaphase FISH also represents a solid and rapid approach, because of the significant number of recurrent (sometimes specific) rearrangements of these entities. Next generation sequencing technologies contribute to enrich genomic data and substantially improve the understanding of oncogenic mechanisms underlying these lymphoid malignancies. Some molecular biomarkers are already part of the diagnostic process (for example, somatic mutation of MYD88 in Waldenström disease) thus reinforcing the essential principle of a multidisciplinary approach for the diagnosis of all the mature lymphoid malignancies.

Construction of a YAC contig and STS map spanning 2.5 Mbp in Xq25, the critical region for the X-linked lymphoproliferative (XLP) gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lanyi, A.; Li, B.F.; Li, S.

1994-09-01

X-linked lymphoproliferative disease (XLP) is characterized by a marked vulnerability in Epstein-Barr virus (EBV) infection. Infection of XLP patients with EBV invariably results in fatal mononucleosis, agammaglobulinemia or B-cell lymphoma. The XLP gene lies within a 10 cM region in Xq25 between DXS42 and DXS10. Initial chromosome studies revealed an interstitial, cytogenetically visible deletion in Xq25 in one XLP family (43-004). We estimated the size of the Xq25 deletion by dual laser flow karyotyping to involve 2% of the X chromosome, or approximately 3 Mbp of DNA sequences. To further delineate the deletion we performed a series of pulsed fieldmore » gel electrophoresis (PFGE) analyses which showed that DXS6 and DXS100, two Xq25-specific markers, are missing from 45-004 DNA. Five yeast artificial chromosomes (YACs) from a chromosome X specific YAC library containing sequences deleted in patient`s 43-004 DNA were isolated. These five YACs did not overlap, and their end fragments were used to screen the CEPH MegaYAC library. Seven YACs were isolated from the CEPH MegaYAC library. They could be arranged into a contig which spans between DXS6 and DXS100. The contig contains a minimum of 2.5 Mbp of human DNA. A total of 12 YAC end clone, lambda subclones and STS probes have been used to order clones within the contig. These reagents were also used in Southern blot and patients showed interstitial deletions in Xq25. The size of these deletions range between 0.5 and 2.5 Mbp. The shortest deletion probably represents the critical region for the XLP gene.« less

CMV retinitis recurs after stopping treatment in virological and immunological failures of potent antiretroviral therapy.

PubMed

Torriani, F J; Freeman, W R; Macdonald, J C; Karavellas, M P; Durand, D M; Jeffrey, D D; Meylan, P R; Schrier, R D

2000-01-28

To determine predictors of clinical relapse of cytomegalovirus (CMV) end-organ disease in a cohort of 17 HIV-infected patients with healed and treated CMV retinitis (CMVR) who responded to HAART with an increase in CD4 cell counts to above 70 cells/mm3 and discontinued CMV maintenance therapy (MT). Seventeen patients were monitored for reactivation of retinitis. The CD4 cell counts, HIV RNA and peripheral blood mononuclear cell (PBMC) lymphoproliferative assays to CMV at 3 month intervals were compared between patients with and without reactivation of CMVR. Positive lymphoproliferative responses were defined as a stimulation index of 3 or greater. Five out of 17 (29%) patients experienced a recurrence of CMVR a mean of 14.5 months after stopping CMV MT and between 8 days and 10 months after CD4 cell counts fell below 50 cells/mm3. Median CD4 cell counts and plasma HIV RNA at reactivation were 37 cells/mm3 and 5.3 log10 copies/ml. Three patients recurred at a previously active site of the retina, one had contralateral CMVR, and one a recurrence of retinitis and pancreatitis simultaneously. Mean lymphoproliferative responses to CMV were 2.4 in patients with reactivation versus 21.0 stimulation index (SI) in patients without reactivation (P= 0.01). A model incorporating four variables (CD4 cell counts and HIV RNA at maintenance discontinuation, highest CD4 cell count, nadir HIV RNA and median lymphoproliferative responses) identified correctly 88% of patients with and without reactivation. CMV disease recurs after virological and immunological failure of HAART if CD4 cell counts drop below 50. In this situation, anti-CMV agents should be resumed before clinical reactivation ensues, because of the risk of contralateral retinal involvement and systemic disease.

Autoimmune lymphoproliferative syndrome and non-Hodgkin lymphoma: what 18F-fluorodeoxyglucose positron emission tomography/computed tomography can do in the management of these patients? Suggestions from a case report.

PubMed

Cistaro, A; Pazè, F; Durando, S; Cogoni, M; Faletti, R; Vesco, S; Vallero, S; Quartuccio, N; Treglia, G; Ramenghi, U

2014-01-01

A young patient with undefined autoimmune lymphoproliferative syndrome (ALPS-U) and low back pain underwent a CT and MRI study that showed enhancing vertebral lesions, some pulmonary nodules and diffuse latero-cervical lymphadenopathy. A (18)F-FDG-PET/CT scan showed many areas of intense (18)F-FDG uptake in multiple vertebrae, in some ribs, in the sacrum, in the liver, in both lungs, in multiple lymph nodes spread in the cervical, thoracic and abdominal chains. A bone marrow biopsy showed a "lymphomatoid granulomatosis", a rare variant of B-cell non-Hodgkin lymphoma (NHL). After the treatment, the (18)F-FDG-PET/CT scan showed a complete metabolic response. Copyright © 2013 Elsevier España, S.L. and SEMNIM. All rights reserved.

Pre- and post-transplant minimal residual disease predicts relapse occurrence in children with acute lymphoblastic leukaemia.

PubMed

Lovisa, Federica; Zecca, Marco; Rossi, Bartolomeo; Campeggio, Mimma; Magrin, Elisa; Giarin, Emanuela; Buldini, Barbara; Songia, Simona; Cazzaniga, Giovanni; Mina, Tommaso; Acquafredda, Gloria; Quarello, Paola; Locatelli, Franco; Fagioli, Franca; Basso, Giuseppe

2018-03-01

Relapse remains the leading cause of treatment failure in children with acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively investigated the prognostic role of minimal residual disease (MRD) before and after HSCT in 119 children transplanted in complete remission (CR). MRD was measured by polymerase chain reaction in bone marrow samples collected pre-HSCT and during the first and third trimesters after HSCT (post-HSCT1 and post-HSCT3). The overall event-free survival (EFS) was 50%. The cumulative incidence of relapse and non-relapse mortality was 41% and 9%. Any degree of detectable pre-HSCT MRD was associated with poor outcome: EFS was 39% and 18% in patients with MRD positivity <1 × 10 -3 and ≥1 × 10 -3 , respectively, versus 73% in MRD-negative patients (P < 0·001). This effect was maintained in different disease remissions, but low-level MRD had a very strong negative impact only in patients transplanted in second or further CR. Also, MRD after HSCT enabled patients to be stratified, with increasing MRD between post-HSCT1 and post-HSCT3 clearly defining cohorts with a different outcome. MRD is an important prognostic factor both before and after transplantation. Given that MRD persistence after HSCT is associated with dismal outcome, these patients could benefit from early discontinuation of immunosuppression, or pre-emptive immuno-therapy. © 2018 John Wiley & Sons Ltd.

Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies

ClinicalTrials.gov

2009-10-14

Immunologic Deficiency Syndromes; Chediak-Higashi Syndrome; Common Variable Immunodeficiency; Graft Versus Host Disease; X-Linked Lymphoproliferative Syndrome; Familial Erythrophagocytic Lymphohistiocytosis; Hemophagocytic Lymphohistiocytosis; X-linked Agammaglobulinemia; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; X-linked Hyper IgM Syndrome; Severe Combined Immunodeficiency; Leukocyte Adhesion Deficiency Syndrome; Virus-Associated Hemophagocytic Syndrome

Seroprevalence of cytomegalovirus in donors & opportunistic viral infections in liver transplant recipients.

PubMed

Varghese, Joy; Subramanian, S; Reddy, Mettu Srinivas; Shanmugam, Naresh; Balajee, G; Srinivasan, Vijaya; Venkataraman, Jayanthi; Mohamed, Rela

2017-04-01

Opportunistic virus infections are common in liver transplant (LT) recipients. There is a risk of developing infection with cytomegalovirus (CMV) and herpes-related viruses such as herpes simplex virus-1 and 2 (HSV-1 & 2), Epstein-Barr virus (EBV) and Varicella Zoster virus (VZV), reactivation of infection and recurrent infection. This study was conducted to determine CMV seropositivity in donors and its influence on LT recipients and seropositivity of CMV, HSV-1 and 2, EB viral capsid antigen (EBVCA) and VZV in LT recipients and their reactivation. Pre-transplant data for IgG and IgM for CMV (and donor), HSV-1 and -2, EB viral capsid antigen (VCA) and VZV were available for 153 recipients. All recipients were on ganciclovir or valganciclovir prophylaxis for three months after LT. For reactivation rates, findings of post-transplant CMV quantitative reverse transcription polymerase chain reaction (CMV qRT-PCR) assay were associated with pre-transplant serological profile. Of the 153 LT recipients, 131 were men (85.6%). The median age of LT was 46 yr (range 9 months-71 yr). Overall exposure to CMV was 71.8 per cent followed by EB VCA (61.4%) and VZV (49.6%). Susceptibility to both HSV-1 and -2 was high across all decades (P<0.001). Seropositivity of CMV in donor was 90.9 per cent (100 out of 110). Post-transplant CMV qRT- PCR was positive in 17 (26.6%; 3 in recipient negative) of 64 samples tested. qRT-PCR assay was positive in one out of four (25%) tested for HSV-1 and nine out of 19 (47.4%) tested for EBV. Two recipients tested for HSV-2 and one for VZV were negative. There were three deaths in recipients (D+ R+) who were also positive for CMV qRT PCR. There was one death due to HSV-1 pneumonia. One patient with EBV reactivation developed post-transplant lymphoproliferative disorder two years after transplant. Transplant recipient were at highest risk of acquiring HSV-1 and -2 more so for HSV-2. CMV exposure in transplant recipients and donors were very high and at

Orthotopic Liver Transplantation in High-Risk Patients

PubMed Central

Gayowski, Timothy; Marino, Ignazio R.; Singh, Nina; Doyle, Howard; Wagener, Marilyn; Fung, John J.; Starzl, Thomas E.

2010-01-01

Background One of the most controversial areas in patient selection and donor allocation is the high-risk patient. Risk factors for mortality and major infectious morbidity were prospectively analyzed in consecutive United States veterans undergoing liver transplantation under primary tacrolimus-based immunosuppression. Methods Twenty-eight pre-liver transplant, operative, and posttransplant risk factors were examined univariately and multivariately in 140 consecutive liver transplants in 130 veterans (98% male; mean age, 47.3 years). Results Eighty-two percent of the patients had post-necrotic cirrhosis due to viral hepatitis or ethanol (20% ethanol alone), and only 12% had cholestatic liver disease. Ninety-eight percent of the patients were hospitalized at the time of transplantation (66% United Network for Organ Sharing [UNOS] 2, 32% UNOS 1). Major bacterial infection, posttransplant dialysis, additional immunosuppression, readmission to intensive care unit (P=0.0001 for all), major fungal infection, posttransplant abdominal surgery, posttransplant intensive care unit stay length of stay (P<0.005 for all), donor age, pretransplant dialysis, and creatinine (P<0.05 for all) were significantly associated with mortality by univariate analysis. Underlying liver disease, cytomegalovirus infection and disease, portal vein thrombosis, UNOS status, Childs-Pugh score, patient age, pretransplant bilirubin, ischemia time, and operative blood loss were not significant predictors of mortality. Patients with hepatitis C (HCV) and recurrent HCV had a trend towards higher mortality (P=0.18). By multivariate analysis, donor age, any major infection, additional immunosuppression, post-transplant dialysis, and subsequent transplantation were significant independent predictors of mortality (P<0.05). Major infectious morbidity was associated with HCV recurrence (P=0.003), posttransplant dialysis (P=0.001), pretransplant creatinine, donor age, median blood loss, intensive care unit

Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality

PubMed Central

Bárcena, Paloma; Jara-Acevedo, María; Tabernero, María Dolores; López, Antonio; Sánchez, María Luz; García-Montero, Andrés C.; Muñoz-García, Noemí; Vidriales, María Belén; Paiva, Artur; Lecrevisse, Quentin; Lima, Margarida; Langerak, Anton W.; Böttcher, Sebastian; van Dongen, Jacques J.M.

2015-01-01

Currently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK). For this purpose, a large panel of markers was evaluated by multiparametric flow cytometry on peripheral blood (PB) CD56low NK cells from 60 patients, including 23 subjects with predefined clonal (n = 9) and polyclonal (n = 14) CD56low NK-cell expansions, and 37 with CLPD-NK of undetermined clonality; also, PB samples from 10 healthy adults were included. Clonality was established using the human androgen receptor (HUMARA) assay. Clonal NK cells were found to show decreased expression of CD7, CD11b and CD38, and higher CD2, CD94 and HLADR levels vs. normal NK cells, together with a restricted repertoire of expression of the CD158a, CD158b and CD161 killer-associated receptors. In turn, NK cells from both clonal and polyclonal CLPD-NK showed similar/overlapping phenotypic profiles, except for high and more homogeneous expression of CD94 and HLADR, which was restricted to clonal CLPD-NK. We conclude that the CD94hi/HLADR+ phenotypic profile proved to be a useful surrogate marker for NK-cell clonality. PMID:26556869

Regional differences in recipient waitlist time and pre- and post-transplant mortality after the 2006 United Network for Organ Sharing policy changes in the donor heart allocation algorithm.

PubMed

Schulze, P Christian; Kitada, Shuichi; Clerkin, Kevin; Jin, Zhezhen; Mancini, Donna M

2014-04-01

This study examined the impact of the United Network for Organ Sharing (UNOS) policy changes for regional differences in waitlist time and mortality before and after heart transplantation. The 2006 UNOS thoracic organ allocation policy change was implemented to allow for greater regional sharing of organs for heart transplantation. We analyzed 36,789 patients who were listed for heart transplantation from January 1999 through April 2012. These patients were separated into 2 eras centered on the July 12, 2006 UNOS policy change. Pre- and post-transplantation characteristics were compared by UNOS regions. Waitlist mortality decreased nationally (up to 180 days: 13.3% vs. 7.9% after the UNOS policy change, p < 0.001) and within each region. Similarly, 2-year post-transplant mortality decreased nationally (2-year mortality: 17.3% vs. 14.6%; p < 0.001) as well as regionally. Waitlist time for UNOS status 1A and 1B candidates increased nationally 17.8 days on average (p < 0.001) with variability between the regions. The greatest increases were in Region 9 (59.2-day increase, p < 0.001) and Region 4 (41.2-day increase, p < 0.001). Although the use of mechanical circulatory support increased nearly 2.3-fold nationally in Era 2, significant differences were present on a regional basis. In Regions 6, 7, and 10, nearly 40% of those transplanted required left ventricular assist device bridging, whereas only 19.6%, 22.3%, and 15.5% required a left ventricular assist device in regions 3, 4, and 5, respectively. The 2006 UNOS policy change has resulted in significant regional heterogeneity with respect to waitlist time and reliance on mechanical circulatory support as a bridge to transplantation, although overall both waitlist mortality and post-transplant survival are improved. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Regional Differences in Recipient Waitlist Time and Pre- and Post-Transplant Mortality After the 2006 United Network for Organ Sharing Policy Changes in the Donor Heart Allocation Algorithm

PubMed Central

Schulze, P. Christian; Kitada, Shuichi; Clerkin, Kevin; Jin, Zhezhen; Mancini, Donna M.

2014-01-01

Objectives This study examined the impact of the United Network for Organ Sharing (UNOS) policy changes for regional differences in waitlist time and mortality before and after heart transplantation. Background The 2006 UNOS thoracic organ allocation policy change was implemented to allow for greater regional sharing of organs for heart transplantation. Methods We analyzed 36,789 patients who were listed for heart transplantation from January 1999 through April 2012. These patients were separated into 2 eras centered on the July 12, 2006 UNOS policy change. Pre- and post-transplantation characteristics were compared by UNOS regions. Results Waitlist mortality decreased nationally (up to 180 days: 13.3% vs. 7.9% after the UNOS policy change, p < 0.001) and within each region. Similarly, 2-year post-transplant mortality decreased nationally (2-year mortality: 17.3% vs. 14.6%; p < 0.001) as well as regionally. Waitlist time for UNOS status 1A and 1B candidates increased nationally 17.8 days on average (p < 0.001) with variability between the regions. The greatest increases were in Region 9 (59.2-day increase, p < 0.001) and Region 4 (41.2-day increase, p < 0.001). Although the use of mechanical circulatory support increased nearly 2.3-fold nationally in Era 2, significant differences were present on a regional basis. In Regions 6, 7, and 10, nearly 40% of those transplanted required left ventricular assist device bridging, whereas only 19.6%, 22.3%, and 15.5% required a left ventricular assist device in regions 3, 4, and 5, respectively. Conclusions The 2006 UNOS policy change has resulted in significant regional heterogeneity with respect to waitlist time and reliance on mechanical circulatory support as a bridge to transplantation, although overall both waitlist mortality and post-transplant survival are improved. PMID:24720925

Clinical risks and healthcare utilization of hematopoietic cell transplantation for sickle cell disease in the USA using merged databases

PubMed Central

Arnold, Staci D.; Brazauskas, Ruta; He, Naya; Li, Yimei; Aplenc, Richard; Jin, Zhezhen; Hall, Matt; Atsuta, Yoshiko; Dalal, Jignesh; Hahn, Theresa; Khera, Nandita; Bonfim, Carmem; Majhail, Navneet S.; Diaz, Miguel Angel; Freytes, Cesar O.; Wood, William A.; Savani, Bipin N.; Kamble, Rammurti T.; Parsons, Susan; Ahmed, Ibrahim; Sullivan, Keith; Beattie, Sara; Dandoy, Christopher; Munker, Reinhold; Marino, Susana; Bitan, Menachem; Abdel-Azim, Hisham; Aljurf, Mahmoud; Olsson, Richard F.; Joshi, Sarita; Buchbinder, Dave; Eckrich, Michael J.; Hashmi, Shahrukh; Lazarus, Hillard; Marks, David I.; Steinberg, Amir; Saad, Ayman; Gergis, Usama; Krishnamurti, Lakshmanan; Abraham, Allistair; Rangarajan, Hemalatha G.; Walters, Mark; Lipscomb, Joseph; Saber, Wael; Satwani, Prakash

2017-01-01

Advances in allogeneic hematopoietic cell transplantation for sickle cell disease have improved outcomes, but there is limited analysis of healthcare utilization in this setting. We hypothesized that, compared to late transplantation, early transplantation (at age <10 years) improves outcomes and decreases healthcare utilization. We performed a retrospective study of children transplanted for sickle cell disease in the USA during 2000–2013 using two large databases. Univariate and Cox models were used to estimate associations of demographics, sickle cell disease severity, and transplant-related variables with mortality and chronic graft-versus-host disease, while Wilcoxon, Kruskal-Wallis, or linear trend tests were applied for the estimates of healthcare utilization. Among 161 patients with a 2-year overall survival rate of 90% (95% confidence interval [CI] 85–95%) mortality was significantly higher in those who underwent late transplantation versus early (hazard ratio (HR) 21, 95% CI 2.8–160.8, P=0.003) and unrelated compared to matched sibling donor transplantation (HR 5.9, 95% CI 1.7–20.2, P=0.005). Chronic graftversus host disease was significantly more frequent among those translanted late (HR 1.9, 95% CI 1.0–3.5, P=0.034) and those who received an unrelated graft (HR 2.5, 95% CI 1.2–5.4; P=0.017). Merged data for 176 patients showed that the median total adjusted transplant cost per patient was $467,747 (range: $344,029–$799,219). Healthcare utilization was lower among recipients of matched sibling donor grafts and those with low severity disease compared to those with other types of donor and disease severity types (P<0.001 and P=0.022, respectively); no association was demonstrated with late transplantation (P=0.775). Among patients with 2-year pre- and post-transplant data (n=41), early transplantation was associated with significant reductions in admissions (P<0.001), length of stay (P<0.001), and cost (P=0.008). Early transplant outcomes

Nonalcoholic fatty liver disease and liver transplantation - Where do we stand?

PubMed Central

Mikolasevic, Ivana; Filipec-Kanizaj, Tajana; Mijic, Maja; Jakopcic, Ivan; Milic, Sandra; Hrstic, Irena; Sobocan, Nikola; Stimac, Davor; Burra, Patrizia

2018-01-01

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) is a challenging and multisystem disease that has a high socioeconomic impact. NAFLD/NASH is a main cause of macrovesicular steatosis and has multiple impacts on liver transplantation (LT), on patients on the waiting list for transplant, on post-transplant setting as well as on organ donors. Current data indicate new trends in the area of chronic liver disease. Due to the increased incidence of metabolic syndrome (MetS) and its components, NASH cirrhosis and hepatocellular carcinoma caused by NASH will soon become a major indication for LT. Furthermore, due to an increasing incidence of MetS and, consequently, NAFLD, there will be more steatotic donor livers and less high quality organs available for LT, in addition to a lack of available liver allografts. Patients who have NASH and are candidates for LT have multiple comorbidities and are unique LT candidates. Finally, we discuss long-term grafts and patient survival after LT, the recurrence of NASH and NASH appearing de novo after transplantation. In addition, we suggest topics and areas that require more research for improving the health care of this increasing patient population. PMID:29662288

CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire

PubMed Central

Suessmuth, Yvonne; Mukherjee, Rithun; Watkins, Benjamin; Koura, Divya T.; Finstermeier, Knut; Desmarais, Cindy; Stempora, Linda; Horan, John T.; Langston, Amelia; Qayed, Muna; Khoury, Hanna J.; Grizzle, Audrey; Cheeseman, Jennifer A.; Conger, Jason A.; Robertson, Jennifer; Garrett, Aneesah; Kirk, Allan D.; Waller, Edmund K.; Blazar, Bruce R.; Mehta, Aneesh K.; Robins, Harlan S.

2015-01-01

Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme Bhigh/CD28low/CD57high/CD8+ effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31+/CD4+ putative thymic emigrants. T-cell receptor β (TCRβ) deep sequencing revealed a striking contraction of CD8+ Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials.gov as #NCT01012492. PMID:25852054

Music in Reducing Anxiety and Pain in Adult Patients Undergoing Bone Marrow Biopsy for Hematologic Cancers or Other Diseases

ClinicalTrials.gov

2017-05-25

Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Lymphoproliferative Disorder; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Pain; Precancerous Condition; Psychosocial Effects of Cancer and Its Treatment

Castleman's disease of the spleen.

PubMed

Mantas, Dimitrios; Damaskos, Christos; Dailiani, Panagiota; Samarkos, Michael; Korkolopoulou, Penelope

2017-06-01

Castleman's disease (CD), also known as giant or angiofolicular lymphoid hyperplasia or lymphoid hamartoma, is a group of atypical lymphoproliferative disorders that share common lymph node histological features and may be localized either to a single lymph node (unicentric) or occur systemically (multicentric). Herein, we present a rare case of a of 75-year-old female patient who was referred to our department and after a thorough work-up, underwent splenectomy with synchronous resection of an accessory spleen, splenic artery lymph nodes, and splenic hilar lymph nodes due to splenic involvement in a multicentric CD. The pathology of the specimens led to the conclusion that it was a case of polycentric HHV-8-positive CD, affecting the spleen, the accessory spleen, and the lymph nodes. Incidence of this rare condition is believed to be approximately 0.001-0.05%. CD has been linked to the human immunodeficiency virus (HIV), human herpes virus 8 (HHV-8), and is associated with malignancies. The pathogenesis mechanism is considered to be a dysregulation and hypersecretion of cytokines, either idiopathic or secondary to a viral infection, with the latter considered the most frequent. Solid organ involvement is very rare as is splenic involvement.

Correlation between sinus and lung cultures in lung transplant patients with cystic fibrosis.

PubMed

Choi, Kevin J; Cheng, Tracy Z; Honeybrook, Adam L; Gray, Alice L; Snyder, Laurie D; Palmer, Scott M; Abi Hachem, Ralph; Jang, David W

2018-03-01

Lung transplantation has revolutionized the treatment of end-stage pulmonary disease due to cystic fibrosis. However, infection of the transplanted lungs can lead to serious complications, including graft failure and death. Although many of these patients have concurrent sinusitis, it is unclear whether bacteria from the sinuses can infect the allograft. This is a single-institution retrospective study of all patients who underwent lung transplantation for cystic fibrosis from 2005 to 2015 at Duke University Hospital. Pre- and posttransplant nasal and pulmonary cultures obtained via nasal endoscopy and bronchoalveolar lavage (BAL), respectively, were analyzed. A total of 141 patients underwent 144 lung transplants. Sinus cultures were available for 76 patients (12 pretransplant, 42 posttransplant, 22 both pre- and posttransplant). Pretransplant BAL cultures were available for 139 patients, and posttransplant BAL cultures were available for all patients. Pseudomonas aeruginosa (PsA) and methicillin-resistant Staphylococcus aureus (MRSA) were the most common organisms cultured. There was a significant correlation between pretransplant sinus and posttransplant BAL cultures for PsA (p = 0.003), MRSA (p = 0.013), and Burkholderia cepacia (p = 0.001). There was a high correlation between pretransplant sinus cultures and posttransplant BAL cultures for PsA, MRSA, and Burkholderia sp. This suggests that the paranasal sinuses may act as a reservoir for allograft colonization in patients with cystic fibrosis. Further studies are needed to determine whether treatment of sinusitis affects allograft colonization and transplant outcomes. © 2017 ARS-AAOA, LLC.

The Intersection of Pulmonary Hypertension and Solid Organ Transplantation.

PubMed

Frost, Adaani E

2016-01-01

Pulmonary hypertension (PH) is a complication and marker of disease severity in many parenchymal lung diseases. It also is a frequent complication of portal hypertension and negatively impacts survival with liver transplant. Pulmonary hypertension is frequently diagnosed in patients with end-stage renal disease who are undergoing dialysis, and it has recently been demonstrated to adversely affect posttransplant outcome in this patient population even though the mechanism of PH is substantially different from that associated with liver disease. The presence of PH in patients with heart failure is frequent, and the necessity for PH therapy prior to heart transplant has evolved in the last decade. We review the frequency of and risk factors for PH in recipients of and candidates for lung, liver, heart, and renal transplants as well as the impact of this diagnosis on posttransplant outcomes.

Outcomes of 5-year survivors of pediatric liver transplantation: report on 461 children from a north american multicenter registry.

PubMed

Ng, Vicky Lee; Fecteau, Annie; Shepherd, Ross; Magee, John; Bucuvalas, John; Alonso, Estella; McDiarmid, Suzanne; Cohen, Geoff; Anand, Ravinder

2008-12-01

Although liver transplantation has been the standard of care therapy for life-threatening liver diseases for >20 years, data on the long-term impact of liver transplantation in children have been primarily limited to single-center experiences. The objective of this study was to characterize and evaluate the clinical course of children who have survived >or=5 years after pediatric liver transplantation in multiple centers across North America. Patients enrolled in the Studies of Pediatric Liver Transplantation database registry who had undergone liver transplantation at 1 of 45 pediatric centers between 1996 and 2001 and survived >5 years from liver transplantation were identified and their clinical courses retrospectively reviewed. The first graft survival for 461 five-year survivors was 88%, with 55 (12%) and 10 (2%) children undergoing a second and third liver transplantation. At the 5-year anniversary clinic visit, liver function was preserved in the majority with daily use of immunosuppression therapy, including a calcineurin inhibitor and oral prednisone, reported by 97% and 25% of children, respectively. The probability of an episode of acute cellular rejection occurring within 5 years after liver transplantation was 60%. Chronic rejection occurred in 5% patients. Posttransplant lymphoproliferative disease was diagnosed in 6% children. Calculated glomerular filtration rate was <90 mL/minute per 1.73 m2 in 13% of 5-year survivors. Age- and gender-adjusted BMI>95th percentile was noted in 12%, with height below the 10th percentile in 29%. Children who are 5-year survivors of liver transplantation have good graft function, but chronic medical conditions and posttransplantation complications affect extrahepatic organs. A comprehensive approach to the management of these patients' multiple unique needs requires the expertise and commitment of health care providers both beyond and within transplant centers to further optimize long-term outcomes for pediatric liver

T LYMPHOCYTES TARGETING NATIVE RECEPTORS

PubMed Central

Rooney, Cliona M; Leen, Ann M; Vera, Juan F; Heslop, Helen E

2013-01-01

Summary The adoptive transfer of T cells specific for native tumor antigens (TAs) is an increasingly popular cancer treatment option because of the ability of these cells to discriminate between normal and tumor tissues and corresponding lack of short or long-term toxicities. Infusions of antigen-specific CD4+ and CD8+ T cells targeting viral antigens derived from Epstein Barr virus (EBV) induce sustained complete tumor remissions in patients with highly immunogenic tumor’s such as post-transplant lymphoproliferative disease, although resistance occurred when the infused T-cell population had restricted antigen specificity. T cells specific for EBV antigens have also produced complete remissions of EBV-positive nasopharyngeal carcinomas and lymphomas developing in immunocompetent individuals, even though in these patients tumor survival is dependent on their ability to evade T-cell immunity. Adapting this strategy to non-viral tumors is more challenging, as the target antigens expressed are less immunogenic and the tumors lack the potent danger signals that are characteristic of viruses. The goals of current studies are to define conditions that promote expansion of antigen-specific T cells ex vivo and to ensure their in vivo persistence and survival by combining with maneuvers such as lymphodepletion, checkpoint inhibition, cytokine infusions, or genetic manipulations. More pragmatic goals are to streamline manufacturing to facilitate the transition of these therapies to late phase trials and to evaluate closely histocompatibility antigen (HLA)-matched banked antigen-specific T-cells so that T-cell therapies can be made more broadly available. PMID:24329788

Knockout of Epstein-Barr Virus BPLF1 Retards B-Cell Transformation and Lymphoma Formation in Humanized Mice

PubMed Central

Li, Guangming; Montgomery, Stephanie A.; Montgomery, Nathan D.; Su, Lishan; Pagano, Joseph S.

2015-01-01

ABSTRACT BPLF1 of Epstein-Barr virus (EBV) is classified as a late lytic cycle protein but is also found in the viral tegument, suggesting its potential involvement at both initial and late stages of viral infection. BPLF1 possesses both deubiquitinating and deneddylating activity located in its N-terminal domain and is involved in processes that affect viral infectivity, viral DNA replication, DNA repair, and immune evasion. A recently constructed EBV BPLF1-knockout (KO) virus was used in conjunction with a humanized mouse model that can be infected with EBV, enabling the first characterization of BPLF1 function in vivo. Results demonstrate that the BPLF1-knockout virus is approximately 90% less infectious than wild-type (WT) virus. Transformation of human B cells, a hallmark of EBV infection, was delayed and reduced with BPLF1-knockout virus. Humanized mice infected with EBV BPLF1-knockout virus showed less weight loss and survived longer than mice infected with equivalent infectious units of WT virus. Additionally, splenic tumors formed in 100% of mice infected with WT EBV but in only 25% of mice infected with BPLF1-KO virus. Morphological features of spleens containing tumors were similar to those in EBV-induced posttransplant lymphoproliferative disease (PTLD) and were almost identical to cases seen in human diffuse large B-cell lymphoma. The presence of EBV genomes was detected in all mice that developed tumors. The results implicate BPLF1 in human B-cell transformation and tumor formation in humanized mice. PMID:26489865

FDG uptake in cervical lymph nodes in children without head and neck cancer.

PubMed

Vali, Reza; Bakari, Alaa A; Marie, Eman; Kousha, Mahnaz; Charron, Martin; Shammas, Amer

2017-06-01

Reactive cervical lymphadenopathy is common in children and may demonstrate increased 18 F-fluoro-deoxyglucose ( 18 F-FDG) uptake on positron emission tomography/computed tomography (PET/CT). We sought to evaluate the frequency and significance of 18 F-FDG uptake by neck lymph nodes in children with no history of head and neck cancer. The charts of 244 patients (114 female, mean age: 10.4 years) with a variety of tumors such as lymphoma and post-transplant lymphoproliferative diseases (PTLD), but no head and neck cancers, who had undergone 18 F-FDG PET/CT were reviewed retrospectively. Using the maximum standardized uptake value (SUVmax), increased 18 F-FDG uptake by neck lymph nodes was recorded and compared with the final diagnosis based on follow-up studies or biopsy results. Neck lymph node uptake was identified in 70/244 (28.6%) of the patients. In 38 patients, the lymph nodes were benign. In eight patients, the lymph nodes were malignant (seven PTLD and one lymphoma). In 24 patients, we were not able to confirm the final diagnosis. Seven out of the eight malignant lymph nodes were positive for PTLD. The mean SUVmax was significantly higher in malignant lesions (4.2) compared with benign lesions (2.1) (P = 0.00049). 18 F-FDG uptake in neck lymph nodes is common in children and is frequently due to reactive lymph nodes, especially when the SUVmax is <3.2. The frequency of malignant cervical lymph nodes is higher in PTLD patients compared with other groups.

The risk of cancer in recipients of living-donor, standard and expanded criteria deceased donor kidney transplants: a registry analysis.

PubMed

Ma, Maggie K M; Lim, Wai H; Turner, Robin M; Chapman, Jeremy R; Craig, Jonathan C; Wong, Germaine

2014-12-27

Kidneys from expanded criteria deceased donors may elicit a strong inflammatory response, predisposing recipients to an increased risk of cancer after transplantation. We aimed to determine the association between donor types and cancer risk after kidney transplantation. Using the Australian and New Zealand Dialysis and Transplant Registry, we assessed the association between different donor types (living donor, standard, and expanded criteria deceased donors) and the risk of cancer after kidney transplantation using adjusted Cox proportional hazard and competing risk models. Over a median follow-up period of 4.4 years in 7,040 patients (34,684 patient-years), 468 patients (6.6%) developed cancer. The overall risks for cancer were 1,080, 1,444, and 2,018 per 100,000 patient-years for recipients of living donor, standard, and expanded criteria deceased donor kidneys, respectively. Compared to recipients of living-donor kidneys, recipients of expanded criteria deceased donor kidneys were at an increased risk of cancer (adjusted hazard ratio [HR], 1.52; 95% confidence interval [95% CI], 1.15-2.02; P = 0.004), particularly for genitourinary cancer (adjusted HR, 1.79; 95% CI, 1.03-3.10; P = 0.038) and post-transplant lymphoproliferative disease (adjusted HR, 2.72; 95% CI, 1.38-5.37; P = 0.004). Recipients of expanded criteria deceased donor kidneys are at substantially increased risk of cancer, especially cancers with a viral etiology. Allocation of expanded criteria deceased donor kidneys to potential recipients should balance the harms, such as the excess risk of cancer against the survival gains and quality-of-life benefits associated with transplantation.

Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration.

PubMed

Brown, S Lori; Greene, Mark H; Gershon, Sharon K; Edwards, Evelyne T; Braun, M Miles

2002-12-01

Etanercept and infliximab are tumor necrosis factor (TNF) antagonists that have been recently approved for the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). This study was undertaken to investigate the occurrence of lymphoproliferative disorders in patients treated with these agents. Relevant data in the MedWatch postmarket adverse event surveillance system run by the US Food and Drug Administration were reviewed. We identified 26 cases of lymphoproliferative disorders following treatment with etanercept (18 cases) or infliximab (8 cases). The majority of cases (81%) were non-Hodgkin's lymphomas. The interval between initiation of therapy with etanercept or infliximab and the development of lymphoma was very short (median 8 weeks). In 2 instances (1 infliximab, 1 etanercept), lymphoma regression was observed following discontinuation of anti-TNF treatment, in the absence of specific cytotoxic therapy directed toward the lymphoma. Although data from a case series such as this cannot establish a clear causal relationship between exposure to these medications and the risk of lymphoproliferative disease, the known predisposition of patients with RA and CD to lymphoma, the known excess of lymphoma in other immunosuppressed populations, and the known immunosuppressive effects of the anti-TNF drugs provide a biologic basis for concern and justification for the initiation of additional epidemiologic studies to formally evaluate this possible association.

In vitro induction of T regulatory cells by a methylated CpG DNA sequence in humans: Potential therapeutic applications in allergic and autoimmune diseases.

PubMed

Lawless, Oliver J; Bellanti, Joseph A; Brown, Milton L; Sandberg, Kathryn; Umans, Jason G; Zhou, Li; Chen, Weiqian; Wang, Julie; Wang, Kan; Zheng, Song Guo

2018-03-01

Allergic and autoimmune diseases comprise a group of inflammatory disorders caused by aberrant immune responses in which CD25+ Forkhead box P3-positive (FOXP3+) T regulatory (Treg) cells that normally suppress inflammatory events are often poorly functioning. This has stimulated an intensive investigative effort to find ways of increasing Tregs as a method of therapy for these conditions. One such line of investigation includes the study of how ligation of Toll-like receptors (TLRs) by CpG oligonucleotides (ODN) results in an immunostimulatory cascade that leads to induction of T-helper (Th) type 1 and Treg-type immune responses. The present study investigated the mechanisms by which calf thymus mammalian double-stranded DNA (CT-DNA) and a synthetic methylated DNA CpG ODN sequence suppress in vitro lymphoproliferative responses to antigens, mitogens, and alloantigens when measured by [3H]-thymidine incorporation and promote FoxP3 expression in human CD4+ T cells in the presence of transforming growth factor (TGF) beta and interleukin-2 (IL-2). Lymphoproliferative responses of peripheral blood mononuclear cells from four healthy subjects or nine subjects with systemic lupus erythematosus to CT-DNA or phytohemagglutinin (PHA) was measured by tritiated thymidine ([3H]-TdR) incorporation expressed as a stimulation index. Mechanisms of immunosuppressive effects of CT-DNA were evaluated by measurement of the degree of inhibition to lymphoproliferative responses to streptokinase-streptodornase, phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), or alloantigens by a Con A suppressor assay. The effects of CpG methylation on induction of FoxP3 expression in human T cells were measured by comparing inhibitory responses of synthetic methylated and nonmethylated 8-mer CpG ODN sequences by using cell sorting, in vitro stimulation, and suppressor assay. Here, we showed that CT-DNA and a synthetic methylated DNA 8-mer sequence could suppress antigen

Abnormal thymic maturation and lymphoproliferation in MRL-Fas lpr/lpr mice can be partially reversed by synthetic oligonucleotides: implications for systemic lupus erythematosus and autoimmune lymphoproliferative syndrome.

PubMed

Ashman, R F; Singh, N; Lenert, P S

2017-06-01

MRL-Fas lpr/lpr mice represent an excellent animal model for studying non-malignant lymphoproliferation, regeneration and systemic autoimmunity. Retro-transposon insertion into the second intron of the pro-apoptotic Fas gene appears to be responsible for both lymphoproliferation and autoimmunity, while other genes are more likely to contribute to the regenerative healing characteristic of this mouse strain. Previous studies have shown that neonatal thymectomy can halt the development of abnormal lymphoproliferation. Whereas at four weeks of age primary and secondary lymphoid organs appear to be grossly intact, vigorous lymphoproliferation and autoantibody production subsequently ensues. This is first noticeable at six weeks of age, at which time lymph nodes, spleens and thymuses, but not the bone marrow, become infiltrated with abnormal B220 + CD3 + CD4 - CD8 - T cells. Around the same time, thymuses show a significant drop in CD4 + CD8 + double-positive T cells generating an abnormal ratio between double-positive and single-positive thymocytes. The objective of current study was to evaluate the effect of synthetic oligonucleotides-toll-like receptor antagonists on early lymphoid development in this strain of mice. Herein, we demonstrate the ability of synthetic oligonucleotides made with the nuclease-resistant phosphorothioate backbone to partially reverse abnormal lymphoproliferation and thymic involution in pre-diseased MRL-Fas lpr/lpr mice when administered intraperitoneally starting from week four of age. This curative effect of oligonucleotides was primary sequence/secondary oligonucleotide structure-independent, suggesting an effect through the toll-like receptor 7. A similar approach may potentially benefit patients with autoimmune lymphoproliferative syndrome who, like MRL-Fas lpr/lpr mice, carry a mutation in the Fas gene.

Spectrum of Epstein-Barr virus-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation.

PubMed

Xuan, Li; Jiang, Xinmiao; Sun, Jing; Zhang, Yu; Huang, Fen; Fan, Zhiping; Guo, Xutao; Dai, Min; Liu, Can; Yu, Guopan; Zhang, Xian; Wu, Meiqing; Huang, Xiaojun; Liu, Qifa

2013-09-01

Epstein-Barr virus (EBV) infection may result in a spectrum of diseases in recipients of transplant. The aim of this study is to investigate the incidence, clinical characteristics, and prognosis of the spectrum of EBV-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 263 recipients undergoing allo-HSCT were prospectively enrolled. The blood EBV-DNA loads were regularly monitored by quantitative real-time polymerase chain reaction. The 3-year cumulative incidence of total EBV-associated diseases, posttransplantation lymphoproliferative diseases (PTLD), EBV fever, and EBV end-organ diseases (pneumonia, encephalitis/myelitis, and hepatitis) were 15.6%±2.5%, 9.9%±2.0%, 3.3%±1.3%, and 3.3%±1.2% (2.2%±1.0%, 1.6%±0.8%, and 0.9%±0.6%), respectively. Fever was the most common symptom of EBV-associated diseases. Patients with PTLD had better response rate to rituximab-based treatments compared with those with EBV end-organ diseases (including PTLD accompanied by EBV end-organ diseases) (P=0.014). The 3-year overall survival was 37.3%±13.7%, 100.0%, and 0.0%±0.0% in patients with PTLD, EBV fever, and EBV end-organ diseases (P=0.001). EBV-associated diseases other than PTLD are not rare in the recipients of allo-HSCT. The clinical manifestations of EBV end-organ diseases are similar to PTLD. EBV end-organ diseases had poorer response to rituximab-based therapy compared with PTLD.

Rare Forms of Castleman Disease Mimicking Malignancy: Mesenteric and Pancreatic Involvement.

PubMed

Ozsoy, Mustafa; Ozsoy, Zehra; Sahin, Suleyman; Arıkan, Yuksel

2018-03-12

Castleman disease is a lymphoproliferative disorder with unknown etiology and pathogenesis. While the disease may involve all parts of the body, the mediastinum appears to be the most common part of involvement. In this study, we present two cases of Castleman disease with different localizations that mimicked malignancy. A 62-year-old female patient presented with jaundice. Laboratory analysis indicated aspartate aminotransferase: 250 U/L, total bilirubin: 4 mg/dl, and carbohydrate antigen (CA) 19-9: 900 U/ml. Computerized tomography (CT) of the abdomen showed a mass originating from the pancreas head which resulted in a biliary tract obstruction. A positron emission tomography-computed tomography (PET/CT) showed that the only site of involvement was the pancreas head. A decision was made to perform pancreaticoduodenectomy. During intra-abdominal exploration, lymphadenopathies were identified in the surroundings of the retropancreatic portal vein and the hepatic artery. Histopathological investigation of the dissected lymph nodes demonstrated findings consistent with granulomatous plasma-cell-rich Castleman disease. A 55-year-old female patient presented with abdominal pain, nausea, and vomiting. Computerized tomography of the abdomen showed an abdominal mass of 7 cm, originating from the mesenterium, with high-contrast uptake in the mesenterium in the lower abdominal quadrant. The mesenteric mass was resected along with segmentary small intestine resection. Histopathological investigation of the mass showed a giant granulomatous structure that consisted of plasma cells consistent with Castleman disease. Castleman disease should be kept in mind during differential diagnosis of locally advanced lymph nodes observed during preoperative investigations and intraoperative exploration.

Epstein-Barr virus lymphoproliferative disease after solid organ transplantation.

PubMed

Prockop, Susan E; Vatsayan, Anant

2017-11-01

Epstein-Barr virus (EBV) was the first identified human oncovirus and is also one of the most ubiquitous viral infections known with established infections in more than 90% of individuals by early adulthood. EBV establishes latency by controlling expression of the viral genome making it silent to immune surveillance. In immunocompetent individuals, up to 1% of circulating T cells are directed at maintaining control over EBV replication. In addition to being involved in oncogenesis of lymphoid and epithelial tumors in immune-competent individuals, loss of immune surveillance over EBV predisposes individuals to EBV malignancies. Lymphoid proliferations from EBV-infected B cells arise in up to 20% of recipients of solid organ transplants (SOTs). One question not answered is why, when EBV requires such active immune surveillance, EBV malignancies are not even more prevalent in severely immune-compromised individuals. A better understanding of who develops complications related to EBV and what the immunologic risks are will ultimately make it feasible to perform prophylactic trials in those at highest risk. This review summarizes our current understanding of factors in SOT recipients that predispose them to the development of an EBV malignancy and that predict response to initial therapy. We then review the current landscape of those therapies, focusing on the goal of restoring long-term EBV-directed immunity to patients at risk. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Pembrolizumab in Untreated B-Cell Non-Hodgkin Lymphoproliferative Diseases

ClinicalTrials.gov

2018-04-06

B-Cell Non-Hodgkin Lymphoma; Waldenstrom Macroglobulinemia; Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Lymphoplasmacytic Lymphoma; Follicular Lymphoma; Indolent Non-Hodgkin Lymphoma; Marginal Zone Lymphoma

Soluble CD30 levels in recipients undergoing heart transplantation do not predict post-transplant outcome.

PubMed

Ypsilantis, Efthymios; Key, Timothy; Bradley, J Andrew; Morgan, C Helen; Tsui, Stephen; Parameshwar, Jayan; Taylor, Craig J

2009-11-01

The pre-transplant serum level of soluble CD30 (sCD30), a proteolytic derivative of the lymphocyte surface receptor CD30, has been suggested as a biomarker for immunologic risk after organ transplantation. Pre-transplant serum sCD30 levels were determined in 200 consecutive adult heart transplant recipients undertaken at a single center. Transplant outcome (acute rejection in the first 12 months and patient survival up to 5 years post-transplant) was determined. Patients treated with a left ventricular assist device (LVAD) prior to transplantation (n = 28) had higher levels of sCD30 (median 64 U/ml, range 12 to 112 U/ml) than those (n = 172) with no LVAD (median 36 U/ml, range 1 to 158 U/ml, p < 0.0001). Recipients were categorized according to whether sCD30 levels were "low" (lower quartile, <24 U/ml, n = 50), "intermediate" (24 to 58 U/ml, n = 100) or "high" (upper quartile, >58 U/ml, n = 50). Neither acute rejection nor recipient survival differed according to sCD30 level, with values (mean +/- SEM) of 0.30 +/- 0.04, 0.23 +/- 0.03 and 0.30 +/- 0.05 acute rejection episodes per 100 days in the low, intermediate and high groups, respectively, with recipient survival rates at 1 year of 77.7%, 84.9% and 86% and at 5 years of 73.6%, 67.9% and 75.8%, respectively. Pre-transplant serum sCD30 level does not predict acute allograft rejection or recipient survival after heart transplantation, although sCD30 levels are increased by LVAD, possibly as a result of biomaterial-host immune interaction.

Solitary pulmonary amyloidoma mimicking lung cancer on 18F-FDG PET-CT scan in systemic lupus erythematosus patient.

PubMed

Barešić, M; Sreter, K B; Brčić, L; Hećimović, A; Janevski, Z; Anić, B

2015-12-01

Localized amyloid deposits (tumoral amyloidosis or amyloidoma) are uncommon form of amyloidosis and nodular pulmonary amyloidomas are rarely found. This incidental finding can mimic a bronchopulmonary neoplasm and may occur secondarily to an infectious, inflammatory or lymphoproliferative disease. We report a case of a 62-year-old female with long-standing systemic lupus erythematosus (SLE) with low compliance who presented with radiologically-verified solitary pulmonary nodule. Work-up included positron emission tomography-computed tomography (PET-CT) scan, which revealed hypermetabolic uptake of (18)F-fluorodeoxyglucose, and lobectomy was performed. Staining of the tissue was positive for Congo red and was green birefringent under polarized light. Immunohistochemical methods excluded lymphoproliferative disease and confirmed amyloidoma. SLE was controlled with antimalarials and glucocorticoids. Pulmonary amyloidoma should be considered in the differential diagnosis of solitary lung nodules. © The Author(s) 2015.

Dermatologic manifestations of solid organ transplantation-associated graft-versus-host disease: A systematic review.

PubMed

Kim, Grace Y; Schmelkin, Leah A; Davis, Mark D P; El-Azhary, Rokea A; Farrell, Ann M; Meves, Alexander; Lehman, Julia S

2018-06-01

Graft-versus-host-disease (GVHD) after solid organ transplantation (SOT) is extremely rare. To investigate the dermatologic manifestations and clinical outcomes of SOT GVHD. Systematic literature review of SOT GVHD. After full-text article review, we included 61 articles, representing 115 patients and 126 transplanted organs. The most commonly transplanted organ was the liver (n = 81). Among 115 patients, 101 (87.8%) developed skin involvement. The eruption appeared an average of 48.3 days (range, 3-243 days) posttransplant and was pruritic in 5 of 101 (4.9%) cases. The eruption was described as morbilliform in 2 patients (1.9%), confluent in 6 (5.9%), and desquamative in 4 (3.9%) cases. In many cases, specific dermatologic descriptions were lacking. The mortality rate was 72.2%. Relative time of death was reported in 23 patients who died during the follow-up period. These patients died an average of 99.2 days (range, 22-270 days) posttransplant, or 50.9 days after the appearance of dermatologic symptoms. Frequent causes of death were sepsis and multiorgan failure. Incomplete descriptions of skin findings and potential publication bias resulting in publication of only the most severe cases. GVHD is a potentially fatal condition that can occur after SOT and often presents with a skin rash. We recommend that dermatologists have a low threshold to consider and pursue this diagnosis in the setting of post-SOT skin eruption. Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Understanding Trends in Kidney Function 1 Year after Kidney Transplant in the United States.

PubMed

Huang, Yihung; Tilea, Anca; Gillespie, Brenda; Shahinian, Vahakn; Banerjee, Tanushree; Grubbs, Vanessa; Powe, Neil; Rios-Burrows, Nilka; Pavkov, Meda; Saran, Rajiv

2017-08-01

Lower eGFR 1 year after kidney transplant is associated with shorter allograft and patient survival. We examined how practice changes in the past decade correlated with time trends in average eGFR at 1 year after kidney transplant in the United States in a cohort of 189,944 patients who received a kidney transplant between 2001 and 2013. We calculated the average eGFR at 1 year after transplant for the recipient cohort of each year using the appropriate Modification of Diet in Renal Disease equation depending on the prevailing methodology of creatinine measurement, and used linear regression to model the effects of practice changes on the national post-transplant eGFR trend. Between the 2001-2005 period and the 2011-2013 period, average 1-year post-transplant eGFR remained essentially unchanged, with differences of 1.34 (95% confidence interval, 1.03 to 1.65) ml/min per 1.73 m 2 and 0.66 (95% confidence interval, 0.32 to 1.01) ml/min per 1.73 m 2 among deceased and living donor kidney transplant recipients, respectively. Over time, the mean age of recipients increased and more marginal organs were used; adjusting for these trends unmasked a larger temporal improvement in post-transplant eGFR. However, changes in immunosuppression practice had a positive effect on average post-transplant eGFR and balanced out the negative effect of recipient/donor characteristics. In conclusion, average 1-year post-transplant eGFR remained stable, despite increasingly unfavorable attributes in recipients and donors. With an aging ESRD population and continued organ shortage, preservation of average post-transplant eGFR will require sustained improvement in immunosuppression and other aspects of post-transplant care. Copyright © 2017 by the American Society of Nephrology.

Effect of transplant center volume on post-transplant survival in patients listed for simultaneous liver and kidney transplantation

PubMed Central

Modi, Rohan M; Tumin, Dmitry; Kruger, Andrew J; Beal, Eliza W; Hayes, Don; Hanje, James; Michaels, Anthony J; Washburn, Kenneth; Conteh, Lanla F; Black, Sylvester M; Mumtaz, Khalid

2018-01-01

AIM To examine the effect of center size on survival differences between simultaneous liver kidney transplantation (SLKT) and liver transplantation alone (LTA) in SLKT-listed patients. METHODS The United Network of Organ Sharing database was queried for patients ≥ 18 years of age listed for SLKT between February 2002 and December 2015. Post-transplant survival was evaluated using stratified Cox regression with interaction between transplant type (LTA vs SLKT) and center volume. RESULTS During the study period, 393 of 4580 patients (9%) listed for SLKT underwent a LTA. Overall mortality was higher among LTA recipients (180/393, 46%) than SLKT recipients (1107/4187, 26%). The Cox model predicted a significant survival disadvantage for patients receiving LTA vs SLKT [hazard ratio, hazard ratio (HR) = 2.85; 95%CI: 2.21, 3.66; P < 0.001] in centers performing 30 SLKT over the study period. This disadvantage was modestly attenuated as center SLKT volume increased, with a 3% reduction (HR = 0.97; 95%CI: 0.95, 0.99; P = 0.010) for every 10 SLKs performed. CONCLUSION In conclusion, LTA is associated with increased mortality among patients listed for SLKT. This difference is modestly attenuated at more experienced centers and may explain inconsistencies between smaller-center and larger registry-wide studies comparing SLKT and LTA outcomes. PMID:29399287

New and emerging therapies for acute and chronic graft versus host disease

PubMed Central

Hill, LaQuisa; Alousi, Amin; Kebriaei, Partow; Mehta, Rohtesh; Rezvani, Katayoun; Shpall, Elizabeth

2017-01-01

Graft versus host disease (GVHD) remains a major cause of morbidity and mortality following allogeneic hematopoietic stem-cell transplantation (HSCT). Despite the use of prophylactic GVHD regimens, a significant proportion of transplant recipients will develop acute or chronic GVHD following HSCT. Corticosteroids are standard first-line therapy, but are only effective in roughly half of all cases with ~50% of patients going on to develop steroid-refractory disease, which increases the risk of nonrelapse mortality. While progress has been made with improvements in survival outcomes over time, corticosteroids are associated with significant toxicities, and many currently available salvage therapies are associated with increased immunosuppression, infectious complications, and potential loss of the graft versus leukemia (GVL) effect. Thus, there is an unmet need for development of newer treatment strategies for both acute and chronic GVHD to improve long-term post-transplant outcomes and quality of life for HSCT recipients. Here, we provide a concise review of major emerging therapies currently being studied in the treatment of acute and chronic GVHD. PMID:29317998

Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial of RG7667, a Combination Monoclonal Antibody, for Prevention of Cytomegalovirus Infection in High-Risk Kidney Transplant Recipients

PubMed Central

Ishida, Julie H.; Patel, Anita; Mehta, Aneesh K.; Gatault, Philippe; McBride, Jacqueline M.; Burgess, Tracy; Derby, Michael A.; Snydman, David R.; Emu, Brinda; Feierbach, Becket; Fouts, Ashley E.; Maia, Mauricio; Deng, Rong; Rosenberger, Carrie M.; Gennaro, Lynn A.; Striano, Natalee S.; Liao, X. Charlene

2016-01-01

ABSTRACT Cytomegalovirus (CMV) infection is a significant complication after kidney transplantation. We examined the ability of RG7667, a combination of two monoclonal antibodies, to prevent CMV infection in high-risk kidney transplant recipients in a randomized, double-blind, placebo-controlled trial. CMV-seronegative recipients of a kidney transplant from a CMV-seropositive donor (D+R−) were randomized to receive RG7667 (n = 60) or placebo (n = 60) at the time of transplant and 1, 4, and 8 weeks posttransplant. Patients were monitored for CMV viremia every 1 to 2 weeks posttransplant for 24 weeks. Patients who had seroconverted (D+R+) or withdrawn before dosing were excluded from the analysis (n = 4). CMV viremia occurred in 27 of 59 (45.8%) patients receiving RG7667 and 35 of 57 (61.4%) patients receiving placebo (stratum-adjusted difference, 15.3%; P = 0.100) within 12 weeks posttransplant and in 30 of 59 (50.8%) patients receiving RG7667 and 40 of 57 (70.2%) patients receiving placebo (stratum-adjusted difference, 19.3%; P = 0.040) within 24 weeks posttransplant. Median time to CMV viremia was 139 days in patients receiving RG7667 compared to 46 days in patients receiving placebo (hazard ratio, 0.53; P = 0.009). CMV disease was less common in the RG7667 than placebo group (3.4% versus 15.8%; P = 0.030). Adverse events were generally balanced between treatment groups. In high-risk kidney transplant recipients, RG7667 was well tolerated, numerically reduced the incidence of CMV infection within 12 and 24 weeks posttransplant, delayed time to CMV viremia, and was associated with less CMV disease than the placebo. (This study has been registered at ClinicalTrials.gov under registration no. NCT01753167.) PMID:27872061

Review of Current Applications of Immunohistochemistry in Pediatric Nonneoplastic Gastrointestinal, Hepatobiliary, and Pancreatic Lesions

PubMed Central

de Nanassy, Joseph; El Demellawy, Dina

2017-01-01

Immunohistochemical (IHC) stains are widely used by pathologists for a variety of considerations in the diagnostic workup of pediatric nonneoplastic lesions in gastrointestinal (GI), hepatic, biliary, and pancreatic lesions. The pathologic changes cover a wide range and types of presentations, including inflammatory (bacterial and viral), metaplastic, posttransplant lymphoproliferative, autoimmune, metabolic, degenerative, developmental, and genetic conditions, among others. The everyday practical value of IHC stains covers primary identification, confirmation, differential, and/or exclusionary roles in the hands and eyes and minds of the practitioners. This article is intended to review and discuss the currently available IHC stains for a variety of pediatric GI, hepatobiliary, and pancreatic lesions as encountered in the day-to-day practice of pathologists and clinicians. It reflects the most recent methods and types of IHC stains with the stated aim of helping to provide a quick reference for diagnostic considerations and thereby facilitate the workup of a broad range of GI and related conditions in a pediatric population. The tables provide a handy reference on a wide range of IHC stains for commonly encountered lesions covering a variety of pediatric GI, hepatobiliary, and pancreatic conditions that are amenable to light microscopic diagnostic interpretation. PMID:28469406

A composite score associated with spontaneous operational tolerance in kidney transplant recipients.

PubMed

Danger, Richard; Chesneau, Mélanie; Paul, Chloé; Guérif, Pierrick; Durand, Maxim; Newell, Kenneth A; Kanaparthi, Sai; Turka, Laurence A; Soulillou, Jean-Paul; Houlgatte, Rémi; Giral, Magali; Ramstein, Gérard; Brouard, Sophie

2017-06-01

New challenges in renal transplantation include using biological information to devise a useful clinical test for discerning high- and low-risk patients for individual therapy and ascertaining the best combination and appropriate dosages of drugs. Based on a 20-gene signature from a microarray meta-analysis performed on 46 operationally tolerant patients and 266 renal transplant recipients with stable function, we applied the sparse Bolasso methodology to identify a minimal and robust combination of six genes and two demographic parameters associated with operational tolerance. This composite score of operational tolerance discriminated operationally tolerant patients with an area under the curve of 0.97 (95% confidence interval 0.94-1.00). The score was not influenced by immunosuppressive treatment, center of origin, donor type, or post-transplant lymphoproliferative disorder history of the patients. This composite score of operational tolerance was significantly associated with both de novo anti-HLA antibodies and tolerance loss. It was validated by quantitative polymerase chain reaction using independent samples and demonstrated specificity toward a model of tolerance induction. Thus, our score would allow clinicians to improve follow-up of patients, paving the way for individual therapy. Copyright © 2017 International Society of Nephrology. All rights reserved.

A composite score associated with spontaneous operational tolerance in kidney transplant recipients

PubMed Central

Danger, Richard; Chesneau, Mélanie; Paul, Chloé; Guérif, Pierrick; Durand, Maxim; Newell, Kenneth A; Kanaparthi, Sai; Turka, Laurence A; Soulillou, Jean-Paul; Houlgatte, Rémi; Giral, Magali; Ramstein, Gérard; Brouard, Sophie

2017-01-01

New challenges in renal transplantation include using biological information to devise a useful clinical test for discerning high- and low-risk patients for individual therapy and ascertaining the best combination and appropriate dosages of drugs. Based on a 20-gene signature from a microarray meta-analysis performed on 46 operationally tolerant patients and 266 renal transplanted recipients with stable function, we applied the sparse Bolasso methodology to identify a minimal and robust combination of six genes and two demographic parameters associated with operational tolerance. This composite score of operational tolerance discriminated operationally tolerant patients with an area under the curve of 0.97 (95% confidence interval 0.94–1.00). The score was not influenced by immunosuppressive treatment, center of origin, donor type, or post-transplant lymphoproliferative disorder history of the patients. This composite score of operational tolerance was significantly associated with both de novo anti-HLA antibodies and tolerance loss. It was validated by quantitative polymerase chain reaction using independent samples and demonstrated specificity toward a model of tolerance induction. Thus, our score would allow clinicians to improve follow-up of patients, paving the way for individual therapy. PMID:28242033

Rituximab in Treating Patients Undergoing Donor Peripheral Blood Stem Cell Transplant for Relapsed or Refractory B-cell Lymphoma

ClinicalTrials.gov

2017-12-05

B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Childhood Burkitt Lymphoma; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

Small Bowel Transplant

PubMed Central

2003-01-01

velocity with no catch-up growth. The quality of life after SBT was reported to be comparable to that of patients on home enteral nutrition. A study found that while the parents of pediatric SBT recipients reported significant limitations in the physical and psychological well being of the children compared with normal school children, the pediatric SBT recipients themselves reported a quality of life similar to other school children. Survival was found to be better in transplants performed since 1991. Patient survival was associated with the type of organ transplanted with better survival in isolated small bowel recipients. Adverse Events Despite improvement in patient and graft survival rates, small bowel transplant is still associated with significant mortality and morbidity. Infection with subsequent sepsis is the leading cause of death (51.3%). Bacterial, fungal and viral infections have all been reported. The most common viral infections are cytomegalorvirus (18-40%) and Epstein-Barr virus. The latter often led to ß-cell post-transplant lymphoproliferative disease. Graft rejection is the second leading cause of death after SBT (10.4%) and is responsible for 57% of graft removal. Acute rejection rates ranged from 51% to 83% in the major programs. Most of the acute rejection episodes were mild and responded to steroids and OKT3. Antilymphocyte therapy was needed in up to 27% of patients. Isolated small bowel allograft and positive lymphocytotoxic cross-match were found to be risk factors for acute rejection. Post-transplant lymphoproliferative disease occurred in 21% of SBT recipients and accounted for 7% of post-transplant mortality. The frequency was higher in pediatric recipients (31%) and in adults receiving composite visceral allografts (25%). The allograft itself is often involved in post-transplant lymphoproliferative disease. The reported incidence of host versus graft disease varied widely among centers (0% - 14%). Surgical complications were reported to

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: Consensus Recommendations for Subsequent Neoplasms

PubMed Central

Morton, Lindsay M.; Saber, Wael; Baker, K. Scott; Barrett, A. John; Bhatia, Smita; Engels, Eric A.; Gadalla, Shahinaz M.; Kleiner, David E.; Pavletic, Steven; Burns, Linda J.

2016-01-01

Subsequent neoplasms (SN) following hematopoietic cell transplantation (HCT) cause significant patient morbidity and mortality. Risks for specific SN types vary substantially, with particularly elevated risks for post-transplant lymphoproliferative disorders, myelodysplastic syndrome/acute myeloid leukemia, and squamous cell malignancies. This consensus document provides an overview of the current state of knowledge regarding SN after HCT and recommends priorities and approaches to overcome challenges and gaps in understanding. Numerous factors have been suggested to impact risk, including patient-related (e.g., age), primary disease-related (e.g., disease type, pre-HCT therapies), and HCT-related characteristics (e.g., type and intensity of conditioning regimen, stem cell source, development of graft-versus-host disease). However, gaps in understanding remain for each of these risk factors, particularly for patients receiving HCT in the current era due to substantial advances in clinical transplantation practices. Additionally, the influence of non-transplant-related risk factors (e.g., germline genetic susceptibility, oncogenic viruses, lifestyle factors) is poorly understood. Clarification of the magnitude of SN risks and identification of etiologic factors will require large-scale, long-term, systematic follow-up of HCT survivors with detailed clinical data. Most investigations of the mechanisms of SN pathogenesis after HCT have focused on immune drivers. Expansion of our understanding in this area will require interdisciplinary laboratory collaborations utilizing measures of immune function and availability of archival tissue from SN diagnoses. Consensus-based recommendations for optimal preventative, screening, and therapeutic approaches have been developed for certain SN after HCT, whereas for other SN, general population guidelines are recommended. Further evidence is needed to specifically tailor preventative, screening, and therapeutic guidelines for SN

Impact of type of calcineurin inhibitor on post-transplant tuberculosis: Single-center study from India.

PubMed

Agarwal, Sanjay K; Bhowmik, Dipankar; Mahajan, Sandeep; Bagchi, Soumita

2017-02-01

Tuberculosis (TB) is an important cause of morbidity and mortality in renal transplant recipients. Immunosuppressive drugs are one of the most important risk factor for post-transplant tuberculosis (PTTB). A paucity of data exists about the impact of the type of calcineurin inhibitor on PTTB. In this retrospective study, all adult patients on calcineurin inhibitor-based immunosuppression were included. Patients receiving TB chemoprophylaxis were excluded. Diabetes, duration of dialysis, hepatitis B and C, past treated TB, induction therapy, type of antimetabolite, acute rejection, new onset of diabetes after renal transplantation (RT) (NODAT) and cytomegalovirus (CMV) were analyzed in tacrolimus (Tac) and cyclosporine (CsA) groups. Primary outcome was incidence of TB and secondary outcomes were timeline of development of TB after RT and pattern of TB in the two groups. Of the 1664 patients included, 582 patients received CsA-based immunosuppression while 1082 received Tac-based immunosuppression. Duration of dialysis, positive tuberculin skin test, use of induction, mycophenolate mofetil use, CMV infection, and NODAT were significantly more, and hepatitis B infection, past treated TB, and acute rejection episodes were significantly less in the Tac group. At the end of follow-up, incidence of TB in the Tac group was significantly less than in the CsA group (6.1% vs 19.9%, P<.001). Mean time for development of TB after RT was similar in both the groups and nodal and disseminated TB were more common in the Tac group. In conclusion, our study shows that use of Tac as compared to CsA significantly decreases incidence of PTTB. Time of infection since transplant was similar in both the groups. However, nodal and disseminated TB were more common in the Tac group. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Epstein-Barr virus-positive cytotoxic T-cell lymphoma followed by chronic active Epstein-Barr virus infection-associated T/NK-cell lymphoproliferative disorder: a case report.

PubMed

Kato, Seiichi; Miyata, Tomoko; Takata, Katsuyoshi; Shimada, Satoko; Ito, Yoshinori; Tomita, Akihiro; Elsayed, Ahmed Ali; Takahashi, Emiko; Asano, Naoko; Kinoshita, Tomohiro; Kimura, Hiroshi; Nakamura, Shigeo

2013-12-01

A 30-year-old female patient presented with intestinal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (EBV+ CTL), which was surgically resected. Fourteen years later, she returned to our hospital with hypersensitivity to mosquito bites and was diagnosed with chronic active EBV infection-associated T/NK-cell lymphoproliferative disorder (CAEBV/TNK-LPD). She developed systemic EBV+ CTL at age 47 years during the 2.5-year clinical course of CAEBV/TNK-LPD, despite multiagent chemotherapy and allogeneic stem cell transplantation. Afterward, she had a rapidly deteriorating clinical course and died at age 48 years. The immunophenotype of the EBV+ CTL was consistently a CD3, CD8, and cytotoxic molecule-positive type with the same clonality in polymerase chain reaction analysis of T-cell receptor-γ chain gene rearrangement. This is the first reported case of EBV+ CTL preceding the clinical presentation of CAEBV/TNK-LPD. The present case was unique in suggesting a close relationship between EBV+ CTL and chronic active EBV infection. © 2013.

Genetic testing for TMEM154 mutations associated with lentivirus susceptibility in sheep

USDA-ARS?s Scientific Manuscript database

In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affect millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV) in the U.S., and Visna/Maedi virus (VMV) elsewhere, these viruses reduce an animal’s health, productivity, ...

Genetic testing for TMEM154 mutations associated with lentivirus susceptibility in sheep

USDA-ARS?s Scientific Manuscript database

Ovine lentiviruses cause incurable, progressive, lymphoproliferative diseases that affect millions of sheep worldwide. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been recently associated with lentivirus infections in U.S. sheep. Sheep with the two most common TMEM1...

Epstein-Barr virus nuclear antigen-2 detection and typing in immunocompromised children correlated with lymphoproliferative disorder biopsy findings.

PubMed

Mendes, Thiago Marques; Oliveira, Léa Campos de; Yamamoto, Lídia; Del Negro, Gilda Maria Barbaro; Okay, Thelma Suely

2008-06-01

Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis, plays a significant role as a cofactor in the process of tumorigenesis, and has consistently been associated with a variety of malignancies especially in immunocompromised patients. Forty-four children and adolescents (21 liver transplant patients, 7 heart transplant, 5 AIDS, 3 autoimmune hepatitis, 2 nephritic syndromes, 2 medullar aplasia, 2 primary immunodeficiency disorder patients, 1 thrombocytopenic purpura and 1 systemic lupus erythematosus) presenting with chronic active EBV infection (VCA-IgM persistently positive; VCA-IgG > 20 AU/mL and positive IgG _ EBNA) had peripheral blood samples obtained during clinically characterized EBV reactivation episodes. DNA samples were amplified in order to detect and type EBV on the basis of the EBNA-2 sequence (EBNA2 protein is essential for EBV-driven immortalization of B lymphocytes). Although we have found a predominance of type 1 EBNA-2 virus (33/44; 75%), 10 patients (22.73%) carried type 2 EBNA-2, and one liver transplant patient (2.27%) a mixture of the two types, the higher proportion of type 2 EBV, as well as the finding of one patient bearing the two types is in agreement with other reports held on lymphoproliferative disorder (LPD) patients, which analyzed tumor biopsies. We conclude that EBNA-2 detection and typing can be performed in peripheral blood samples, and the high prevalence of type 2 in our casuistic indicates that this population is actually at risk of developing LPD, and should be monitored.

Kidney Involvement of Patients with Waldenström Macroglobulinemia and Other IgM-Producing B Cell Lymphoproliferative Disorders.

PubMed

Higgins, Larissa; Nasr, Samih H; Said, Samar M; Kapoor, Prashant; Dingli, David; King, Rebecca L; Rajkumar, S Vincent; Kyle, Robert A; Kourelis, Taxiarchis; Gertz, Morie A; Dispenzieri, Angela; Lacy, Martha Q; Buadi, Francis K; Ansell, Stephen M; Gonsalves, Wilson I; Thompson, Carrie A; Fervenza, Fernando C; Zand, Ladan; Hwa, Yi L; Jevremovic, Dragan; Shi, Min; Leung, Nelson

2018-05-30

Kidney involvement in Waldenström macroglobulinemia is less well described compared with kidney manifestations in multiple myeloma. Of the 1363 patients seen with Waldenström macroglobulinemia and other IgM-secreting B cell lymphoproliferative disorders seen at the Mayo Clinic between 1996 and 2015, 57 kidney biopsies were retrospectively studied. The biopsy findings were correlated with clinical, kidney, and hematologic characteristics. Criteria for inclusion were evidence of a monoclonal IgM protein and availability of a kidney and a bone marrow biopsy for review. Glomerular and tubulointerstitial pathologies were categorized according to whether they were related to the monoclonal IgM. Of the 57 patients identified, monoclonal gammopathy-related kidney lesions were identified in 82% (47 of 57 biopsies), whereas nonmonoclonal gammopathy-related kidney lesions were seen in 18% (ten of 57). Monoclonal gammopathy-related kidney lesions included monoclonal Ig-related amyloidosis ( n =19; 33%), nonamyloid glomerulopathy ( n =20, 35%), and tubulointerstitial nephropathies ( n =8; 14%). The most common monoclonal gammopathy-related kidney lesion was monoclonal Ig-related amyloidosis ( n =19; 33%) followed by cryoglobulinemic GN ( n =13; 28%). Lymphoma infiltration was the most common tubulointerstitial lesion ( n =4; 9%). The hematologic diagnosis was Waldenström macroglobulinemia in 74% ( n =42), monoclonal gammopathy of renal significance in 16% ( n =9), and marginal zone lymphoma ( n =2), chronic lymphocytic leukemia ( n =2), and low-grade B cell lymphoma ( n =2) in 4% each. Our study confirms a diverse variety of kidney lesions in patients with monoclonal IgM gammopathy. Copyright © 2018 by the American Society of Nephrology.

Esophageal Dysmotility, Gastro-esophageal Reflux Disease, and Lung Transplantation: What Is the Evidence?

PubMed

Wood, Richard K

2015-12-01

Lung transplantation is an effective and life-prolonging therapy for patients with advanced lung disease (ALD). However, long-term patient survival following lung transplantation is primarily limited by development of an inflammatory and fibrotic process involving the lung allograft known as bronchiolitis obliterans syndrome (BOS). Although the precise cause of BOS remains uncertain and is likely multifactorial, chronic aspiration of gastro-duodenal contents is one possible contributing factor. Multiple small, cross-sectional studies performed over the past two decades have reported a high prevalence of gastro-esophageal reflux disease (GERD) and esophageal dysmotility in the ALD population and several investigations suggest the prevalence may increase following lung transplantation. More recent studies evaluating the direct effect of gastro-duodenal contents on airways have demonstrated a possible biologic link between GERD and BOS. Despite the recent advances in our understanding of BOS, further investigations are needed to establish GERD as a causative factor in its development. This review will discuss the existing literature that has identified an association of GERD with ALD and post-transplant populations, with a focus on recent advances in the field.

Renal transplantation in children with sickle cell disease: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

PubMed

Warady, B A; Sullivan, E K

1998-05-01

Sickle cell disease is a rare cause of end-stage renal disease (ES-RD) in pediatrics accounting for only 0.5% and 0.2% of the patients registered in the dialysis and transplant arms of the NAPRTCS database, respectively. Accordingly, the single-center experience with this disorder is extremely rare, and little information on patient and graft outcome is available. Between 1989-1995, 9 patients with sickle cell nephropathy (5 male and 4 female) received 10 transplants [7 cadaver (CAD) and 3 living-related donor (LRD)]. The mean age at the time of the first transplant was 16.0 +/- 1.6 years. Prior to transplantation, all patients received maintenance dialysis (4 HD, 4 PD, 1 HD/PD) for 21.4 +/- 16.1 months (range 3-47 months), and all had received > 5 lifetime random blood transfusions. There was a mean 15.9 consecutive days of hospitalization from transplantation to discharge. Initial immunosuppression consisted of methyl predinsolone/prednisone (9 patients) cyclosporine (7 patients) and azathioprine (8 patients). ATG/ALG or OKT3 were used in 3 CAD transplants. There have been 21 acute rejection episodes in 7 of the 9 patients. Two patients had no rejections and 2 patients had 6 rejections each. Six of the 21 rejection episodes occurred within the first 100 days post-transplant. Nine (43%) of the rejections were completely reversed, the reversal rate varying from 71% for first rejections to 29% for second and subsequent rejections. Four (40%) of the 10 grafts have failed. Graft survival at 12 and 24 months post-transplant is 0.89 +/- 0.11 and 0.71 +/- 0.18, respectively. Patient survival is 89%. The present experience suggests that renal transplantation is a viable option for the adolescent patient with sickle cell nephropathy and ESRD.

Cyclophosphamide for Prevention of Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation in Patients With Hematological Malignancies

ClinicalTrials.gov

2017-05-17

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Myeloid Leukemia in Remission; Adult Erythroleukemia (M6a); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Adult Pure Erythroid Leukemia (M6b); Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell

Drug-drug interactions between immunosuppressants and antidiabetic drugs in the treatment of post-transplant diabetes mellitus.

PubMed

Vanhove, Thomas; Remijsen, Quinten; Kuypers, Dirk; Gillard, Pieter

2017-04-01

Post-transplant diabetes mellitus is a frequent complication of solid organ transplantation that generally requires treatment with lifestyle interventions and antidiabetic medication. A number of demonstrated and potential pharmacokinetic drug-drug interactions (DDIs) exist between commonly used immunosuppressants and antidiabetic drugs, which are comprehensively summarized in this review. Cyclosporine (CsA) itself inhibits the cytochrome P450 (CYP) 3A4 enzyme and a variety of drug transporters. As a result, it increases exposure to repaglinide and sitagliptin, will likely increase the exposure to nateglinide, glyburide, saxagliptin, vildagliptin and alogliptin, and could theoretically increase the exposure to gliquidone and several sodium-glucose transporter (SGLT)-2 inhibitors. Currently available data, although limited, suggest that these increases are modest and, particularly with regard to gliptins and SGLT-2 inhibitors, unlikely to result in hypoglycemia. The interaction with repaglinide is more pronounced but does not preclude concomitant use if repaglinide dose is gradually titrated. Mycophenolate mofetil and azathioprine do not engage in DDIs with any antidiabetic drug. Although calcineurin inhibitors (CNIs) and mammalian target of rapamycin inhibitors (mTORi) are intrinsically prone to DDIs, their disposition is not influenced by metformin, pioglitazone, sulfonylureas (except possibly glyburide) or insulin. An effect of gliptins on the disposition of CNIs and mTORi is unlikely, but has not been definitively ruled out. Based on their disposition profiles, glyburide and canagliflozin could affect CNI and mTORi disposition although this requires further study. Finally, delayed gastric emptying as a result of glucagon-like peptide-1 agonists seems to have a limited, but not necessarily negligible effect on CNI disposition. Copyright © 2016 Elsevier Inc. All rights reserved.

Liver transplantation outcomes among Caucasians, Asian Americans, and African Americans with hepatitis B.

PubMed

Bzowej, Natalie; Han, Steven; Degertekin, Bulent; Keeffe, Emmet B; Emre, Sukru; Brown, Robert; Reddy, Rajender; Lok, Anna S

2009-09-01

Several previous studies found that Asians transplanted for hepatitis B virus (HBV) infection had worse post-transplant outcomes than Caucasians. Data on post-transplant outcomes of African Americans and waitlist outcomes of Asian Americans and African Americans with hepatitis B are scant. The aim of this study was to compare waitlist and post-transplant outcomes among Asian Americans, African Americans, and Caucasians who had HBV-related liver disease. Data from a retrospective-prospective study on liver transplantation for HBV infection were analyzed. A total of 274 patients (116 Caucasians, 135 Asians, and 23 African Americans) from 15 centers in the United States were enrolled. African Americans were younger and more Asian Americans had hepatocellular carcinoma (HCC) at the time of liver transplant listing. The probability of undergoing transplantation and the probability of survival on the waitlist were comparable in the 3 racial groups. Of the 170 patients transplanted, 19 died during a median follow-up of 31 months. The probability of post-transplant survival at 5 years was 94% for African Americans, 85% for Asian Americans, and 89% for Caucasians (P = 0.93). HCC recurrence was the only predictor of post-transplant survival, and recurrence rates were similar in the 3 racial groups. Caucasians had a higher rate of HBV recurrence: 4-year recurrence was 19% versus 7% and 6% for Asian Americans and African Americans, respectively (P = 0.043). In conclusion, we found similar waitlist and post-transplant outcomes among Caucasians, Asian Americans, and African Americans with hepatitis B. Our finding of a higher rate of HBV recurrence among Caucasians needs to be validated in other studies. (c) 2009 AASLD.

Predictors of post-traumatic psychological growth in the late years after lung transplantation.

PubMed

Fox, Kristen R; Posluszny, Donna M; DiMartini, Andrea F; DeVito Dabbs, Annette J; Rosenberger, Emily M; Zomak, Rachelle A; Bermudez, Christian; Dew, Mary Amanda

2014-04-01

Although lung transplantation improves quality of life, most psychosocial research focuses on adverse psychological and social functioning outcomes. Positive effects, particularly in the late-term years as physical morbidities increase, have received little attention. We provide the first data on a psychological benefit - post-traumatic growth (PTG) - and we focused on long-term (>5 yr) survivors. Among 178 patients from a prospective study of mental health during the first two yr post-transplant, we recontacted survivors 6-11 yr post-transplant. We assessed PTG (i.e., positive psychological change resulting from the transplant) and examined its relationship to other patient characteristics with multivariable regression analyses. Sixty-four patients (86% of survivors) were assessed (M = 8.1 yr post-transplant, SD = 1.2). Mean PTG exceeded the scale's midpoint (M = 38.6, SD = 10.0; scale midpoint = 25). Recipients experiencing greater PTG were female (p = 0.022), less educated (p = 0.014), and had a history of post-transplant panic disorder (p = 0.005), greater friend support (p = 0.048), and better perceived health (p = 0.032). Neither other pre- or post-transplant mood and anxiety disorders nor transplant-related morbidities (acute rejection, bronchiolitis obliterans syndrome) predicted PTG. PTG exceeded levels observed in other chronic disease populations, suggesting that lung transplantation may uniquely foster positive psychological change in long-term survivors. PTG occurs despite physical and psychiatric morbidities. Whether PTG promotes other positive post-transplant psychosocial outcomes deserves attention. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Existence of circulating anti-endothelial cell antibodies after heart transplantation is associated with post-transplant acute allograft rejection.

PubMed

Lehle, Karla; Kroher, Johannes; Kolat, Philipp; von Süßkind-Schwendi, Marietta; Schmid, Christof; Haneya, Assad; Rupprecht, Leopold; Hirt, Stephan

2016-05-01

Anti-endothelial cell antibodies (AECA) may be involved in the development of heart allograft rejection. Its detection might be a cheap and noninvasive method to identify high-risk patients. An indirect immunofluorescence method on human umbilical vein endothelial cells was used to investigate the presence of AECAs in 260 pre- and post-transplant serum samples sequentially collected from 34 patients within the first year after heart transplantation (HTX). The presence of AECAs before (23.5 %) and early after HTX (14.7 %) was associated with a significantly increased risk of early acute rejection (75 and 60 %, respectively) compared to 33 % in AECA-negative patients (p = 0.049). Moreover, rejections from AECA-positive patients were more severe (p = 0.057) with a significantly increased incidence of multiple (p = 0.025). The mean number of the sum of rejection episodes was significantly higher in AECA-positive patients (p ≤ 0.05). Patients free of AECAs mainly received mycophenolate mofetil as primary immunosuppression (p = 0.067). Nevertheless, the presence of AECAs did not affect long-term outcome and mortality of HTX patients. Despite a low number of patient samples, the detection of AECAs before and early after HTX could be used as a biomarker for an increased risk of early acute rejection in high-risk patients. This easy method might be a valuable tool to support screening procedures to improve individualized immunosuppressive therapy.

Reluctance to Accept Alcohol Treatment by Alcoholic Liver Disease Transplant Patients: A Qualitative Study

PubMed Central

Heyes, Cathy M.; Schofield, Toni; Gribble, Robert; Day, Carolyn A.; Haber, Paul S.

2016-01-01

Background Liver transplantation (LT) is the optimum treatment for patients with end-stage alcoholic liver disease (ALD). However, despite a recognized risk of relapse to harmful drinking, ALD transplant patients are reluctant to use speciality alcohol treatment to support their abstinence, even when offered within the LT context. This study aimed to understand and identify factors contributing to alcohol treatment reluctance by ALD patients undergoing transplantation. Methods We conducted an in-depth qualitative study of ALD transplant patients. Minimally structured face-to-face interviews explored participants' alcohol-related experiences and their reasons for not using alcohol treatment during the course of their transplantation. Thematic analysis was used to analyze and interpret interview data to understand treatment reluctance based on participants' experiences. Results Five major themes were identified among 3 subgroups of patients (pretransplant and posttransplant abstainers and posttransplant relapsers): (i) the “contract” of mandatory abstinence, (ii) the “gap in the program” involving the lack of candour between patient and staff about alcohol-related matters and the lack of addiction services, (iii) a preference by participants to self-manage their alcohol use disorder, (iv) social support as a facilitator of abstinence and the risk of relapse when social support is diminished, and (v) the fear of stigmatization. Each of these factors were dynamically interrelated and differed slightly for each subgroup. Conclusions The LT services may benefit from the inclusion of integrated specialist addiction services in their model of care. Such an approach may enhance the acceptability of alcohol treatment and reduce the risk of relapse among ALD transplant participants, especially for those whose social supports have diminished. PMID:27795986

Monitoring of Cytomegalovirus (CMV)-Specific Cell-Mediated Immunity in Heart Transplant Recipients: Clinical Utility of the QuantiFERON-CMV Assay for Management of Posttransplant CMV Infection.

PubMed

Chiereghin, Angela; Potena, Luciano; Borgese, Laura; Gibertoni, Dino; Squarzoni, Diego; Turello, Gabriele; Petrisli, Evangelia; Piccirilli, Giulia; Gabrielli, Liliana; Grigioni, Francesco; Lazzarotto, Tiziana

2018-04-01

The clinical utility of the QuantiFERON-CMV (QFN-CMV) assay in heart transplant recipients was assessed. Forty-four cytomegalovirus (CMV)-seropositive patients were enrolled: 17 received antiviral prophylaxis, and 27 were managed preemptively. CMV-DNAemia monitoring was performed by the use of a quantitative real-time PCR assay. The QFN-CMV assay was retrospectively performed on blood samples collected at five posttransplant time points. A higher proportion of patients with an indeterminate QFN-CMV result after the suspension of prophylaxis than of patients who showed a global T-cell responsiveness developed CMV infection ( P = 0.036). Patients who reconstituted a CMV-specific response following the first CMV-DNAemia-positive result (42.9%) showed a median CMV-DNAemia peak 1 log of magnitude lower than that seen with patients with indeterminate results, and all controlled viral replication spontaneously. The 25% of patients with an indeterminate result developed CMV disease. In the preemptive strategy group, no differences in the development of subsequent infection, magnitude of viral load, and viral control were observed on the basis of QFN-CMV measurements performed before and after the first CMV-DNAemia-positive result. Considering both CMV prevention strategies, viral relapse was associated with the failure to reconstitute CMV-specific cell-mediated immunity (CMI) after the resolution of the first episode of CMV infection ( P = 0.032). QFN-CMV measurements can be a useful tool for identifying patients (i) at higher risk of developing infection after discontinuing antiviral prophylaxis, (ii) with late CMV infection who would benefit from appropriate antiviral interventions, and (iii) at higher risk of viral relapses. QFN-CMV measurements taken within 1 month posttransplantation (early period) are not revealing. Copyright © 2018 American Society for Microbiology.

Seroprevalence of cytomegalovirus in donors & opportunistic viral infections in liver transplant recipients

PubMed Central

Varghese, Joy; Subramanian, S.; Reddy, Mettu Srinivas; Shanmugam, Naresh; Balajee, G.; Srinivasan, Vijaya; Venkataraman, Jayanthi; Mohamed, Rela

2017-01-01

Background & objectives: Opportunistic virus infections are common in liver transplant (LT) recipients. There is a risk of developing infection with cytomegalovirus (CMV) and herpes-related viruses such as herpes simplex virus-1 and 2 (HSV-1 & 2), Epstein-Barr virus (EBV) and Varicella Zoster virus (VZV), reactivation of infection and recurrent infection. This study was conducted to determine CMV seropositivity in donors and its influence on LT recipients and seropositivity of CMV, HSV-1 and 2, EB viral capsid antigen (EBVCA) and VZV in LT recipients and their reactivation. Methods: Pre-transplant data for IgG and IgM for CMV (and donor), HSV-1 and -2, EB viral capsid antigen (VCA) and VZV were available for 153 recipients. All recipients were on ganciclovir or valganciclovir prophylaxis for three months after LT. For reactivation rates, findings of post-transplant CMV quantitative reverse transcription polymerase chain reaction (CMV qRT-PCR) assay were associated with pre-transplant serological profile. Results: Of the 153 LT recipients, 131 were men (85.6%). The median age of LT was 46 yr (range 9 months-71 yr). Overall exposure to CMV was 71.8 per cent followed by EB VCA (61.4%) and VZV (49.6%). Susceptibility to both HSV-1 and -2 was high across all decades (P<0.001). Seropositivity of CMV in donor was 90.9 per cent (100 out of 110). Post-transplant CMV qRT- PCR was positive in 17 (26.6%; 3 in recipient negative) of 64 samples tested. qRT-PCR assay was positive in one out of four (25%) tested for HSV-1 and nine out of 19 (47.4%) tested for EBV. Two recipients tested for HSV-2 and one for VZV were negative. There were three deaths in recipients (D+ R+) who were also positive for CMV qRT PCR. There was one death due to HSV-1 pneumonia. One patient with EBV reactivation developed post-transplant lymphoproliferative disorder two years after transplant. Interpretation & conclusions: Transplant recipient were at highest risk of acquiring HSV-1 and -2 more so for HSV

Acute Kidney Injury after Liver Transplantation.

PubMed

Durand, François; Francoz, Claire; Asrani, Sumeet K; Khemichian, Saro; Pham, Thomas A; Sung, Randall S; Genyk, Yuri S; Nadim, Mitra K

2018-05-29

Since the implementation of the MELD score-based allocation system, the number of transplant candidates with impaired renal function has increased. The aims of this review are to present new insights in the definitions and predisposing factors that result in acute kidney injury (AKI), and to propose guidelines for the prevention and treatment of post liver transplantation (LT) AKI. This review is based on both systematic review of relevant literature and expert opinion. Pretransplant AKI is associated with posttransplant morbidity, including prolonged post LT AKI which then predisposes to posttransplant chronic kidney disease (CKD). Prevention of posttransplant AKI is essential in the improvement of long term outcomes. Accurate assessment of baseline kidney function at evaluation is necessary, taking into account that serum creatinine overestimates glomerular filtration rate (GFR). New diagnostic criteria for AKI have been integrated with traditional approaches in patients with cirrhosis to potentially identify AKI earlier and improve outcomes. Delayed introduction or complete elimination of calcineurin inhibitors during the first weeks post LT in patients with early posttransplant AKI may improve GFR in high risk patients but with higher rates of rejection and more adverse events. Biomarkers may in the future provide diagnostic information such as etiology of AKI, and prognostic information on renal recovery post-LT, and potentially impact the decision for simultaneous liver-kidney transplantation. Overall, more attention should be paid to pretransplant and early posttransplant AKI to reduce the burden of late CKD.

Bone mineral density before and after OLT: long-term follow-up and predictive factors.

PubMed

Guichelaar, Maureen M J; Kendall, Rebecca; Malinchoc, Michael; Hay, J Eileen

2006-09-01

Fracturing after liver transplantation (OLT) occurs due to the combination of preexisting low bone mineral density (BMD) and early posttransplant bone loss, the risk factors for which are poorly defined. The prevalence and predictive factors for hepatic osteopenia and osteoporosis, posttransplant bone loss, and subsequent bone gain were studied by the long-term posttransplant follow-up of 360 consecutive adult patients with end-stage primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Only 20% of patients with advanced PBC or PSC have normal bone mass. Risk factors for low spinal BMD are low body mass index, older age, postmenopausal status, muscle wasting, high alkaline phosphatase and low serum albumin. A high rate of spinal bone loss occurred in the first 4 posttransplant months (annual rate of 16%) especially in those with younger age, PSC, higher pretransplant bone density, no inflammatory bowel disease, shorter duration of liver disease, current smoking, and ongoing cholestasis at 4 months. Factors favoring spinal bone gain from 4 to 24 months after transplantation were lower baseline and/or 4-month bone density, premenopausal status, lower cumulative glucocorticoids, no ongoing cholestasis, and higher levels of vitamin D and parathyroid hormone. Bone mass therefore improves most in patients with lowest pretransplant BMD who undergo successful transplantation with normal hepatic function and improved gonadal and nutritional status. Patients transplanted most recently have improved bone mass before OLT, and although bone loss still occurs early after OLT, these patients also have a greater recovery in BMD over the years following OLT.

X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia disease: a combined immune deficiency with magnesium defect.

PubMed

Ravell, Juan; Chaigne-Delalande, Benjamin; Lenardo, Michael

2014-12-01

To describe the role of the magnesium transporter 1 (MAGT1) in the pathogenesis of 'X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia' (XMEN) disease and its clinical implications. The magnesium transporter protein MAGT1 participates in the intracellular magnesium ion (Mg) homeostasis and facilitates a transient Mg influx induced by the activation of the T-cell receptor. Loss-of-function mutations in MAGT1 cause an immunodeficiency named 'XMEN syndrome', characterized by CD4 lymphopenia, chronic EBV infection, and EBV-related lymphoproliferative disorders. Patients with XMEN disease have impaired T-cell activation and decreased cytolytic function of natural killer (NK) and CD8 T cells because of decreased expression of the NK stimulatory receptor 'natural-killer group 2, member D' (NKG2D). Patients may have defective specific antibody responses secondary to T cell dysfunction, but B cells have not been shown to be directly affected by mutations in MAGT1. XMEN disease has revealed a novel role for free intracellular magnesium in the immune system. Further understanding of the MAGT1 signaling pathway may lead to new diagnostic and therapeutic approaches.

[Acquired angioedema – clinical characteristic of the patients diagnosed in 2012-2016 with acquired C1 inhibitor deficiency].

PubMed

Stobiecki, Marcin; Czarnobilska, Ewa; Obtułowicz, Krystyna

Acquired angioedema is a rare disease caused by a deficiency of C1 esterase inhibitor with recurrent swelling symptoms. It may occur in the course of lymphoproliferative disorders or autoimmune diseases. Symptoms resemble hereditary angioedema, and the only differentiating features is negative family history, late onset of symptoms and accompanying lymphoproliferative disorder. The aim of the study was to analyze the cases of acquired angioedema. The retrospective analysis of 341 patients from the registry of patients with C1 inhibitor deficiency. Results: We identified 4 patients among 119 with HAE (3.57%) diagnosed in this same period of time 2012-2016 who fulfilled the criteria of acquired edema. In two cases the primary reason of angioedema was lymphoproliferive disease, in two monoclonal gammapathy of unknown reason. We analyzed also the results of laboratory tests C4, C1 inhibitor, C1q. In all cases the face was dominated localization. After the treatment of primary lymphoproliferive disease, in two cases, we observed total remission of angioedema. Only one patient with gammapathy require treatment with C1 inhibitor during the attacks. In these case we observed both plasma deriver, and recombinant C1 inhibitor were effective.

EBNA3C-Mediated Regulation of Aurora Kinase B Contributes to Epstein-Barr Virus-Induced B-Cell Proliferation through Modulation of the Activities of the Retinoblastoma Protein and Apoptotic Caspases

PubMed Central

Jha, Hem Chandra; Lu, Jie; Saha, Abhik; Cai, Qiliang; Banerjee, Shuvomoy; Prasad, Mahadesh A. J.

2013-01-01

Epstein-Barr virus (EBV) is an oncogenic gammaherpesvirus that is implicated in several human malignancies, including Burkitt's lymphoma (BL), posttransplant lymphoproliferative disease (PTLD), nasopharyngeal carcinoma (NPC), and AIDS-associated lymphomas. Epstein-Barr nuclear antigen 3C (EBNA3C), one of the essential EBV latent antigens, can induce mammalian cell cycle progression through its interaction with cell cycle regulators. Aurora kinase B (AK-B) is important for cell division, and deregulation of AK-B is associated with aneuploidy, incomplete mitotic exit, and cell death. Our present study shows that EBNA3C contributes to upregulation of AK-B transcript levels by enhancing the activity of its promoter. Further, EBNA3C also increased the stability of the AK-B protein, and the presence of EBNA3C leads to reduced ubiquitination of AK-B. Importantly, EBNA3C in association with wild-type AK-B but not with its kinase-dead mutant led to enhanced cell proliferation, and AK-B knockdown can induce nuclear blebbing and cell death. This phenomenon was rescued in the presence of EBNA3C. Knockdown of AK-B resulted in activation of caspase 3 and caspase 9, along with poly(ADP-ribose) polymerase 1 (PARP1) cleavage, which is known to be an important contributor to apoptotic signaling. Importantly, EBNA3C failed to stabilize the kinase-dead mutant of AK-B compared to wild-type AK-B, which suggests a role for the kinase domain in AK-B stabilization and downstream phosphorylation of the cell cycle regulator retinoblastoma protein (Rb). This study demonstrates the functional relevance of AK-B kinase activity in EBNA3C-regulated B-cell proliferation and apoptosis. PMID:23986604

Extranodal marginal zone B cell lymphoma of the orbit in a patient with sarcoidosis: a case report.

PubMed

Richards, Nikisha Q; Kidwell, Earl D R; Ramadan, Ali M; Naab, Tammey J

2014-10-20

To describe a case of extranodal marginal zone B-cell lymphoma (EMZL) "mucosa associated lymphoid tissue (MALT)" of the orbit that presented with stage IV disease in a patient with sarcoidosis. Clinicopathologic case report. Biopsies of the lesion were performed in the operating room and the samples were submitted for pathology processing. Pathology analysis identified the lesion as an extranodal marginal zone B-cell lymphoma "mucosa associated lymphoid tissue (MALT)" via flow cytometry, histopathology, cytogenetics, and immunohistochemical staining and fluorescent in situ hybridization (FISH). The institutional review board of Howard University Hospital waived the need for IRB approval for this intraoperative finding. A 70-year-old Black woman with biopsy-proven sarcoidosis presented complaining of foreign body sensation, redness, swelling of her left upper eyelid and tearing. The patient was found to have an orbital lymphoproliferative malignancy. It is still unclear if the presence of immunosuppression or an autoimmune disease increases the risk of lymphoproliferative malignancies {6}. Malignancy should always be suspected and investigated.

Epidemiology of skin diseases in renal transplant recipients in a tertiary hospital.

PubMed

Chen, Qi Ping; Aw, Derrick C W

2010-12-01

There is no published epidemiological data on skin diseases in kidney transplant recipients in this tropical country, which has multi-ethnic groups with the Chinese as the predominant ethnic group. Skin diseases of 143 renal transplant recipients were studied in a skin clinic of a tertiary institution during annual surveillance visits from June 2006 to March 2009. Our study showed that except the common drug specific skin manifestations, sebaceous hyperplasia (56.6%), seborrheic keratosis (60.8%), melanocytic naevi (76.9%), skin tags (37.1%) and viral (29.4%) and fungal (20.3%) infections were the most prevalent skin diseases among renal transplant recipients living in Singapore. The prevalence of pre-malignant and malignant tumours was very low (11.2% actinic keratosis, 1.4% Bowen's disease, 1.4% squamous cell carcinoma, 0.7% basal cell carcinoma, 0.7% keratoacanthoma). Male predominance was seen in sebaceous hyperplasia (72.4% vs 32.1%), actinic keratosis (17.2% vs 1.8%), viral (36.8% vs 19.6%) and fungal (27.6% vs 8.9%) infections. Our study also showed increased prevalence of sebaceous hyperplasia with increased age but its prevalence was significantly higher than that reported in the age matched general population. The prevalence of seborrheic keratosis, actinic keratosis and viral infection correlated positively with post-transplant duration. Our study provides epidemiological data for the prevalence of skin diseases in renal transplant recipients. It emphasises the importance of dermatologic follow-up for renal transplant patients in order to obtain a diagnosis and manage treatable skin diseases.

Seroprevalence of Epstein-Barr Virus, Cytomegalovirus, and Polyomaviruses in Children with Inflammatory Bowel Disease.

PubMed

Hradsky, Ondrej; Copova, Ivana; Zarubova, Kristyna; Durilova, Marianna; Nevoral, Jiri; Maminak, Miroslav; Hubacek, Petr; Bronsky, Jiri

2015-11-01

Young age and thiopurine therapy are risk factors for lymphoproliferative disease among patients with inflammatory bowel disease (IBD). The aims of this study were to evaluate the prevalence of seropositivity for the Epstein-Barr virus (EBV) and human cytomegalovirus (CMV) among children and adolescents with IBD, to assess the viral load of EBV, CMV, and BK and JC polyomaviruses (BKV, JCV) in these patients, and to assess the influence of different therapeutic regimens on seroprevalence and viral load. Children who had been followed in our center were tested for EBV, CMV, BKV, and JCV in a cross-sectional study. One hundred and six children were included who had Crohn's disease (68%), ulcerative colitis (29%), and unclassified IBD (3%). We found that 64% of patients were EBV seropositive. The proportion of EBV seropositive patients increased during childhood. Azathioprine therapy (p = 0.003) was associated with EBV seropositivity in a multiple logistic regression model, after adjusting for gender, age, and disease activity at determination. We found a significant association between the number of polymerase chain reaction copies and infliximab dose (p = 0.023). We did not find any significant association between CMV serology and CMV, BKV, or JCV viral load, or any other therapeutic regimen or clinical characteristics. Treatment with azathioprine appears to be a risk factor for early EBV seropositivity in children with IBD, and the infliximab dose was associated with a higher EBV viral load.

A Comprehensive Review of Celiac Disease/Gluten-Sensitive Enteropathies.

PubMed

McAllister, Brian P; Williams, Emmanuelle; Clarke, Kofi

2018-06-02

. Simple algorithms for care based on a comprehensive multidisciplinary approach are proposed. Refractory and non-responsive celiac diseases in the setting of a gluten-free diet are examined as are novel non-dietary therapies. Finally, the association of other disease states including psychiatric illness, infertility, lymphoproliferative malignancy, and mortality is explored with special attention paid to autoimmune and atopic disease.

[Kikuchi-Fujimoto disease prior to childhood-systemic lupus erythematosus diagnosis].

PubMed

Martins, Sofia S; Buscatti, Izabel M; Freire, Pricilla S; Cavalcante, Erica G; Sallum, Adriana M; Campos, Lucia M A; Silva, Clovis A

2014-01-01

Kikuchi-Fujimoto disease (KFD) is a self-limiting histiocytic necrotizing lymphadenitis of unknown origin. Of note, KFD was infrequently reported in adult systemic lupus erythematosus (SLE), with rare occurrence in childhood-SLE (C-SLE) patients. To our knowledge, the prevalence of KFD in the paediatric lupus population was not studied. Therefore, in a period of 29 consecutive years, 5,682 patients were followed at our institution and 289 (5%) met the American College of Rheumatology classification criteria for SLE, one had isolated KFD (0.03) and only one had KFD associated to C-SLE diagnoses, which case was reported herein. A 12 year-old female patient had high fever, fatigue and cervical and axillary lymphadenopathy. The antinuclear antibodies (ANA) were negative, with positive IgM and IgG herpes simplex virus type 1 and type 2 serologies. Fluorine-18-fluoro-deoxy-glucose positron emission tomography/computed tomography (PET/CT) imaging demonstrated diffuse lymphadenopathy. The axillary lymph node biopsy showed necrotizing lymphadenitis with histiocytes, without lymphoproliferative disease, compatible with KFD. After 30 days, she presented spontaneous regression and no therapy was required. Nine months later, she developed malar rash, photosensitivity, oral ulcers, lymphopenia and ANA 1:320 (homogeneous nuclear pattern). At that moment the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score was 10 and she was treated with prednisone (1.0mg/kg/day) and hidroxychloroquine showing progressive improvement of hers signs and symptoms. In conclusion, KFD is a benign and rare disease in our paediatric lupus population. We also would like to reinforce the relevance of autoimmune diseases diagnosis during the follow-up of patients with KFD. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.