IL-6, a multifunctional cytokine produced by monocytes, fibroblasts, and endothelial cells, promotes the growth of EBV-immortalized B cells in vitro and renders these cells tumorigenic in athymic mice. In the present study, serum/plasma IL-6 bioactivity was found to be abnormally elevated, albeit transiently, in 17 of 18 solid organ transplant recipients with posttransplant lymphoproliferative disease (PTLD), with a mean maximal level of 196.7 U/ml. This represents a 16.4 increase above the normal mean (11.3 U/ml). In contrast, only 3 of 10 solid organ transplant recipients with uncomplicated courses posttransplant had abnormally elevated serum/plasma IL-6 bioactivity (mean maximal level 41.4 U/ml, P = 0.0007). When transferred to single cell culture, the 11 PTLD tissues produced 640 to 1.25 x 10(6) IL-6 U/ml in the culture supernatant, with a mean maximal level of 35,025 IL-6 U/ml. Cell separation experiments demonstrated that the adherent cells, identified as non-B cells, were the principal source of IL-6 production in vitro by PTLD tissue. Control cultures of inflammatory lymphoid tissue negative for lymphoproliferative disease as well as of PBL from patients with acute EBV-induced infectious mononucleosis consistently produced < 10 IL-6 U/ml. Thus, IL-6 is produced at high levels by PTLD tissues and may play a critical role in the pathogenesis of PTLD. PMID:8514888
Tosato, G; Jones, K; Breinig, M K; McWilliams, H P; McKnight, J L
We report a 12-year-old girl suffering from end-stage renal disease due to focal-segmental sclerosis and retardation of statomotoric\\u000a and mental development of unknown origin. Renal transplantation (TX) was performed 7 months after initiation of peritoneal\\u000a dialysis at the age of 11 years. Immunosuppressive therapy included cyclosporine A, mycophenolate mofetil and methylprednisolone.\\u000a The patient developed spiking fever up to 40°C without
Christoph Licht; Karen Hell; Frank Eifinger; Bernd Hoppe; Uwe Querfeld
Post-transplant lymphoproliferative disorders (PTLD) are a serious complication after solid organ or allogeneic hematopoietic stem cell transplantation and include a range of diseases from benign proliferations to malignant lymphomas. Risk factors for developing PTLD include Epstein-Barr virus (EBV) infection, recipient age, transplanted organ, type of immunosuppression, and genetics. Uncontrolled proliferation of EBV-infected B cells is implicated in EBV-positive PTLD, whereas the pathogenesis of EBV-negative PTLD may be similar to non-Hodgkin's lymphoma in the general population. The World Health Organization (WHO) classifies PTLD into four categories: early lesions, polymorphic PTLD, monomorphic PTLD, and classical Hodgkin's lymphoma (cHL). Treatment is aimed at cure of PTLD, while maintaining transplanted organ function. However, there are no established guidelines for the treatment of PTLD. Immune suppression reduction (ISR) is the first line of treatment in most cases, with more recent data suggesting early use of rituximab. In more aggressive forms of PTLD, upfront chemotherapy may offer a better and more durable response. Sequential therapy using rituximab followed by chemotherapy has demonstrated promising results and may establish a standard of care. Novel therapies including anti-viral agents, adoptive immunotherapy, and monoclonal antibodies targeting cytokines require further study in the prevention and treatment of PTLD. PMID:25655616
Singavi, Arun K; Harrington, Alexandra M; Fenske, Timothy S
Management of aggressive, usually late-occurring, post-transplant lymphoproliferative disorders (PTLDs), a life-threatening complication after solid organ transplants, remains controversial. Four children affected by aggressive CD20+ PTLDs received a chemo-immunotherapy regimen for remission induction based on fludarabine, cyclophosphamide, doxorubicin, and rituximab, associated with a rapid discontinuation of immunosuppression (IS). Subsequent consolidation chemotherapy consisted of Berlin-Frankfurt-Münster-modified blocks. All patients achieved a complete remission, which persisted for 25, 68+, 80+, and 103+ months after diagnosis. Therapy was well tolerated. No patients developed allograft rejection during PTLD treatment. Our experience suggests that this chemo-immunotherapeutic approach may be an effective treatment strategy while allowing for a concomitant discontinuation of IS. PMID:21294246
Giraldi, Eugenia; Provenzi, Massimo; Fiocchi, Roberto; Colledan, Michele; Cornelli, Pieremilio; Torre, Giuliano; Rambaldi, Alessandro; Conter, Valentino
Lymphoproliferative diseases (LPDs) associated with Epstein-Barr virus (EBV) infection cause significant morbidity and mortality in bone marrow and solid organ transplant recipients. To gain insight into LPD pathogenesis and to identify potential effective therapeutic approaches, we investigated early molecular events leading to B-cell transformation by gene expression profiling of EBV-infected B-cells from tonsils by Affymetrix microarray 72 hr postinfection when the B-cells hyperproliferation phase starts. Cell cycle and apoptosis were the most significantly affected pathways and enriched gene sets. In particular, we found significantly increased expression of cyclin-dependent kinase (CDK)1 and CCNB1 (cyclin B1) and of one of their downstream targets BIRC5 (survivin). Importantly, the strong upregulation of the antiapoptotic protein survivin was confirmed in lymphoblastoid cell lines (LCLs) and 71% of EBV-positive post-transplant EBV-LPD lesions scored positive for survivin. The validity of early transforming events for the identification of therapeutic targets for EBV-LPD was confirmed by the marked antiproliferative effect of the CDK inhibitor flavopiridol on LCLs and by the strong induction of apoptosis by survivin inhibition with YM155 or terameprocol. Our results suggest that targeting of CDKs and/or survivin in post-transplant EBV-LPD by specific inhibitors might be an important approach to control and eliminate EBV-transformed B-cells that should be further considered. PMID:23640782
Bernasconi, Michele; Ueda, Seigo; Krukowski, Patricia; Bornhauser, Beat C; Ladell, Kristin; Dorner, Marcus; Sigrist, Juerg A; Campidelli, Cristina; Aslandogmus, Roberta; Alessi, Davide; Berger, Christoph; Pileri, Stefano A; Speck, Roberto F; Nadal, David
Development of Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is a serious complication following heart transplantation (HTX). This study investigates EBV DNA load in adult heart transplant recipients, its association with immunosuppression, and its potential as a marker for development of PTLD. EBV DNA load was measured prospectively by quantitative real-time polymerase chain reaction (PCR) in 172 stable HTX patients. Sixty-seven patients (39.0% of total) had a positive EBV PCR at initial examination [median 4.9 (range 1.1-16.9) years post-HTX]. In follow-up testing of 67 positive patients 6 months later, 36 patients continued to have a positive EBV PCR. Overall incidence of EBV DNA was significantly associated with calcineurin inihibitors, azathioprine medication, and with the absence of mycophenolate mofetil (MMF) treatment. In patients with positive EBV DNA levels at initial examination and negative levels at retesting, cyclosporine A levels were found to be significantly higher at initial examination (148.4 +/- 70.2 vs. 119.6 +/- 53.5 ng/ml, P < 0.05). Three patients (1.7%, 3/172) were diagnosed with PTLD during the course of the study (mean follow up 4.0 years). EBV DNA viral load determination does not appear to be useful for risk prediction or early diagnosis of PTLD in adults after HTX, but an association of EBV DNA load with qualitative and quantitative immunosuppression is demonstrated. PMID:18564989
Doesch, Andreas O; Konstandin, Mathias; Celik, Sultan; Kristen, Arnt; Frankenstein, Lutz; Sack, Falk-Udo; Schnabel, Philipp; Schnitzler, Paul; Katus, Hugo A; Dengler, Thomas J
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare condition that originates from dendritic cells. We report on the first case of Epstein-Barr virus (EBV)-driven post-transplant lymphoproliferative disorder (PTLD) of donor origin in a BPDC patient post-allogeneic haematopoietic stem cell transplantation (HSCT). Flow cytometry study identified a cell population CD4+/CD56+/CD45RA+/CD123+/TCL1+ suggestive of BPDCN diagnosis, which was confirmed by a lymph node biopsy (cells positive for BCL11a, BDCA-2, CD2AP, CD123, TCL1 and S100). Cytogenetic analysis revealed a complex karyotype: (19 metaphase) 47,XX,t(1;6)(q21;q2?5),-13?+?2mar/47, XX, +21 /46,XX . The patient was started on acute myeloid leukaemia (AML) induction schedule, and subsequently an allogeneic HSCT was performed. On day +36 post-HSCT, bone marrow biopsy/aspirate showed complete morphological remission, and chimerism study showed 100% donor chimera. However, on day +37, the patient was found to have enlarged cervical and supraclavicular lymphoadenopathy, splenomegaly and raised lactic dehydrogenase. EBV-DNA copies in blood were elevated, consistent with a lytic cycle. A lymph node biopsy showed EBV encoded RNA and large atypical B cells (CD45dim-, CD4+/CD56+, monoclonal for k-chain, CD19+/CD20+/CD21+/CD22+/CD38+/CD43+/CD79?-/CD5-/CD10-), consistent with PTLD monomorphic type. Chimerism study showed that PTLD was of donor origin. This case together with the recent literature findings on BPDCN and PTLD are discussed. PMID:22915052
Piccin, Andrea; Morello, Enrico; Svaldi, Mirija; Haferlach, Torsten; Facchetti, Fabio; Negri, Giovanni; Vecchiato, Cinzia; Fisogni, Simona; Pusceddu, Irene; Cortelazzo, Sergio
Post-transplant lymphoproliferative disorder (PTLD) is characterised by frequent extranodal manifestation, in 20 - 25 % including the gastrointestinal tract. This entity, which is more frequent after solid organ transplantation, rarely occurs after bone marrow transplantation (BMT). We report the case of a 43-year-old male presenting with a short history of rectal bleeding, diarrhoea and weight loss. He had received a bone marrow transplant two years previously for an acute lymphocytic leukaemia of B-cell origin. On sigmoidoscopy, deep ulcerations of the rectal and sigmoideal mucosa were found. Further investigations revealed a diffuse infiltration of the liver, spleen, both kidneys and lungs. Histologically, a monomorphic post-transplant lymphoproliferative disorder was diagnosed, the subtype was a high grade diffuse-large cell Non-Hodgkin's lymphoma of B-cell origin. The biopsies showed that a major proportion of cells expressed Epstein-Barr virus encoded proteins typical for latent as well as lytic EBV infection. This is a common feature of PTLD and possibly plays a critical role in its pathogenesis. The current therapeutic approach to the subtype of PTLD we saw in this patient is CHOP chemotherapy, comprising the anti-CD 20 antibody rituximab if CD 20-positivity is present. This patient had a fatal course of the disease and died a few days after the first chemotherapy cycle due to severe multiple organ failure. PMID:19280542
Godt, C; Regnery, A; Schwarze, B; Junker, K; Porschen, R
Post-transplant lymphoproliferative disorder (PTLD) can occur after solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). The majority of PTLDs are related to the reactivation of Epstein-Barr virus (EBV) in the lymphoid organs. PLTDs in HSCT recipients tend to present with systemic involvement, and isolated PTLD in these patients is rare. Only 14 isolated cerebral PTLDs have been reported in HSCT recipients, and none have been reported in lymphoma patients. When diagnosing PTLD in a lymphoma patient, it is challenging to discriminate between a PTLD that originated from previous disease and a newly developed clone and to distinguish between donor and recipient origin. In this report, we present the first case of a B-cell lymphoma patient who developed isolated PTLD in the CNS, and we confirmed that the PTLD originated in a distinct clone and from a different origin. Furthermore, the role of EBV-DNA monitoring in such patients is discussed. PMID:24126003
Tang, Tzung-Chih; Chuang, Wen-Yu; Chang, Hung
We report a novel regimen for refractory post-transplant T-cell lymphoma (PTL). Our patient presented with non-Epstein-Barr virus (EBV) related, T-cell post-transplant lymphoproliferative disease (PTLD) 3.5 years after liver transplantation. Initially diagnosed as polyclonal PTLD, the disease progressed to a monoclonal, T-cell PTL that was refractory to several chemotherapy regimens but responded to a regimen consisting of fludarabine, cyclophosphamide, cytarabine, and alemtuzumab. Consolidation therapy included high-dose chemotherapy, autologous hematopoietic stem cell rescue, and radiation therapy. She remains in remission 2.5 years later. T-cell PTL is a rare disease with a poor prognosis; this regimen provides a novel, potentially curative approach for its treatment. PMID:17318876
Williams, Kirsten M; Higman, Meghan A; Chen, Allen R; Schwartz, Cindy L; Wharam, Moody; Colombani, Paul; Arceci, Robert J
Posttransplant lymphoproliferative disorders (PTLDs) were diagnosed in 43 patients from the Pittsburgh-Denver series between June 1980 and March 1987. This constitutes a detection rate of 1.7%. Major categories of clinical presentation included a mononucleosislike syndrome, gastrointestinal/abdominal disease, and solid organ disease. The median time of onset in patients initially immunosuppressed with cyclosporine-A (CsA)-containing regimens was 4.4 months after transplant, regardless of tumor clonality. A strong association of PTLD with Epstein-Barr virus (EBV) was observed. A histologic spectrum of lesions from polymorphic to monomorphic was observed. Whereas polymorphic lesions could be either clonal or nonclonal, monomorphic lesions appeared to be clonal in composition. The presence of large atypical cells (atypical immunoblasts) or necrosis did not appreciably worsen the prognosis. Twelve patients had clonal, 13 had nonclonal, and five had both clonal and nonclonal tumors. Clonality was indeterminate in 13 cases. Most patients were treated with a regimen based on reduced immunosuppression and supportive surgery. Almost all nonclonal and about half of the clonal lesions respond to this conservative therapy, indicating that it is an appropriate first line of treatment. This behavior suggests that a spectrum of lesions ranging from infectious mononucleosis to malignant lymphoma constitutes the entity known as PTLD. Some monoclonal tumors can undergo regression, however, apparently in response to host immune control mechanisms. Because of its short latency and strong association with EBV, PTLD is an important model for the study of virus-associated tumor progression in humans. Images Figure 1 Figure 2A Figure 2B Figure 3 Figure 4 Figure 5 Figure 6 PMID:2845789
Nalesnik, M. A.; Jaffe, R.; Starzl, T. E.; Demetris, A. J.; Porter, K.; Burnham, J. A.; Makowka, L.; Ho, M.; Locker, J.
Posttransplant lymphoproliferative disorder (PTLD) remains one of the most important complications of intensive immunosuppressive therapy. A 65-year-old Caucasian woman received a primary en bloc kidney transplant from a deceased 2-year-old donor. After antithymocyte globulin induction she was treated with a maintenance regimen including cyclosporine and mycophenylate mofetil (MMF). She had a history of recurrent dermatomyositis, suggesting a flawed immune system. After a benign course for 9 months and after an increase in MMF from 2 to 3 g daily, she presented with pneumonia owing to Candida albicans, which was responsive to antibiotics, as was the PTLD. Persistent fever led to a diagnosis of PTLD. The immunosuppressive regimen was converted to sirolimus (SRL) and rituximab, with over 90% necrosis of the neoplasm at 1 month. However, owing to concern at exploration, the allografts were extirpated. This case documented the benefit of the rituximab-SRL combination to treat PTLD while maintaining dermatomyositis in remission. PMID:18589184
Kaposztas, Z; Etheridge, W B; Kahan, B D
Post-transplant lymphoproliferative disorder (PTLD) caused by Epstein-Barr virus (EBV) is a severe complication in high-risk allogeneic hematopoietic stem cell transplant (HSCT) recipients. Central nervous system (CNS) involvement of PTLD is a very rare event in patients with HSCT. As no established standard therapy in CNS-EBV-PTLD is available, the aim of this study was analysis of the safety and efficacy of intrathecal rituximab therapy in a group of eight children and adolescents with CNS-EBV-PTLD. Seven patients responded to therapy: all clinical symptoms and EBV-DNA viral load resolved after a median 2 (range: 1-7) doses of rituximab. However, some magnetic resonance imaging (MRI) changes in brain scan persisted in two patients. In all patients, except one, no adverse events of the therapy were observed. In conclusion, intrathecal rituximab administration seems to be an effective and safe method of treatment of CNS-EBV-PTLD in pediatric stem cell recipients. We recommend this treatment modality for further investigation. PMID:22873830
Czyzewski, Krzysztof; Styczynski, Jan; Krenska, Anna; Debski, Robert; Zajac-Spychala, Olga; Wachowiak, Jacek; Wysocki, Mariusz
Up to 35% of posttransplant lymphoproliferative disorder (PTLD) cases occur within 1 year of transplantation, and over 50% are associated with Epstein-Barr virus (EBV). EBV primary infection and reactivation are PTLD predictive factors, but there is no consensus for their treatment. We conducted a prospective single-center study on 299 consecutive heart-transplant patients treated with the same immunosuppressive regimen and monitored by repetitive EBV viral-load measurements and endomyocardial biopsies to detect graft rejection. Immunosuppression was tapered on EBV reactivation with EBV viral loads >10(5) copies/mL or primary infection. In the absence of response at 1 month or a viral load >10(6) copies/mL, patients received one rituximab infusion (375 mg/m(2) ). All patients responded to treatment without increased graft rejection. One primary infection case developed a possible PTLD, which completely responded to diminution of immunosuppression, and one patient, whose EBV load was unevaluable, died of respiratory complications secondary to PTLD. Compared with a historical cohort of 820 patients, PTLD incidence was decreased (p = 0.033) by a per-protocol analysis. This is the largest study on EBV primary infection/reactivation treatment, the first using rituximab following solid organ transplantation to prevent PTLD and the first to demonstrate an acceptable tolerability profile in this setting. PMID:24666832
Choquet, S; Varnous, S; Deback, C; Golmard, J L; Leblond, V
Post-transplant lymphoproliferative disorders are life-threatening complications following hematopoietic or solid organ transplantation. They represent a spectrum of mostly EBV-driven lymphoplasmacytic proliferations. While the oncogenic effect of EBV is related to latent infection, lytic infection also has a role in lymphomagenesis. In vitro, EBV replication is linked to plasma cell differentiation and XBP1 activation, although this phenomenon has never been addressed in vivo. We analyzed for the first time latent and lytic intratumoral EBV infection in a series of 35 adult patients with a diagnosis of post-transplant lymphoproliferative disorder (26M/9F, median age 54 years). A complete EBV study was performed including the analysis of the latent EBER, latent membrane protein-11, and EBV nuclear antigens as well as the immediate-early BZLF1/ZEBRA and early BMRF1/EADE31 lytic genes. XBP1 activation was assessed by nuclear protein expression. EBV infection was observed in 28 (80%) cases being latency II and III the most frequently observed 22 (79%). Intratumoral EBV replication was detected in 17 (60%) cases. Among these, XBP1 activation was observed in 11/12 evaluable cases associated with strong cytoplasmic immunoglobulin expression consistent with plasma cell differentiation. Intriguingly, the combination of latency III infection and EBV replication identified a high-risk subgroup of patients with significantly shorter survival (overall survival at 1 year 18% vs 48%) and early-onset (median of 7 vs 26 months) post-transplant lymphoproliferative disorder. Moreover, these patients appear to be more heavily immunosuppressed, so they exhibit lower rates of rejection and graft vs host disease but higher rates of cytomegalovirus reactivation. In conclusion, EBV replication is associated with plasma cell differentiation and XBP1 activation with prognostic implications. Both latency III and lytic EBV infection are related to aggressive and early-onset post-transplant lymphoproliferative disorder. These results suggest that immunohistochemical study of latent and lytic EBV genes in the clinical practice may help to select higher-risk patients to new therapies including antiviral treatments. PMID:24762547
Gonzalez-Farre, Blanca; Rovira, Jordina; Martinez, Daniel; Valera, Alexandra; Garcia-Herrera, Adriana; Marcos, Maria Angeles; Sole, Carla; Roue, Gael; Colomer, Dolors; Gonzalvo, Elena; Ribera-Cortada, Imma; Araya, Monica; Lloreta, Josep; Colomo, Luis; Campo, Elias; Lopez-Guillermo, Armando; Martinez, Antonio
2B4 is a surface molecule involved in activation of the natural killer (NK) cell–mediated cytotoxicity. It binds a protein termed Src homology 2 domain–containing protein (SH2D1A) or signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which in turn has been proposed to function as a regulator of the 2B4-associated signal transduction pathway. In this study, we analyzed patients with X-linked lymphoproliferative disease (XLP), a severe inherited immunodeficiency characterized by critical mutations in the SH2D1A gene and by the inability to control Epstein-Barr virus (EBV) infections. We show that, in these patients, 2B4 not only fails to transduce triggering signals, but also mediates a sharp inhibition of the NK-mediated cytolysis. Other receptors involved in NK cell triggering, including CD16, NKp46, NKp44, and NKp30, displayed a normal functional capability. However, their activating function was inhibited upon engagement of 2B4 molecules. CD48, the natural ligand of 2B4, is highly expressed on the surface of EBV+ B cell lines. Remarkably, NK cells from XLP patients could not kill EBV+ B cell lines. This failure was found to be the consequence of inhibitory signals generated by the interaction between 2B4 and CD48, as the antibody-mediated disruption of the 2B4–CD48 interaction restored lysis of EBV+ target cells lacking human histocompatibility leukocyte antigen (HLA) class I molecules. In the case of autologous or allogeneic (HLA class I+) EBV+ lymphoblastoid cell lines, restoration of lysis was achieved only by the simultaneous disruption of 2B4–CD48 and NK receptor–HLA class I interactions. Molecular analysis revealed that 2B4 molecules isolated from either XLP or normal NK cells were identical. As expected, in XLP-NK cells, 2B4 did not associate with SH2D1A, whereas similar to 2B4 molecules isolated from normal NK cells, it did associate with Src homology 2 domain–containing phosphatase 1. PMID:10934222
Parolini, Silvia; Bottino, Cristina; Falco, Michela; Augugliaro, Raffaella; Giliani, Silvia; Franceschini, Roberta; Ochs, Hans D.; Wolf, Hermann; Bonnefoy, Jean-Yves; Biassoni, Roberto; Moretta, Lorenzo; Notarangelo, Luigi D.; Moretta, Alessandro
Rituximab is commonly used as a first line therapy to treat posttransplant lymphoproliferative disorders (PTLDs). It has also proved useful in the management of refractory antibody mediated graft rejection. We report an unusual case in which a heart transplant recipient being treated with rituximab for PTLD developed altered mental status, hallucinations and visual symptoms and magnetic resonance imaging (MRI) findings of symmetrical enhancement suggestive of posterior reversible leukoencephalopathy syndrome (PRES). Resolution of these clinical symptoms and radiological findings after discontinuation of therapy confirmed the diagnosis. This is the first case of PRES seen due to rituximab in a heart transplant recipient. Another unique feature of the case is the development of PRES after second cycle of rituximab as compared to prior reports in nonheart transplant patients in which the syndrome developed after first dose administration. The objective of this case report is to increase the awareness of this rare entity amongst immunocompromised transplant patients. PMID:25648447
Jaiswal, A; Sabnani, I; Baran, D A; Zucker, M J
Lymphoproliferative disorders occur with a greater frequency in recipients of solid organ transplants. Unlike in the general population, these tumors tend to arise in extranodal sites and are often confined to a single organ. We report on a patient with lymphoproliferative disease confined to the hilum of the renal allograft. The only clinical clue to the presence of the tumor
Biff F. Palmer; Arthur I. Sagalowsky; Dwayne A. McQuitty; Ingemar Dawidson; Miguel A. Vazquez; Christopher Y. Lu
Post-transplant lymphoproliferative disorders (PTLD) are severe complications after solid organ transplantation with no consensus on best treatment practice. Chemotherapy is a therapeutic option with a high response and a significant relapse rate leading to a low long-term tolerance rate. Currently, most centres use anthracycline-based drug combinations, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). We assessed the efficacy and safety of a dose-adjusted ACVBP (doxorubicin reduced to 50 mg/m(2), cyclophosphamide adjusted to renal function, vindesine, bleomycin, prednisone) regimen in patients failing to respond to a reduction in immunosuppressive therapy. Favourable responses were observed in 24 (73%) of the 33 treated patients. Fourteen (42%) patients died, mostly from PTLD progression. Actuarial survival was 60% at 5 years and 55% at 10 years. Survival prognostic factors were: number of involved sites (P = 0.007), clinical stage III/IV (P = 0.004), bulky tumour (P < 0.0001), B symptoms (P = 0.03), decreased serum albumin (P = 0.03) and poor performance status (P = 0.06). Both the international and the PTLD prognostic index were predictive for survival (P = 0.001 and P = 0.002, respectively). Overall 128 cycles were given. Grade 3 or 4 neutropenia was recorded after 26 (20%) chemotherapy cycles in 19 (58%) patients. Forty-one (32%) infections were recorded in 26 (79%) patients. This study demonstrated that an individual dose-adjustment of ACVBP regimen was manageable in PTLD patients and favourably impacted on long-term survival. PMID:16889621
Fohrer, Cécile; Caillard, Sophie; Koumarianou, Argyro; Ellero, Bernard; Woehl-Jaeglé, Marie-Lorraine; Meyer, Carole; Epailly, Eric; Chenard, Marie-Pierre; Lioure, Bruno; Natarajan-Ame, Shanti; Maloisel, Frédéric; Lutun, Philippe; Kessler, Romain; Moulin, Bruno; Bergerat, Jean-Pierre; Wolf, Philippe; Herbrecht, Raoul
Post-transplant lymphoproliferative disorder (PTLD) describes a spectrum of conditions with highest incidence in the first year post-solid organ transplant in pediatric patients. Central nervous system (CNS) involvement with PTLD carries high mortality risk with no consensus on optimal therapeutic regimen. We present the case of a 7-year old heart transplant patient diagnosed with widespread monomorphic, CD20+, Epstein-Barr virus-positive PTLD, including CNS involvement. In addition to immunosuppression reduction and rituximab, she was treated with multiagent systemic and intrathecal chemotherapy. She achieved a prompt and complete clinical and radiologic remission, which has been sustained for over 46 months since diagnosis. PMID:25066638
Mahapatra, Sidharth; Chin, Clifford C; Iagaru, Andrei; Heerema-McKenney, Amy; Twist, Clare J
Previously, retroviral neoplasms reported in wild upland game birds in the United States of America have typically been associated with reticuloendotheliosis virus (REV) infection. The information presented herein described the first reports of lymphoproliferative disease virus (LPDV) infection in ...
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...
Chronic hepatitis C virus (HCV) infection has been associated with liver cancer and cirrhosis, autoimmune disorders such as thyroiditis and mixed cryoglobulinema, and alterations in immune function and chronic inflammation, both implicated in B cell lymphoproliferative diseases that may progress to non-Hodgkin lymphoma (NHL). HCV bound to B cell surface receptors can induce lymphoproliferation, leading to DNA mutations and/or lower antigen response thresholds. These findings and epidemiological reports suggest an association between HCV infection and NHL. We performed a systematic review of the literature to clarify this potential relationship. We searched the English-language literature utilizing Medline, Embase, Paper First, Web of Science, Google Scholar, and the Cochrane Database of Systematic Reviews, with search terms broadly defined to capture discussions of HCV and its relationship with NHL and/or lymphoproliferative diseases. References were screened to further identify relevant studies and literature in the basic sciences. A total of 62 reports discussing the relationship between HCV, NHL, and lymphoproliferative diseases were identified. Epidemiological studies suggest that at least a portion of NHL may be etiologically attributable to HCV, particularly in areas with high HCV prevalence. Studies that showed a lack of association between HCV infection and lymphoma may have been influenced by small sample size, short follow-up periods, and database limitations. The association appears strongest with the B-cell lymphomas relative to other lymphoproliferative diseases. Mechanisms by which chronic HCV infection promotes lymphoproliferative disease remains unclear. Lymphomagenesis is a multifactorial process involving genetic, environmental, and infectious factors. HCV most probably have a role in the lymphomagenesis but further study to clarify the association and underlying mechanisms is warranted. PMID:25473174
Khoury, Tawfik; Chen, Shmuel; Adar, Tomer; Jacob, E Ollech; Mizrahi, Meir
In both conditions, post-transplant lymphoproliferative disorder (PTLD) and hemophagocytic lymphohistiocytosis (HLH), infection with Epstein-Barr virus (EBV) is a key mechanism: almost all PTLD in allogeneic stem cell transplantation (alloSCT) is caused by EBV-related neoplastic lymphoproliferation, and secondary HLH is most frequently triggered by EBV infection. Therefore, concomitant EBV-driven PTLD and HLH early after alloSCT require an approach to eliminate EBV and balance immune activation simultaneously. We report on a patient who developed simultaneous PTLD and signs of HLH on day 64 after alloSCT. Treatment was comprised of stopping cyclosporine, short-course dexamethasone, and 3 courses of rituximab. The patient showed full recovery and complete remission of lymphadenopathy. This result indicates that immediate reduction in EBV-carrying B cells by rituximab, suppression of general inflammation, and parallel support of reconstitution of long-term T-cell function, might be an appropriate therapeutic approach in this rare situation. PMID:25179757
Weber, T; Wickenhauser, C; Monecke, A; Gläser, C; Stadler, M; Desole, M; Ligeti, K; Behrmann, C; Müller-Tidow, C; Müller, L P
There have been only five reported cases of primary posttransplant T-cell lymphoma. We report the first case associated with the use of sirolimus (Rapamycin, Wyeth-Ayerst, Philadelphia, PA). The patient, receiving prednisone, cyclosporine, and sirolimus treatment, developed ascites, diarrhea, and weight loss 7 months after his second renal transplant. Tissue obtained at laparotomy established the diagnosis of primary T-cell lymphoma. Latent membrane protein-1 for Epstein-Barr virus was negative, but in-site hybridization test for Epstein-Barr-encoded RNA was positive. Despite aggressive chemotherapy, the patient died 8 months posttransplant. This is the sixth reported case of primary intestinal posttransplant T-cell lymphoma, but it is the first case associated with the use of sirolimus. The incidence of posttransplant lymphoproliferative disease in patients receiving sirolimus should be studied. PMID:12829924
Michael, J; Greenstein, S; Schechner, R; Tellis, V; Vasovic, L V; Ratech, H; Glicklich, D
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...
Patients with autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosis (SLE) have T-cell dysregulation and produce abnormal, activated T lymphocytes and an atypical peripheral T-cell population, termed double negative T cells (DNTs). T-cell functions, including DNT transition in T-cell development and T-cell activation, are critically dependent on Notch signaling. We hypothesized that inhibiting Notch signaling would be effective in ALPS and SLE by reducing the production of abnormal DNTs and by blocking aberrant T-cell activation. We tested this hypothesis using murine models of ALPS and SLE. Mice were randomized to treatment with the notch pathway inhibitor (gamma-secretase inhibitor), N-S-phenyl-glycine-t-butyl ester (DAPT), or vehicle control. Response to treatment was assessed by measurement of DNTs in blood and lymphoid tissue, by monitoring lymph node and spleen size with ultrasound, by quantifying cytokines by bead-array, by ELISA for total IgG and anti–double-stranded DNA (dsDNA) specific antibodies, and by histopathologic assessment for nephritis. We found a profound and statistically significant decrease in all disease parameters, comparing DAPT-treated mice to controls. Using a novel dosing schema, we avoided the reported toxicities of gamma-secretase inhibitors. Inhibiting the Notch signaling pathway may thus present an effective, novel, and well-tolerated treatment for autoimmune and lymphoproliferative diseases. PMID:17925488
Seif, Alix E.; Brown, Valerie I.; Bruno, Marlo; Bunte, Ralph M.; Chang, Yueh J.; Choi, John K.; Fish, Jonathan D.; Hall, Junior; Reid, Gregor S.; Ryan, Theresa; Sheen, Cecilia; Zweidler-McKay, Patrick; Grupp, Stephan A.
We report three patients who developed severe supraglottic airway obstruction due to Epstein-Barr virus lymphoproliferative\\u000a disease following allogeneic bone marrow transplantation. In addition to enlarged pharyngeal lymphoid tissue seen in all three\\u000a patients, two had supraglottic airway narrowing and two developed pulmonary lymphoproliferative disease. They were treated\\u000a with unmanipulated T cells or EBV-specific cytotoxic T lymphocytes. Life-threatening upper airway obstruction
Barry D. Fletcher; Helen E. Heslop; Sue C. Kaste; Sara Bodner
STAT5 is activated in a broad spectrum of human hematologic malignancies. We addressed whether STAT5 activation is necessary for the myelo- and lymphoproliferative disease induced by TEL\\/JAK2 using a genetic approach. Whereas mice transplanted with bone marrow transduced with retrovirus expressing TEL\\/JAK2 develop a rapidly fatal myelo- and lymphoproliferative syndrome, reconstitution with bone marrow derived from Stat5ab-deficient mice expressing TEL\\/JAK2
Juerg Schwaller; Evan Parganas; Demin Wang; Danielle Cain; Jon C. Aster; Ifor R. Williams; Chien-Kuo Lee; Rachel Gerthner; Toshio Kitamura; Julie Frantsve; Ema Anastasiadou; Mignon L. Loh; David E. Levy; James N. Ihle; D. Gary Gilliland
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 ...
X-linked lymphoproliferative disease, also known as Duncan's syndrome, is a rare genetic disorder that causes exaggerated immune responses to Epstein-Barr virus (EBV) infection and often leads to death. Patient presentation varies but can include signs and symptoms typical of EBV, pancytopenia, and fulminant hepatitis. PMID:20593037
Chadha, S. Nicole; Amrol, David
Gene rearrangement and monoclonality have been detected in normal cells and in lymphoproliferative disease by using the polymerase chain reaction and primers for the V and J regions of the lg heavy chain gene or T-cell receptor ychain gene. Using the lg primers monoclonality was detected in 20 of 20 normal B-lymphocyte clones and in 39 of 52 cases of
K. J. Trainor; M. J. Brisco; J. H. Wan; S. Neoh; S. Grist; A. A. Morley
Epstein Barr virus (EBV) infection is commonly associated with human cancer and, in particular, with lymphoid malignancies. Although the precise role of the virus in the pathogenesis of different lymphomas is largely unknown, it is well recognized that the expression of viral latent proteins and miRNA can contribute to its pathogenetic role. In this study, we compared the gene and miRNA expression profile of two EBV-associated aggressive B non-Hodgkin lymphomas known to be characterized by differential expression of the viral latent proteins aiming to dissect the possible different contribution of such proteins and EBV-encoded miRNAs. By applying extensive bioinformatic inferring and an experimental model, we found that EBV+ Burkitt lymphoma presented with significant over-expression of EBV-encoded miRNAs that were likely to contribute to its global molecular profile. On the other hand, EBV+ post-transplant diffuse large B-cell lymphomas presented a significant enrichment in genes regulated by the viral latent proteins. Based on these different viral and cellular gene expression patterns, a clear distinction between EBV+ Burkitt lymphoma and post-transplant diffuse large B-cell lymphomas was made. In this regard, the different viral and cellular expression patterns seemed to depend on each other, at least partially, and the latency type most probably played a significant role in their regulation. In conclusion, our data indicate that EBV influence over B-cell malignant clones may act through different mechanisms of transcriptional regulation and suggest that potentially different pathogenetic mechanisms may depend upon the conditions of the interaction between EBV and the host that finally determine the latency pattern. PMID:25566237
Navari, Mohsen; Fuligni, Fabio; Laginestra, Maria A.; Etebari, Maryam; Ambrosio, Maria R.; Sapienza, Maria R.; Rossi, Maura; De Falco, Giulia; Gibellini, Davide; Tripodo, Claudio; Pileri, Stefano A.; Leoncini, Lorenzo; Piccaluga, Pier P.
Abstract Early identification of patients at risk of a severe course of hantaviral disease and lack of effective medication represent a global challenge in the treatment of this emerging infection. We describe a 67-year-old female patient with a history of chronic lymphoproliferative disease involving the spleen and an extremely severe acute Puumala hantavirus infection. She was treated with the bradykinin receptor antagonist icatibant and recovered. She is the second patient with a spleen abnormality and severe Puumala infection treated with icatibant in our hospital. We suggest that patients with spleen abnormalities may be more susceptible to severe hantavirus disease. The activation of the kinin-kallikrein system and the formation of bradykinin in hantavirus-infected endothelial cells indicate that the role of bradykinin receptor antagonist icatibant in the treatment of hantavirus disease is worth studying. PMID:25496418
Laine, Outi; Leppänen, Ilona; Koskela, Sirpa; Antonen, Jaakko; Mäkelä, Satu; Sinisalo, Marjatta; Vaheri, Antti; Mustonen, Jukka
Epstein Barr virus (EBV)-associated lymphoproliferative diseases (LPDs) express all EBV latent antigens (type III latency) in immunodeficient patients and limited antigens (type I and II latencies) in immunocompetent patients. Post-transplantation lymphoproliferative disease (PTLD) is the prototype exhibiting type III EBV latency. Although EBV antigens are highly immunogenic, PTLD cell proliferation remains unchecked because of the underlying immunosuppression. The restoration of anti-EBV immunity by EBV-specific T cells of either autologous or allogeneic origin has been shown to be safe and effective in PTLDs. Cellular therapy can be improved by establishing a bank of human leukocyte antigen-characterized allogeneic EBV-specific T cells. In EBV+ LPDs exhibiting type I and II latencies, the use of EBV-specific T cells is more limited, although the safety and efficacy of this therapy have also been demonstrated. The therapeutic role of EBV-specific T cells in EBV+ LPDs needs to be critically reappraised with the advent of monoclonal antibodies and other targeted therapy. Another strategy involves the use of epigenetic approaches to induce EBV to undergo lytic proliferation when expression of the viral thymidine kinase renders host tumor cells susceptible to the cytotoxic effects of ganciclovir. Finally, the prophylactic use of antiviral drugs to prevent EBV reactivation may decrease the occurrence of EBV+ LPDs. PMID:25613733
Tse, Eric; Kwong, Yok-Lam
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
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.
Haemophagocytic lymphohistiocytosis complicating Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood is a rare and life-threatening entity. We report a child with this condition presenting with a toxic epidermal necrolysis-like eruption. PMID:23573996
Sharma, Niyati; Clark, Jonathan; Pham, Hiep; Efron, Daryl; MacGregor, Duncan; O'Keefe, Rodney; Orchard, David
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
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
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.
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
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
While the outcome for pediatric patients with lymphoproliferative disorders (LPD) or lymphoid malignancies, such as acute lymphoblastic leukemia (ALL), has improved dramatically, patients often suffer from therapeutic sequelae. Additionally, despite intensified treatment, the prognosis remains dismal for patients with refractory or relapsed disease. Thus, novel biologically targeted treatment approaches are needed. These targets can be identified by understanding how a loss of lymphocyte homeostasis can result in LPD or ALL. Herein, we review potential molecular and cellular therapeutic strategies that (i) target key signaling networks (e.g., PI3K/AKT/mTOR, JAK/STAT, Notch1, and SRC kinase family-containing pathways) which regulate lymphocyte growth, survival, and function; (ii) block the interaction of ALL cells with stromal cells or lymphoid growth factors secreted by the bone marrow microenvironment; or (iii) stimulate innate and adaptive immune responses. PMID:18716718
Seif, Alix E.; Reid, Gregor S. D.; Teachey, David T.; Grupp, Stephan A.
Treatment of primary EV and PTLD in pediatric LT recipients (pLT) involves IS reduction/cessation. Retrospective review of pLT at our institution from 2001-2009 was conducted to characterize risk factors for GR after EV/ PTLD. Of 184 pLT, EV occurred in 61 (33%) at mean 16.5 m (0-82) and PTLD in 18 (9.8%) at mean 17.7 m (3-78) post-LT. Median age at pLT was 11 m (1-245 m) and follow-up six yr. For EV, 86% underwent IS reduction and 51% received antivirals. GR occurred in 12 (27.9%) with EV and 15 (83.3%) after PTLD diagnosis (relative risk of GR for PTLD 2.98). GR treated with methylprednisolone bolus in half and/or oral IS in half. Following GR therapy, four had PTLD relapses, no graft loss and one EV patient required re-transplantation. GR history before EV was a risk factor for GR after EV (p = 0.024). GR at any point after pLT was a risk factor for PTLD (p = 0.001). Children with EV and GR prior to EV should be monitored closely for GR after IS reduction and GR is a significant risk factor for PTLD. Most children with PTLD eventually developed GR. PMID:22554096
Weiner, Chana; Weintraub, Lauren; Wistinghausen, Birte; Tomaino, Juli; Arnon, Ronen; Kerkar, Nanda; Miloh, Tamir
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
Montero, Rosa M.; Olsburgh, Jonathon
Autoimmune lymphoproliferative syndrome arises early in childhood in people who inherit mutations in genes that mediate lymphocyte apoptosis, or programmed cell death. In the immune system, antigen-induced lymphocyte apoptosis maintains immune homeostasis by limiting lymphocyte accumulation and minimizing reactions against self-antigens. In autoimmune lymphoproliferative syndrome, defective lymphocyte apoptosis manifests as chronic, nonmalignant adenopathy and splenomegaly; the expansion of an unusual population of CD4-CD8- T cells; and the development of autoimmune disease. Most cases of autoimmune lymphoproliferative syndrome involve heterozygous mutations in the lymphocyte surface protein Fas (CD95, Apo1) that impair a major apoptotic pathway. Prospective evaluations of patients and their families have revealed an ever-expanding spectrum of autoimmune lymphoproliferative syndrome and its major complications. PMID:12819469
Sneller, Michael C; Dale, Janet K; Straus, Stephen E
Epstein-Barr virus (EBV) associated lymphoproliferative disease (LPD) are commonly derived from B-cells, however, it is becoming more and more apparently that EBV can also infect T-lymphocytes. Systemic EBV positive T-cell LPD of childhood is rare and characterized by an extremely aggressive course and poor prognosis. Here, we report a 22-year-old female of systemic EBV positive TLPD with acute EBV infection and review the clinical features of this disorder. A 22-year-old previously healthy female without immunocompromised status presented with persisting coach and fever resistant to conventional therapies. Physical examination showed hemorrhage and hepatosplenomegaly. Laboratory examinations revealed severe pancytopenia, disseminated intra-vascular coagulopathy (DIC), and anti-EBV-IgM positivity. Peripheral blood smears and bone marrow investigation identified a number of atypical lymphocytes. Flow cytometry (FCM) did not show any significant evidence of leukemia or lymphoma. The lymph node biopsy showed apparent infiltration of lymphocytes, which expressed CD2+, CD3+, CD7+ and TIA1+. There was no CD20+ or CD56+ cells. EBV early RNA (EBER) was positive. Cytogenetic analysis showed a normal karyotype. T-cell receptor (TCR) gene rearrangement revealed a polyclonal pattern. The patient received prednisolone and IVIG therapy with a transient good condition, and then died of multiorgan failure one week after diagnosis. PMID:25400806
Chen, Guoshu; Chen, Li; Qin, Xiaohua; Huang, Zhuoya; Xie, Xiaoling; Li, Guowei; Xu, Bing
Hitherto, detection of lymphoproliferative disease virus (LPDV), a C-type retrovirus of turkeys, has proved difficult since no tissue culture or serological assay has been available. Development of serological tests has been hampered by the problems of raising virus-specific antisera. An indirect enzyme-linked immunosorbent assay (ELISA) is reported, using a viral antiserum raised with bromelain-digested virus. The assay specifically detected purified virus at a concentration of 250 ng/ml or greater. In an experiment to detect virus in plasma from turkeys over a period of 4 weeks following LPDV infection, ELISA results correlated closely with the viral reverse transcriptase activity. Both assays were of similar sensitivity and detected small amounts of virus in high-speed pellets of turkey plasma. Evidence is presented indicating that LPDV-infected or hyperimmunized turkeys do not produce readily detectable circulating viral antibodies. In reciprocal ELISA tests, using antibodies to group-specific antigens of other avian retrovirus groups (avian sarcoma-leukosis (ASLV) and reticuloendotheliosis (REV] no antigenic cross-reaction was found between LPDV, ASLV and REV. PMID:2448156
Patel, J. R.; Shilleto, R. W.
The correction of post-transplant hyperlipidaemia warrants the judicious and timely use of pharmacological agents with dietary modification and exercise. Reduction in hyperlipidaemia may have some role in decreasing the incidence of chronic rejection of allografts. The awareness that the morbidity and mortality of atherosclerotic disease may be lowered by active intervention will result in a better quality of life for transplant recipients. PMID:9497947
Jindal, R. M.
Posttransplantation lymphoproliferative disorder (PTLD) is a devastating post-transplantation complication often associated with Epstein-Barr virus (EBV). Although the type and length of immunosuppression are risk factors, a patient's inherent immune capacity also likely contributes to this disorder. This report uses severe-combined immunodeficient mice given injections of human peripheral blood leukocytes (hu PBL-SCID [Severe Combined Immunodeficient] mice) to test the hypothesis that cytokine genotype associates with the development of EBV-associated lymphoproliferative disease (LPD). We observed that the A/A (adenosine/adenosine) genotype for base + 874 of the interferon gamma (IFN-gamma) gene was significantly more prevalent in PBLs producing rapid, high-penetrance LPD in hu PBL-SCID mice, compared to PBLs producing late, low-penetrance LPD or no LPD. In examining the relationship between genotype and cytolytic T-lymphocyte (CTL) function, transforming growth factor beta (TGF-beta) inhibited restimulation of CTLs in PBLs with adenosine at IFNG base + 874, but not in PBLs homozygous for thymidine. Importantly, neutralization of TGF-beta in hu PBL-SCID mice injected with A/A genotype PBLs resulted in reduced LPD development and expanded human CD8(+) cells. Thus, our data show that TGF-beta may promote tumor development by inhibiting CTL restimulation and expansion. Further, our data indicate that IFNG genotype may provide valuable information for both identifying transplant recipients at greater risk for PTLD and developing preventive and curative strategies. PMID:15498860
Dierksheide, Julie E; Baiocchi, Robert A; Ferketich, Amy K; Roychowdhury, Sameek; Pelletier, Ronald P; Eisenbeis, Charles F; Caligiuri, Michael A; VanBuskirk, Anne M
Between June 1988 and May 1996, 428 patients underwent allogeneic BMT (288 related donor (RD) and 140 unrelated donor (UD)) at the Vancouver General Hospital. Eight patients (UD six and RD two) developed a post-transplant lymphoproliferative disorder (PTLD). Median age at BMT was 38 years (range 22–51). Five of the six UD allografts were T cell depleted. Cyclosporine ± methotrexate
INM Micallef; M Chhanabhai; JD Shepherd; HC Fung; SH Nantel; CL Toze; H-G Klingemann; HJ Sutherland; DE Hogge; TJ Nevill; A Le; MJ Barnett
To improve the diagnostic accuracy and understanding of the pathogenesis of lymphoproliferative diseases (LPDs) occurring in immunosuppressed transplant recipients (post-transplantation LPD), clonality of Epstein-Barr virus-induced human LPDs in mice with severe combined immunodeficiency was examined by analyzing: 1) human immunoglobulin genes and their products, 2) the clonality of Epstein-Barr virus DNA, and 3) genetic alteration of c-myc or bcl-2 genes. A spectrum of clonality was found in the LPDs comparable with that reported for post-transplantation LPDs, although rearrangements of c-myc or bcl-2 genes were not detected. It is confirmed that this system is useful in terms of clonality for understanding the early phases in the pathogenesis of post-transplantation LPD or LPD in immune deficient patients. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5 PMID:8380952
Nakamine, Hirokazu; Masih, Aneal S.; Okano, Motohiko; Taguchi, Yuichi; Pirruccello, Samuel J.; Davis, Jack R.; Mahloch, Mark L.; Beisel, Kirk W.; Kleveland, Kimberly; Sanger, Warren G.; Purtilo, David T.
Reduced pretransplant blood myeloid dendritic cell (mDC) levels are associated with post-transplant BK viremia and cytomegalovirus (CMV) disease after kidney transplantation. To elucidate potential mechanisms by which mDC levels might influence these outcomes, we studied the association of mDC levels with mDC IL-12 production and T-cell level/function. Peripheral blood (PB) was studied in three groups: (i) end stage renal disease patients on hemodialysis (HD; n = 81); (ii) chronic kidney disease stage IV-V patients presenting for kidney transplant evaluation or the day of transplantation (Eval/Tx; n = 323); and (iii) healthy controls (HC; n = 22). Along with a statistically significant reduction in mDC levels, reduced CD8(+) T-cell levels were also demonstrated in the kidney disease groups compared with HC. Reduced PB mDC and monocyte-derived DC (MoDC) IL-12 production was observed after in vitro LPS stimulation in the HD versus HC groups. Finally, ELISpot assays demonstrated less robust CD3(+) INF-? responses by MoDCs pulsed with CMV pp65 peptide from HD patients compared with HC. PB mDC level deficiency in patients with kidney disease is associated with deficient IL-12 production and T-cell level/function, which may explain the known correlation of CD8(+) T-cell lymphopenia with deficient post-transplant antiviral responses. PMID:24963818
Chen, Ping; Sun, Qianmei; Huang, Yanfei; Atta, Mohamed G; Turban, Sharon; Segev, Dorry L; Marr, Kieren A; Naqvi, Fizza F; Alachkar, Nada; Kraus, Edward S; Womer, Karl L
The exact relationship between lymphomatoid granulomatosis (LyG) and posttransplant lymphoproliferative disorders (PTLDs) is not clear. Both are observed in immunodeficient patients and are Epstein-Barr virus driven. These disorders are, however, considered distinct based upon the immune response elicited; LyG is T-cell rich while PTLDs are T-cell poor. We describe a case of LyG-type diffuse large B-cell lymphoma (DLBCL) in a
A. Saxena; K. M. Dyker; S. Angel; O. Moshynska; S. Dharampaul; D. W. Cockroft
Reactivation of the Epstein-Barr virus (EBV) after allogeneic stem cell transplantation (allo-SCT) may evoke a protective cellular immune response or may be complicated by the development of EBV-lymphoproliferative disease (EBV-LPD). So far, very little is known about the incidence, recurrence, and sequelae of EBV reactivation following allo-SCT. EBV reactivation was retrospectively monitored in 85 EBV-seropositive recipients of a T-cell--depleted (TCD)
Joost W. J. van Esser; Bronno van der Holt; Ellen Meijer; Hubert G. M. Niesters; J. J. Cornelissen; R. Trenschel; S. F. Thijsen; Loon van A. M; L. F. Verdonck; F. Frassoni; A. Bacigalupo; B. Löwenberg; U. W. Schaefer; J. W. Gratama; A. D. M. E. Osterhaus
X-linked lymphoproliferative disease (XLP1) arises from mutations in the gene encoding SLAM-associated protein (SAP) and leads to abnormalities of NKT-cell development, NK-cell cytotoxicity, and T-dependent humoral function. Curative treatment is limited to allogeneic hematopoietic stem cell (HSC) transplantation. We tested whether HSC gene therapy could correct the multilineage defects seen in SAP?/? mice. SAP?/? murine HSCs were transduced with lentiviral vectors containing either SAP or reporter gene before transplantation into irradiated recipients. NKT-cell development was significantly higher and NK-cell cytotoxicity restored to wild-type levels in mice receiving the SAP vector in comparison to control mice. Baseline immunoglobulin levels were significantly increased and T-dependent humoral responses to NP-CGG, including germinal center formation, were restored in SAP-transduced mice. We demonstrate for the first time that HSC gene transfer corrects the cellular and humoral defects in SAP?/? mice providing proof of concept for gene therapy in XLP1. PMID:23223356
Rivat, Christine; Booth, Claire; Alonso-Ferrero, Maria; Blundell, Michael; Sebire, Neil J.; Thrasher, Adrian J.
Patients with autoimmune lymphoproliferative syndrome (ALPS) have defective lymphocyte apoptosis, with increased risk for lymphoid malignancies. Herein, we report a patient with ALPS who developed histiocytic sarcoma in a background of sinus histiocytosis and massive lymphadenopathy (SHML) or Rosai-Dorfman disease (RDD). This patient had documented ALPS type Ia with a germline missense mutation in exon 9 of the TNFRSF6 gene (973 A>T, D244V) encoding Fas (CD95/Apo-1). He presented at 10 months with hepatosplenomegaly and autoimmune hemolytic anemia and was diagnosed with ALPS. At age 6 and˝, he developed classical Hodgkin lymphoma, which was treated using standard chemotherapy. Two years later, biopsy of a PET-positive axillary node showed features of ALPS and focal involvement by SHML. Thereafter, the patient continued to have continued lymphadenopathy and progressive splenomegaly, leading to exploratory surgery at age 13 for suspicion of lymphoma. Paraabdominal nodes revealed sheets of malignant-looking histiocytes with increased mitotic activity and areas of necrosis, indicative of histiocytic sarcoma. Spleen and lymph nodes also showed involvement by RDD. Both components had an identical phenotype of S-100+/CD68+/CD163+. The occurrence of malignancies involving two separate hematopoietic lineages in ALPS is not previously reported. Given the central role of defective Fas signaling in ALPS, histiocytes may be yet another lineage at risk for neoplastic transformation secondary to a block in apoptosis. PMID:20216376
Venkataraman, Girish; McClain, Kenneth L.; Pittaluga, Stefania; Rao, V. Koneti; Jaffe, Elaine S.
Recipients of a partially T-cell-depleted (TCD) allogeneic stem cell transplantation (allo-SCT) developing reactivation of Epstein-Barr virus (EBV) with quantified viral DNA levels exceeding 1000 genome equivalents\\/milliliter (geq\\/mL) are at high risk for EBV-lymphoproliferative disease (EBV-LPD). We studied whether preemptive therapy with rituximab prevents EBV-LPD, LPD-mortality, and abrogates viral reactivation in high-risk patients. We monitored 49 recipients of a TCD allo-SCT
Joost W. J. van Esser; Hubert G. M. Niesters; Bronno van der Holt; Ellen Meijer; Albert D. M. E. Osterhaus; Jan Willem Gratama; Leo F. Verdonck; B. Löwenberg; Jan J. Cornelissen
X-linked lymphoproliferative disease (XLP) is a rare congenital immunodeficiency that leads to an extreme, usually fatal increase in the number of lymphocytes upon infection with EBV. It is most commonly defined molecularly by loss of expression of SLAM-associated protein (SAP). Despite this, there is little understanding of how SAP deficiency causes lymphocytosis following EBV infection. Here we show that T cells from individuals with XLP are specifically resistant to apoptosis mediated by TCR restimulation, a process that normally constrains T cell expansion during immune responses. Expression of SAP and the SLAM family receptor NK, T, and B cell antigen (NTB-A) were required for TCR-induced upregulation of key pro-apoptotic molecules and subsequent apoptosis. Further, SAP/NTB-A signaling augmented the strength of the proximal TCR signal to achieve the threshold required for restimulation-induced cell death (RICD). Strikingly, TCR ligation in activated T cells triggered increased recruitment of SAP to NTB-A, dissociation of the phosphatase SHP-1, and colocalization of NTB-A with CD3 aggregates. In contrast, NTB-A and SHP-1 contributed to RICD resistance in XLP T cells. Our results reveal what we believe to be novel roles for NTB-A and SAP in regulating T cell homeostasis through apoptosis and provide mechanistic insight into the pathogenesis of lymphoproliferative disease in XLP. PMID:19759517
Snow, Andrew L.; Marsh, Rebecca A.; Krummey, Scott M.; Roehrs, Philip; Young, Lisa R.; Zhang, Kejian; van Hoff, Jack; Dhar, Deepali; Nichols, Kim E.; Filipovich, Alexandra H.; Su, Helen C.; Bleesing, Jack J.; Lenardo, Michael J.
Quantification of minimal residual disease (MRD) following allogeneic hematopoietic cell transplantation (allo-HCT) predicts post-transplant relapse in patients with chronic lymphocytic leukemia (CLL). We utilized an MRD-quantification method that amplifies immunoglobulin heavy chain (IGH) loci using consensus V and J segment primers followed by high-throughput sequencing (HTS), enabling quantification with a detection limit of one CLL cell per million mononuclear cells. Using this IGH–HTS approach, we analyzed MRD patterns in over 400 samples from 40 CLL patients who underwent reduced-intensity allo-HCT. Nine patients relapsed within 12 months post-HCT. Of the 31 patients in remission at 12 months post-HCT, disease-free survival was 86% in patients with MRD <10?4 and 20% in those with MRD ?10?4 (relapse hazard ratio (HR) 9.0; 95% confidence interval (CI) 2.5–32; P<0.0001), with median follow-up of 36 months. Additionally, MRD predicted relapse at other time points, including 9, 18 and 24 months post-HCT. MRD doubling time <12 months with disease burden ?10?5 was associated with relapse within 12 months of MRD assessment in 50% of patients, and within 24 months in 90% of patients. This IGH–HTS method may facilitate routine MRD quantification in clinical trials. PMID:23419792
Logan, A C; Zhang, B; Narasimhan, B; Carlton, V; Zheng, J; Moorhead, M; Krampf, M R; Jones, C D; Waqar, A N; Faham, M; Zehnder, J L; Miklos, D B
Primary CNS lymphoma (PCNSL) is a rare B cell variant non-Hodgkins lymphoma that is confined to the brain, leptomeninges, spinal cord and eyes. Its incidence is increasing, primarily due to increase in the number of organ transplantations being undertaken. The majority of the PTLD (post-transplant lymphoproliferative disorder) is seen in kidney transplant recipients simply because they constitute a larger group of transplant recipients each year as compared to other solid organ transplantations. Primary infection of previously infected EBV seronegative patients and immunosuppression are found to be the main etiologic factors in the development of PTLD-PCNSL. There are no clear guidelines on treatment regimens, and it should be individualized according to patient comorbidities. We report a case of PCNS lymphoproliferative disorder in a kidney transplant recipient, which underwent complete remission with decreasing immunosuppression. The patient could not undergo chemotherapy/radiotherapy due to underlying comorbidities. We highlight the available treatment modalities for PTLD-PCNSL. PMID:22476860
Valavoor, Shahul H; Ashraf, Zubair; Narwal, Rawan; Ratnam, Shobha
BackgroundEBV-associated T/NK-cell lymphoproliferative diseases (TNKLPD) is a rare spectrum of disease that occurs more commonly in Asia, and Central and South America. It commonly affects children and young adults and is an aggressive disease that is poorly understood with no known biologic markers that can predict prognosis. The systemic form of TNKLPD includes chronic active EBV infection of T/NK type, aggressive NK cell leukemia and systemic EBVż+żT-cell lymphoproliferative disease of childhood.MethodsIn this study, we analyse the clinicopathologic and genetic features of 22 cases of systemic TNKLPD in non-immunocompromised patients, including chronic active EBV infection of T/NK cell type and systemic EBVż+żT-cell lymphoproliferative disease of childhood. We also performed gene expression profiling in a subset of cases to identify markers that may be of prognostic relevance and validated our results using immunohistochemistry.ResultsThe median age is 14.9 years and two of our 22 cases occurring in patients older than 30 years. Fifteen of 17 cases (88%) with adequate data were of T-cell origin. Eleven of 22 cases revealed polymorphic cellular infiltrate (P-group) while the rest showed monomorphic lymphoid infiltrate (M-group). We found a significant difference in survival between P-group vs M-group patients with median survival not yet reached in P-group, and 1 month in M-group (p =0.0001), suggesting a role for morphology in predicting patient outcome. We also performed gene expression profiling in a subset of patients and compared the genes differentially expressed between P-group and M-group cases to identify markers of prognostic value. We identified cyclin E2 gene and protein to be differentially expressed between patients with good outcome (P-group, median expression 8%) and poor outcome (M-group, median expression 42%) (p =0.0005). In addition, the upregulation of cyclin E2 protein in M-group cases correlated with a higher Ki67 proliferation rate (Pearson correlation r =0.73, p =0.0006) detected by immunohistochemistry. High cyclin E2 expression was also significantly associated with shorter survival (p =0.0002).ConclusionOur data suggests the potential role of monomorphic morphology, high cyclin E2 and Ki67 expression as adverse prognostic factors for TNKLPD. PMID:25475054
Ng, Siok-Bian; Ohshima, Koichi; Selvarajan, Viknesvaran; Huang, Gaofeng; Choo, Shoa-Nian; Miyoshi, Hiroaki; Wang, Shi; Chua, Hsin-Chieh; Yeoh, Allen; Quah, Thuan-Chong; Koh, Liang-Piu; Tan, Poh-Lin; Chng, Wee-Joo
Post-transplant lymphoproliferative disorder (PTLD) is generally caused by an uncontrolled B-cell proliferation induced by Epstein-Barr virus (EBV) in the setting of impaired EBV-specific T-cell immunity. PTLD has been described in allogeneic hematopoietic stem cell transplant (HSCT) and rarely in autologous HSCT. Anti-thymocyte globulin (ATG) is being increasingly utilized for acute rejection in organ transplantation, severe autoimmune diseases and aplastic anemia. Mainly, the use of rabbit ATG has been associated with PTLD, which is considered to be more immunosuppressive than equine ATG. The sole administration of equine ATG has rarely been associated with PTLD. Due to the increased use of these potent and novel immunosuppressive agents, it is paramount to be aware of these complications. We present a 55-year-old man with an autologous HSCT who presented with an unusual case of monoclonal plasmacytic PTLD. His lymphoproliferative disorder occurred 3 years after his HSCT and 1 month after the use of equine ATG administered for severe aplastic anemia. We review current concepts of EBV-PTLD, including risk factors, the potential for preemptive therapy and various management strategies. PMID:20680523
Viola, George M; Zu, Youli; Baker, Kelty R; Aslam, Saima
Epstein-Barr virus (EBV) early-antigen (EA) serologic profile was examined in conjunction with peripheral blood EBV DNA load, to assess its value in evaluating the risk of developing posttransplantation lymphoproliferative disease (PTLD). The cohort included 26 pediatric recipients of solid-organ transplants, 6 of whom developed PTLD. All 6 patients had high peripheral blood EBV DNA loads. Of the remaining 20 patients who did not develop PTLD, 14 had high EBV DNA loads, and 6 had low EBV DNA loads. None of the patients who developed PTLD had significant EA immunoglobulin G (IgG) titers. However, all 14 patients with high EBV DNA loads and without PTLD had high EA IgG titers, either at the time of initial high EBV DNA load or during the ensuing weeks. Here, we report that EBV DNA load analysis, combined with EA serologic analysis, is a potentially useful prognostic marker for evaluating the risk of developing PTLD. PMID:14673764
Carpentier, Linda; Tapiero, Bruce; Alvarez, Fernando; Viau, Carole; Alfieri, Caroline
We report the prevalence of BK virus (BKV) infection before renal transplantation and the dynamics of BKV viremia from pre- to post-transplantation. We assessed 60 kidney transplanted patients from a single cohort in Italy, treated with identical immunosuppressive therapy, for BK viremia at pre-transplantation, 12 h, and three and six months post-transplantation. Polymerase chain reaction showed that the prevalence of plasma BKV replication--considered a marker of infection--was 20% in pre-transplant patients. All pre-transplant-positive patients remained positive post-transplant, whereas the majority of pre-transplant-negative patients remained negative. Viremia dynamics classification revealed three clusters of patients: Cluster A++, pre-transplant-positive patients (20%) who tested positive at least once post-transplant; Cluster B-+, pre-transplant-negative patients (28%) who tested positive at least once post-transplant; and Cluster C- -, pre-transplant-negative patients (52%) who remained negative throughout. These clusters presented significant differences related to the prevalence of substantially positive patients with high plasma viral load (>10(3) copies/mL) in cluster A, but not in donors' or grafts' characteristics. We suggest that pre-transplant viral status should be considered as an additional risk factor for post-transplant BKV replication. Therefore, pre-transplant BKV infection screening in kidney transplant patients should be performed for improving planning of personalized immunosuppressant schemes and specific post-transplant surveillance. PMID:24506672
Mitterhofer, Anna Paola; Tinti, Francesca; Pietropaolo, Valeria; Umbro, Ilaria; Anzivino, Elena; Bellizzi, Anna; Zavatto, Assunta; Poli, Luca; Berloco, Pasquale Bartolomeo; Taliani, Gloria
Allogeneic marrow transplantation can cure sickle cell disease; however, HLA-matched donors are difficult to find, and the toxicities of myeloablative conditioning are prohibitive for most adults with this disease. We developed a nonmyeloablative bone marrow transplantation platform using related, including HLA-haploidentical, donors for patients with sickle cell disease. The regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation, and graft-versus-host disease prophylaxis with posttransplantation high-dose cyclophosphamide, mycophenolate mofetil, and tacrolimus or sirolimus. After screening 19 patients, we transplanted 17, 14 from HLA-haploidentical and 3 from HLA-matched related donors. Eleven patients engrafted durably. With a median follow-up of 711 days (minimal follow up 224 days), 10 patients are asymptomatic, and 6 patients are off immunosupression. Only 1 patient developed skin-only acute graft-versus-host disease that resolved without any therapy; no mortality was seen. Nonmyeloablative conditioning with posttransplantation high-dose cyclophosphamide expands the donor pool, making marrow transplantation feasible for most patients with sickle cell disease, and is associated with a low risk of complications, even with haploidentical related donors. Graft failure, 43% in haploidentical pairs, remains a major obstacle but may be acceptable in a fraction of patients if the majority can be cured without serious toxicities. PMID:22955919
Bolańos-Meade, Javier; Fuchs, Ephraim J; Luznik, Leo; Lanzkron, Sophie M; Gamper, Christopher J; Jones, Richard J; Brodsky, Robert A
Background Multipotent mesenchymal stromal cells suppress T-cell function in vitro, a property that has underpinned their use in treating clinical steroid-refractory graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. However the potential of mesenchymal stromal cells to resolve graft-versus-host disease is confounded by a paucity of pre-clinical data delineating their immunomodulatory effects in vivo. Design and Methods We examined the influence of timing and dose of donor-derived mesenchymal stromal cells on the kinetics of graft-versus-host disease in two murine models of graft-versus-host disease (major histocompatibility complex-mismatched: UBI-GFP/BL6 [H-2b]?BALB/c [H-2d] and the sibling transplant mimic, UBI-GFP/BL6 [H-2b]?BALB.B [H-2b]) using clinically relevant conditioning regimens. We also examined the effect of mesenchymal stromal cell infusion on bone marrow and spleen cellular composition and cytokine secretion in transplant recipients. Results Despite T-cell suppression in vitro, mesenchymal stromal cells delayed but did not prevent graft-versus-host disease in the major histocompatibility complex-mismatched model. In the sibling transplant model, however, 30% of mesenchymal stromal cell-treated mice did not develop graft-versus-host disease. The timing of administration and dose of the mesenchymal stromal cells influenced their effectiveness in attenuating graft-versus-host disease, such that a low dose of mesenchymal stromal cells administered early was more effective than a high dose of mesenchymal stromal cells given late. Compared to control-treated mice, mesenchymal stromal cell-treated mice had significant reductions in serum and splenic interferon-?, an important mediator of graft-versus-host disease. Conclusions Mesenchymal stromal cells appear to delay death from graft-versus-host disease by transiently altering the inflammatory milieu and reducing levels of interferon-?. Our data suggest that both the timing of infusion and the dose of mesenchymal stromal cells likely influence these cells’ effectiveness in attenuating graft-versus-host disease. PMID:20801899
Christensen, Melinda E.; Turner, Brie E.; Sinfield, Laura J.; Kollar, Katarina; Cullup, Hannah; Waterhouse, Nigel J.; Hart, Derek N.J.; Atkinson, Kerry; Rice, Alison M.
Summary Background Organ transplant recipients (OTR) are at high risk of developing non-melanoma skin cancer and premalignant epidermal dysplasia (carcinoma in situ/Bowen’s disease and actinic keratoses). Epidermal dysplasia is often widespread and there are few comparative studies of available treatments. Objectives To compare topical methylaminolaevulinate (MAL) photodynamic therapy (PDT) with topical 5% fluorouracil (5-FU) cream in the treatment of post-transplant epidermal dysplasia. Methods Eight OTRs with epidermal dysplasia were recruited to an open-label, single-centre, randomized, intrapatient comparative study. Treatment with two cycles of topical MAL PDT 1 week apart was randomly assigned to one area of epidermal dysplasia, and 5-FU cream was applied twice daily for 3 weeks to a clinically and histologically comparable area. Patients were reviewed at 1, 3 and 6 months after treatment. The main outcome measures were complete resolution rate (CRR), overall reduction in lesional area, treatment-associated pain and erythema, cosmetic outcome and global patient preference. Results At all time points evaluated after completion of treatment, PDT was more effective than 5-FU in achieving complete resolution: eight of nine lesional areas cleared with PDT (CRR 89%, 95% CI: 0·52-0·99), compared with one of nine lesional areas treated with 5-FU (CRR 11%, 95% CI: 0·003-0·48) (P = 0·02). The mean lesional area reduction was also proportionately greater with PDT than with 5-FU (100% vs. 79% respectively). Cosmetic outcome and patient preference were also superior in the PDT-treated group. Conclusions Compared with topical 5-FU, MAL PDT was a more effective and cosmetically acceptable treatment for epidermal dysplasia in OTRs and was preferred by patients. Further studies are now required to confirm these results and to examine the effect of treating epidermal dysplasia with PDT on subsequent development of squamous cell carcinoma in this high risk population. PMID:17223873
Perrett, C.M.; McGregor, J.M.; Warwick, J.; Karran, P.; Leigh, I.M.; Proby, C.M.; Harwood, C.A.
Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder in which genetic defects in proteins that mediate lymphocyte apoptosis, most often Fas, are associated with enlargement of lymph nodes and the spleen and a variety of autoimmune manifestations. Some patients with ALPS have relatives with these same apoptotic defects, however, who are clinically well. This study showed that the circulating levels of interleukin 10 (IL-10) were significantly higher (P <.001) in 21 patients with ALPS than in healthy controls. Moreover, the peripheral blood mononuclear cells (PBMCs) and lymphoid tissues of these patients with ALPS contained significantly higher levels of IL-10 messenger RNA (mRNA; P <.001 and P <.01, respectively). By fractionating PBMC populations, disproportionately high concentrations of IL-10 mRNA were found in the CD4(-)CD8(-) T-cell population, expansion of which is virtually pathognomonic for ALPS. Immunohistochemical staining showed intense IL-10 protein signals in lymph node regions known to contain CD4(-)CD8(-) T cells. Nonetheless, in vitro studies showed no influence of IL-10 on the survival of CD4(-)CD8(-) T cells. Overexpression of IL-10 in patients with inherited apoptotic defects is strongly associated with the overt manifestations of ALPS. PMID:11342444
Lopatin, U; Yao, X; Williams, R K; Bleesing, J J; Dale, J K; Wong, D; Teruya-Feldstein, J; Fritz, S; Morrow, M R; Fuss, I; Sneller, M C; Raffeld, M; Fleisher, T A; Puck, J M; Strober, W; Jaffe, E S; Straus, S E
The term monoclonal B-cell lymphocytosis (MBL) was recently introduced to identify individuals with a population of monoclonal B cells in the absence of other features that are diagnostic of a B-cell lymphoproliferative disorder. MBL is often identified through hospital investigation of a mild lymphocytosis, and approximately 1% of such individuals develop progressive disease requiring treatment per year. However, in population studies using high-sensitivity flow cytometry, MBL may be detectable in more than 10% of adults aged over 60 years, and clinical progression is rare. The majority of MBL cases have features that are characteristic of chronic lymphocytic leukaemia, but an increasing amount of information is becoming available about MBL with the features of other B-cell lymphoproliferative disorders. In addition to flow cytometry findings, the incidental detection of an occult B-cell lymphoproliferative disorder is also occurring in a significant proportion of tissue biopsy samples. In this review, the clinical and biological relationship between MBL and B-cell lymphoproliferative disorders will be discussed, with a focus on identifying the differences between low levels of peripheral blood or bone marrow involvement with lymphoma and the monoclonal B-cell populations that commonly occur in elderly adults. PMID:21261685
Rawstron, Andy C
The records and neuro-imaging studies of 8 cases of posttransplant primary CNS lymphoma (PT-PCNSL) diagnosed at Mayo Clinic Rochester between 1970 and 1998 were reviewed retrospectively. All patients received organ transplantation. Patients who had hematologic transplantation were not included in the analysis. The median and mean age of the 4 men and 4 women was 45 years (range, 34 to 50 years). The median duration of symptoms before diagnosis was 36 days (range, 5 to 98 days). At diagnosis, the neurologic examination was focally abnormal in 6 of 8 patients. Compared with the initial computed tomographic study, MRI showed 25 additional brain lesions. Only 43.7% of lesions enhanced with contrast agent; of those that did, all but one were heterogeneous. Ependymal contact occurred in 5 patients. MRI lesion burden increased proportionally to the interval between scans. Diagnostic tissue was obtained by stereotactic biopsy from 6 patients and by open biopsy from 2. Hemorrhage occurred in the biopsy area in 4 patients who had stereotactic biopsy and 2 died (all had normal coagulation studies). Slides available for review (7 patients) showed that the tumors were of CD20-positive lineage and were positive for Epstein-Barr virus, using in situ hybridization. Six patients died. Median survival for the cohort was 13 weeks. PT-PCNSL has clinical and imaging features distinct from typical PCNSL. In our series, (1) PT-PCNSL presented nonspecifically and progressed rapidly, (2) stereotactic brain biopsy had significant morbidity, and (3) despite multimodal therapy, survival was poor. PMID:11265232
Phan, T. G.; O'Neill, B. P.; Kurtin, P. J.
X-linked lymphoproliferative disease type 1 (XLP1) is a rare immune deficiency caused by mutations in SH2D1A. Allogeneic hematopoietic cell transplantation (HCT) is often performed because of the morbidity and mortality associated with XLP1. There is limited experience using reduced-intensity conditioning (RIC) regimens for these patients. Here we report our 8-year single-center experience. Sixteen consecutive patients diagnosed with XLP1 underwent allogeneic HCT between 2006 and 2013 after a RIC regimen consisting of alemtuzumab, fludarabine, and melphalan. Patient phenotypes included hemophagocytic lymphohistiocytosis (HLH) after Epstein-Barr virus (n = 5) or human herpesvirus 6 (n = 1), macrophage activation syndrome (n = 1), interstitial pneumonitis and encephalitis (n = 1), B cell lymphoma (n = 8), and hypogammaglobulinemia (n = 2). One patient was asymptomatic. Fourteen of 16 patients received 8/8 HLA-matched unrelated or related bone marrow grafts, whereas 2 patients received mismatched unrelated grafts. Acute graft-versus-host disease (GVHD) prophylaxis consisted of methylprednisolone and cyclosporine in all but 1 patient, who additionally received methotrexate. All patients had hematopoietic recovery. There were no cases of hepatic veno-occlusive disease or pulmonary hemorrhage. One patient (6%) developed acute GVHD and later also developed chronic GVHD (6%). Five patients (31%) developed mixed chimerism. Only 1 patient with mixed chimerism (6%) experienced a decline of donor chimerism to less than 50% but returned to full donor chimerism after infusion of donor lymphocytes and a CD34(+) selected stem cell boost. Infectious complications were frequent, particularly viral reactivation. One-year survival estimated by Kaplan-Meier analysis was 80%, with long-term survival estimated at 71%. Survival was similar for patients with or without a history of HLH (86% versus 75%, respectively, P = .70). There were no occurrences of lymphoma or HLH after HCT. RIC HCT with alemtuzumab, fludarabine, and melphalan is an effective treatment for patients with XLP1, offering good survival rates regardless of prior disease manifestations, including HLH. PMID:24923536
Marsh, Rebecca A; Bleesing, Jack J; Chandrakasan, Shanmuganathan; Jordan, Michael B; Davies, Stella M; Filipovich, Alexandra H
The Swedish Cancer Environment Register (CER) is a linkage of census data (e.g., on occupations) with the Swedish Cancer Register. It has been used in different studies to generate hypotheses on occupational risk factors for malignant tumors. In this study the risk for malignant lymphoma and multiple myeloma in occupations with potential exposure to phenoxyacetic acids or other related substances were investigated. An increased standardized incidence ratio (SIR) of 1.3 for multiple myeloma was verified in farmers (no. of cases = 335). This finding applied to both sexes, and the SIR increased over successive time periods. Regarding malignant lymphoma an increased SIR of 1.2 was found in farmers (no. = 227) for the latest time period studied (i.e. 1979-1984). When non-Hodgkin's lymphoma was studied separately, an increased risk (SIR = 1.2) was found only in carpenters (no. = 149), whereas for Hodgkin's disease, sawmill workers (no. = 10) had an increased SIR of 2.1. Physicians also had an elevated risk for malignant lymphoma. A major shortcoming in register studies such as CER is that no individual exposure data on different agents are available. Lack of an association between an occupation and a specific malignant disease, therefore, may not be taken as evidence that persons within that occupation are not at increased risk for that disease. PMID:1519615
Eriksson, M; Hardell, L; Malker, H; Weiner, J
Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases.
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, the time course and similarity of the 2 cases of EBV-PTLD and the effect on day 28 T-cell counts support a relationship between the development of EBV-PTLD and the administration of rabbit ATG. The differences between equine and rabbit ATG are not yet clearly defined, and they should not be considered interchangeable in this regimen without further study. PMID:14506660
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
Hepatitis C virus (HCV) is a global health problem affecting 3% of the world's population (about 180 million) and a cause of both hepatic and extrahepatic diseases. B-cell lymphoproliferative disorders, whose prototype is mixed cryoglobulinemia, represent the most closely related as well as the most investigated HCV- related extrahepatic disorder. The association between extrahepatic (lymphoma) as well as hepatic malignancies
Anna Linda Zignego; Carlo Giannini; Ferri Francoise; Lunel Fabiani; Clodoveo Ferri; Reggio Emilia; Ferri C. Hepatitis
Given the favorable immunologic effects of IL-2 post transplant, we conducted a feasibility study examining rIL-2 1.0×106 IU\\/m2\\/day (SQ) beginning on D+14 post-transplant and continuing for 90 days in 12 patients with low-grade lymphoproliferative disorders. Prior to high-dose chemotherapy and autologous peripheral blood stem cell transplantation (HDCT), 11 patients underwent cytoreduction with fludarabine and cyclophosphamide (Flu\\/Cy); 11 were in complete remission (CR)
Jamie K. Waselenko; Ann Burrows; Douglas A. Nelson; Margaret Lucas; John Ekstrand; William Jeffrey Edenfield; Rick C. Myhand
The role of the Epstein-Barr virus in the development of post-transplant lymphomas is well established. However, not all lymphomas that arise in these patients contain Epstein-Barr virus, suggesting that other cofactors are involved in tumor pathogenesis. We propose that immunologic interactions that result from the introduction of immunocompetent donor cells during transplantation contribute to a lymphomagenic environment in the host. Murine models of lymphoma that arises following transfer of allogeneic hematopoietic cells are discussed and are related to the transplant setting. One contemporary viewpoint of transplantation immunology holds that interactions between the host and donor components of the immune system determine the ultimate degree of tolerance or reciprocal immunoreactivity (eg, rejection, graft-versus-host disease) within the transplant patient. We conclude that host–donor immunologic microchimerism may also be an over-looked factor in the development of posttransplant lymphomas. PMID:21165166
Nalesnik, Michael A.; Starzl, Thomas E.
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
Cai, Qingqing; Chen, Kailin; Young, Ken H
We retrospectively reviewed the course of 1,000 renal transplants performed in 835 recipients (758 non-diabetics) to assess the incidence of new onset posttransplant diabetes in former nondiabetics. A total of 119 (15.7%) recipients manifested posttransplant diabetes, of whom 64 (53.8%) became hyperglycemic within 3 weeks of transplantation. Actuarial survival analysis indicated a statistically significant selection of blacks; 68 (57.1 %)
Eli A. Friedman; Tai-ping Shyh; Monica M. Beyer; Thomas Manis; Khalid M. H. Butt
Comparison of two real-time quantitative polymerase chain reaction strategies for minimal residual disease evaluation in lymphoproliferative disorders: correlation between immunoglobulin gene mutation load and real-time quantitative polymerase chain reaction performance.
We compared two strategies for minimal residual disease evaluation of B-cell lymphoproliferative disorders characterized by a variable immunoglobulin heavy chain (IGH) genes mutation load. Twenty-five samples from chronic lymphocytic leukaemia (n?=?18) or mantle cell lymphoma (n?=?7) patients were analyzed. Based on IGH variable region genes, 22/25 samples carried > 2% mutations, 20/25?>?5%. In the IGH joining region genes, 23/25 samples carried > 2% mutations, 18/25?>?5%. Real-time quantitative polymerase chain reaction was performed on IGH genes using two strategies: method A utilizes two patient-specific primers, whereas method B employs one patient-specific and one germline primer, with different positions on the variable, diversity and joining regions. Twenty-three samples (92%) resulted evaluable using method A, only six (24%) by method B. Method B poor performance was specifically evident among mutated IGH variable/joining region cases, although no specific mutation load above, which the real-time quantitative polymerase chain reaction failed was found. The molecular strategies for minimal residual disease evaluation should be adapted to the B-cell receptor features of the disease investigated. PMID:24254547
Della Starza, Irene; Cavalli, Marzia; Del Giudice, Ilaria; Barbero, Daniela; Mantoan, Barbara; Genuardi, Elisa; Urbano, Marina; Mannu, Claudia; Gazzola, Anna; Ciabatti, Elena; Guarini, Anna; Foŕ, Robin; Galimberti, Sara; Piccaluga, Pierpaolo; Gaidano, Gianluca; Ladetto, Marco; Monitillo, Luigia
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.
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. PMID:24188918
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
Kaposi sarcoma-associated herpesvirus (KSHV) is known to be associated with 3 distinct lymphoproliferative disorders: primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and MCD-associated plasmablastic lymphoma. We report 3 cases of a previously undescribed KSHV-associated lymphoproliferative disorder. The disease presented as localized lymphadenopathy and showed a favorable response to chemotherapy or radiotherapy. Histologically, the lymphoproliferation is characterized by plasmablasts that preferentially involved germinal centers of the lymphoid follicles, forming confluent aggregates. They were negative for CD20, CD27, CD79a, CD138, BCL6, and CD10 but showed monotypic kappa or lambda light chain. Clusters of CD10(+)CD20(+) residual follicle center cells were identified in some of the follicles. The plasmablasts were positive for both KSHV and EBV, and most of them also expressed viral interleukin-6 (vIL-6). Unexpectedly, molecular analysis of whole tissue sections or microdissected KSHV-positive aggregates demonstrated a polyclonal or oligoclonal pattern of immunoglobulin (Ig) gene rearrangement. The plasmablasts showed somatic mutation and intraclonal variation in the rearranged Ig genes, and one case expressed switched Ig heavy chain (IgA), suggesting that they originated from germinal center B cells. We propose calling this distinctive entity "KSHV-associated germinotropic lymphoproliferative disorder." PMID:12384445
Du, Ming-Qing; Diss, Tim C; Liu, Hongxiang; Ye, Hongtao; Hamoudi, Rifat A; Cabeçadas, José; Dong, Henry Y; Harris, Nancy Lee; Chan, John K C; Rees, John W; Dogan, Ahmet; Isaacson, Peter G
Similarly to Epstein-Barr virus (EBV), the human herpesvirus-8 (HHV-8) is a ?-herpesvirus, recently recognized to be associated with the occurrence of rare B cell lymphomas and atypical lymphoproliferations, especially in the human immunodeficiency virus (HIV) infected subjects. Moreover, the human herpesvirus-6 (HHV-6), a ?-herpesvirus, has been shown to be implicated in some non-malignant lymph node proliferations, such as the Rosai Dorfman disease, and in a proportion of Hodgkin’s lymphoma cases. HHV-6 has a wide cellular tropism and it might play a role in the pathogenesis of a wide variety of human diseases, but given its ubiquity, disease associations are difficult to prove and its role in hematological malignancies is still controversial. The involvement of another ?-herpesvirus, the human cytomegalovirus (HCMV), has not yet been proven in human cancer, even though recent findings have suggested its potential role in the development of CD4+ large granular lymphocyte (LGL) lymphocytosis. Here, we review the current knowledge on the pathogenetic role of HHV-8 and human ?-herpesviruses in human lymphoproliferative disorders. PMID:22110893
Quadrelli, C.; Barozzi, P.; Riva, G.; Vallerini, D.; Zanetti, E.; Potenza, L.; Forghieri, F.; Luppi, M.
We describe 2 cases of autoimmune lymphoproliferative syndrome (ALPS), which is a rare disorder of auto-immunity, chronic persistent or recurrent lymphadenopathy, splenomegaly, hepatomegaly and hyper gamma globulinemia (1gG, 1gA). Both cases presented in neonatal period which is a rare age of presentation in this disease. A 20 days old female neonate presented with respiratory symptoms which rapidly progressed needing ventilatory support. There was hepatomegaly and no auscultatory findings in the chest. Serial CBCs (complete blood counts) showed persistent leucocytosis with predominant lymphocytosis. Her chest X-ray showed left sided consolidation which responded poorly to antibiotics. Her prompt clinical response to steroids raised the suspicion of autoimmunity and the diagnosis was established after a negative bone marrow examination for leukemia and a positive result for ALPS on flow cytometry. The second case presented with anemia, thrombocytopenia starting in neonatal period followed by persistent lymphadenopathy, hepatosplenomegaly and recurrent infections which responded poorly to antibiotics. Diagnosis was delayed due to low index of suspicion, and finally achieved with multiple radiological studies, histopathology and flow cytometry. PMID:24906264
Naveed, Muhammad; Khamis Butt, Umar Bin; Mannan, Jovaria
Immune thrombocytopenic purpura (ITP), a condition of low platelets, can occur from primary causes, often referred to as idiopathic thrombocytopenic purpura, or secondary to an underlying disease, such as an autoimmune disorder or an infection. Secondary ITP can also occur with lymphoproliferative malignancies, such as chronic lymphocytic leukemia (CLL), Hodgkin's disease (HD), and non-Hodgkin's lymphomas (NHL). ITP associated with lymphoproliferative disorders has the same mechanism of platelet destruction as in idiopathic or primary ITP. The current treatment paradigm for secondary ITP varies according to the underlying condition. Standard treatments for primary ITP, which include corticosteroids, intravenous immunoglobulin (IVIg), anti-D, and splenectomy, are often successful in secondary ITP. However, in most situations with secondary ITP, treatment should focus on resolving the underlying disorder before treating the shortage of platelets, and, in the circumstances of ITP developing in patients with lymphoproliferative disorders, responses are frequently linked to remission of the primary malignancy. PMID:19245932
Liebman, Howard A
The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene. In this report, we present the histopathological and immunophenotypic features seen in the lymph nodes (n = 16), peripheral blood (n = 10), bone marrow (n = 2), spleen (n = 3), and liver (n = 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-alphabeta CD3+ CD4-CD8- (double-negative, DN) T cells that were negative for CD45RO. CD45RA+ T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation, as measured by in situ detection of DNA fragmentation and staining with MIB-1, respectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity, such as perforin, TIA-1, and CD57. CD25 was negative. In addition, most lymph nodes exhibited florid follicular hyperplasia, often with focal progressive transformation of germinal centers; in some cases, follicular involution was seen. A polyclonal plasmacytosis also was present. The spleens were markedly enlarged, more than 10 times normal size. There was expansion of both white pulp and red pulp, with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood, the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA+ T cells were increased in the four cases studied. Polyclonal B cell lymphocytosis with expansion of CD5+ B cells was a characteristic finding. Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS. Of note, two affected family members of one proband developed lymphoma (T-cell-rich B-cell lymphoma and nodular lymphocyte predominance Hodgkin's disease, respectively). PMID:9811346
Lim, M S; Straus, S E; Dale, J K; Fleisher, T A; Stetler-Stevenson, M; Strober, W; Sneller, M C; Puck, J M; Lenardo, M J; Elenitoba-Johnson, K S; Lin, A Y; Raffeld, M; Jaffe, E S
Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder of apoptosis, most commonly due to mutations in the FAS (TNFRSF6) gene. It presents with chronic lymphadenopathy, splenomegaly, and symptomatic multilineage cytopenias in an otherwise healthy child. Unfortunately, these clinical findings are also noted in other childhood lymphoproliferative conditions, such as leukemia, lymphoma, and hemophagocytic lymphohistiocytosis, which can confound the diagnosis. This report describes a 6-year-old girl with symptoms misdiagnosed as hemophagocytic lymphohistiocytosis and treated with chemotherapy before the recognition that her symptoms and laboratory values were consistent with a somatic FAS mutation leading to ALPS. This case should alert pediatricians to include ALPS in the differential diagnosis of a child with lymphadenopathy, splenomegaly, and cytopenias; obtain discriminating screening laboratory biomarkers, such as serum vitamin B-12 and ferritin levels; and, in the setting of a highly suspicious clinical scenario for ALPS, pursue testing for somatic FAS mutations when germ-line mutation testing is negative. PMID:24101757
Rudman Spergel, Amanda; Walkovich, Kelly; Price, Susan; Niemela, Julie E.; Wright, Dowain; Fleisher, Thomas A.
The enhanced risk of development of lymphoproliferative disorders in patients with inflammatory bowel disease has been attributed to immunosuppressive/immunomodulatory therapies. Infliximab is a chimeric monoclonal immunoglobulin G1 antibody directed against tumor necrosis factor alpha (TNF-?) that was approved by the Food and Drug Administration (FDA) in 1998 as an effective therapeutic agent against inflammatory bowel disease. Malignant lymphomas of both B and T cell lineage have been described in patients undergoing therapy involving TNF-? blockade. To date, eight cases of Epstein-Barr virus (EBV)-negative hepatosplenic T cell lymphoma associated with infliximab have been reported to the FDA's Adverse Event Reporting System, as well as several other T cell lymphoproliferative disorders with aggressive clinical outcomes. We present the histologic, immunophenotypic, and molecular features of a T cell lymphoproliferative disorder involving the axillary lymph node of a 33-year-old male following infliximab treatment for ulcerative colitis. These EBV-negative lymphomas suggest that lymphoproliferative disorders following infliximab treatment for inflammatory bowel disease may involve EBV-independent immune dysregulation. The spectrum of lymphoproliferative disorders associated with infliximab and the potential mechanisms by which they occur are discussed. PMID:19669196
Schmidt, Lindsay A; Lim, Megan S
Forty-two patients relapsing after an unmanipulated haploidentical BM transplant and post-transplant CY (PT-CY), were given 108 DLI, with median interval from transplant of 266 days (range, 67-1372). DLI were given at escalating doses, expressed as CD3+ cells/kg, without GVHD prophylaxis, and ranged from 1 × 10(3) to 1 × 10(7) cells/kg (median 5 × 10(5) cells/kg). The average number of DLI per patient was 2.6 (range, 1-6). The diagnosis was leukemias (n=32) grafted with a myeloablative regimen and Hodgkin's disease (n=10), grafted with a nonmyeloablative regimen. Leukemic patients with molecular relapse (n=20), received DLI alone (n=17) or in association with azacytidine (n=3); leukemic patients with hematologic relapse (n=12) received chemotherapy followed by DLI (n=11) or DLI alone (n=1); Hodgkin patients received DLI following 1-3 courses of chemotherapy. In these three groups the incidence of acute GVHD II-III was 15%, 17% and 10%; response rate was 45%, 33% and 70%; 2-year actuarial survival was 43%, 19% and 80% respectively. This study confirms that escalating doses of DLI can be given in the haploidentical setting with PT-CY, with a relatively low risk of acute GVHD. Response rates and survival are dependent on the underlying disease. PMID:25310304
Ghiso, A; Raiola, A M; Gualandi, F; Dominietto, A; Varaldo, R; Van Lint, M T; Bregante, S; Di Grazia, C; Lamparelli, T; Galaverna, F; Stasia, A; Luchetti, S; Geroldi, S; Grasso, R; Colombo, N; Bacigalupo, A
Background Although cardiovascular disease is thouht to be common in cirrhosis, there are no systematic investigations on the prevalence of electrocardiographic (ECG) abnormalities in these patients and data on the occurrence of post-transplant cardiac events in comparison with the general population are lacking. We aimed to study the prevalence and predictors of ECG abnormalities in patients with cirrhosis undergoing liver transplantation and to define the risk of cardiac events post-transplant compared to the general population. Methods Cirrhotic patients undergoing first-time liver transplantation between 1999–2007 were retrospectively enrolled. ECGs at pre-transplant evaluation were reviewed using the Minnesota classification and compared to healthy controls. Standardized incidence ratios for post-transplant cardiac events were calculated. Results 234 patients with cirrhosis were included, 186 with an available ECG (36% with alcoholic and 24% with viral cirrhosis; mean follow-up 4 years). Cirrhotics had a prolonged QTc interval, a Q wave, abnormal QRS axis deviation, ST segment depression and a pathologic T wave more frequently compared to controls (p?0.05 for all). Arterial hypertension, older age, cirrhosis severity and etiology were related to ECG abnormalities. Compared to the general Swedish population, patients were 14 times more likely to suffer a cardiac event post-transplant (p?0.001). A prolonged QTc interval and Q wave were related to post-transplant cardiac events (p?0.05 for all). Conclusions Pre-transplant ECG abnormalities are common in cirrhosis and are associated with cardiovascular risk factors and cirrhosis severity and etiology. Post-transplant cardiac events are more common than in the general population. PMID:24708568
Familial aggregation of lymphoproliferative disorders from the Scandinavian family cancer database Print This Page Familial Aggregation of Lymphoproliferative Disorders from the Scandinavian Family Cancer Database Our Research
As survival rates for pediatric solid organ transplantation have continued to improve, researchers and healthcare providers have increasingly focused on understanding and enhancing the HRQOL and psychosocial functioning of their patients. This manuscript reviews the psychosocial functioning of pediatric transplant recipients during the "later years," defined as more than three yr post-transplant, and focuses on the day-to-day impact of living with a transplant after the immediate period of adjustment and early years after surgery. Key topics reviewed include HRQOL, cognitive functioning, impact on the family, regimen adherence, and transition of responsibility for self-management tasks. Overall, pediatric transplant recipients evidence impairment in HRQOL, neuropsychological outcomes, and family functioning as compared to non-transplant recipients. However, the degree of impairment is influenced by a variety of factors including, disease severity, age, solid organ type, and study methodologies. Studies are limited by small samples, cross-sectional design, and the lack of universal assessment battery to allow for comparisons across solid organ populations. Areas for future research are discussed. PMID:25220845
Fredericks, Emily M; Zelikovsky, Nataliya; Aujoulat, Isabelle; Hames, Anna; Wray, Jo
Epstein-Barr virus (EBV) was the first human virus to be associated with oncogenesis. Over the past few decades, cumulative research has revealed that latent EBV infection may be implicated in the pathogenesis of a heterogeneous group of lymphoproliferative disorders and malignancies occurring in both immunocompetent and immunocompromised hosts. Many of these diseases have either primary or secondary cutaneous manifestations. Serologic studies and EBV-encoded RNA in situ hybridization stains have been used to show the association of EBV with disease; while these findings may imply a role, they do not equate with causation. In part II of this continuing medical education review, the salient features of EBV-associated lymphoproliferative disorders and solid tumors are detailed. PMID:25497918
Eminger, Lindsay A; Hall, Lawrence David; Hesterman, Kathleen S; Heymann, Warren R
Objective Current methods do not predict the acute renal allograft injury immediately after kidney transplantation. We evaluated the diagnostic performance of urinary calprotectin for predicting immediate posttransplant allograft injury. Methods In a multicenter, prospective-cohort study of 144 incipient renal transplant recipients, we postoperatively measured urinary calprotectin using an enzyme-linked immunosorbent assay and estimated glomerular filtration rate (eGFR) after 4 weeks, 6 months, and 12 months. Results We observed a significant inverse association of urinary calprotectin concentrations and eGFR 4 weeks after transplantation (Spearman r?=??0.33; P<0.001). Compared to the lowest quartile, patients in the highest quartile of urinary calprotectin had an increased risk for an eGFR less than 30 mL/min/1.73 m2 four weeks after transplantation (relative risk, 4.3; P<0.001; sensitivity, 0.92; 95% CI, 0.77 to 0.98; specificity, 0.48; 95% CI, 0.31 to 0.66). Higher urinary calprotectin concentrations predicted impaired kidney function 4 weeks after transplantation, as well as 6 months and 12 months after transplantation. When data were analyzed using the urinary calprotectin/creatinine-ratio similar results were obtained. Urinary calprotectin was superior to current use of absolute change of plasma creatinine to predict allograft function 12 months after transplantation. Urinary calprotectin predicted an increased risk both in transplants from living and deceased donors. Multivariate linear regression showed that higher urinary calprotectin concentrations and older donor age predicted lower eGFR four weeks, 6 months, and 12 months after transplantation. Conclusions Urinary calprotectin is an early, noninvasive predictor of immediate renal allograft injury after kidney transplantation. PMID:25402277
Bistrup, Claus; Marcussen, Niels; Pagonas, Nikolaos; Seibert, Felix S.; Arndt, Robert; Zidek, Walter; Westhoff, Timm H.
Posterior reversible encephalopathy syndrome (PRES) is characterized by headache, nausea, vomiting, seizures and visual disturbances. PRES has been usually associated with hypertension, chronic renal disease, malignancy and chemotherapeutic agents. We report the association of PRES with Autoimmune lymphoproliferative syndrome, which to our best knowledge has not been reported before. PMID:23560015
Chandramohan, Vaishnavi; Nagarajan, Vinoth Ponnurangam; Sathyamoorthi, Muthamil Selvan; Kumar, Sathish; Shanmugasundaram, Chitrambalam; Periakaruppan, Gokulakrishnan; Scott, Julius Xavier
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
Chung, Mu-Chi; Wu, Ming-Ju; Chang, Chao-Hsiang; Muo, Chih-Hsin; Yu, Tung-Min; Ho, Hao-Chung; Shu, Kuo-Hsiung; Chung, Chi-Jung
Transplantation of allogeneic hematopoietic stem cells with or without immunocompetent lymphocytes has proved a successful strategy in the treatment of hematological malignancies. We have recently shown that this approach can also cure mouse prostate cancer, provided that it is combined with tumor-specific vaccination. Whether the response to alloantigens acts by providing helper function to enhance vaccine-specific responses or in other ways impinges on vaccine immunogenicity remains to be clarified, and this question is of clinical relevance. In this study, we have addressed this issue by comparing the immunogenicity of dendritic cells pulsed with a peptide derived from a tumor/viral model Ag in recipients of donor cells either syngeneic to the host or differing for either Y-encoded or multiple minor H antigens. We report that vaccination elicits comparable proliferation and differentiation of peptide-specific CD8(+) T cells despite concurrent expansion and differentiation of minor H antigen-specific IFN-? effector T cells. Depletion of alloreactive CD4(+) T cells reduced alloreactivity but not vaccine-induced CD8(+) T cell priming, suggesting that alloresponses do not provide helper functions in peripheral lymphoid tissues. Vaccine-mediated T cell priming was also preserved in the case of multiple minor H antigen disparities, prone to graft-versus-host disease. Thus, in the context of nonmyeloablative allotransplantation aimed at restoring an effective tumor-specific T cell repertoire, minor H antigen-specific T cells do not interfere with vaccine-induced T cell priming, supporting the notion that posttransplant vaccination is a valuable strategy to boost tumor and pathogen-specific protective immunity. PMID:21209285
Manzo, Teresa; Hess Michelini, Rodrigo; Basso, Veronica; Ricupito, Alessia; Chai, Jian-Guo; Simpson, Elizabeth; Bellone, Matteo; Mondino, Anna
Cardiovascular diseases (CVD) are a major cause of morbidity and leading cause of mortality in almost 50% of patients (pts) with chronic kidney disease (CKD), including kidney transplant recipients. Left ventricular hypertrophy (LVH) is the most common structural alteration and powerful risk factor for cardiovascular complications in the uremic patients. The aim of this study is to analyze predictors of the left ventricular remodelling in the first year after kidney transplantation based on comparison of echocardiographic findings, which had been done before and twelve months after transplantation. In five years retrospective study, we followed up 30 kidney transplant patients in the first post-transplant year. All patients data - blood pressure, BMI, ECG, blood haemoglobin, serum protein, calcium, phosphorus, product of calcium and phosphorus, the values of parathyroid hormone, serum creatinine and creatinine clearance were recorded just before kidney transplantation and in one month interval after transplantation in the first post-transplant year. Echocardiographic examination was done before transplantation and one year after kidney transplantation. Before transplantation, 33% of patients had normal echocardiographic finding and 67% of patients had echocardiographic signs of left ventricular hypertrophy. After first post-transplant year, 63% of patients showed normal echocardiographic finding of LV, while 37% of patients remained with LV hypertrophy. Diastolic dysfunction of LV until the end of study had been reduced in 40% of pts compared to 70% pts at the beginning of the study. The positive echocardiographic remodelling of LV significantly correlated with rising values of haemoglobin (p<0.05), creatinine clearance (p=0.039) and with the reduction of the serum creatinine values (p=0.047), as well as values of parathyroid hormone (p=0.022). These results confirmed positive relationship between echocardiographic remodelling of left ventricular hypertrophy and elimination uraemia-related risk factors after successful renal transplantation. PMID:20433432
Dzemidzi?, Jasminka; Rasi?, Senija; Saracevi?, Adnan; Rebi?, Damir; Uncanin, Snezana; Srna, Amira; Muslimovi?, Alma
The impact of dialysis modality on posttransplant outcomes remains controversial. The authors have compared primary failure, delayed graft function (DGF), acute rejection episodes as well as patient and allograft survivals among patients undergoing renal transplantation between 2004 and 2009, according to the modality of hemodialysis (HD) versus peritoneal dialysis (PD). We studied 306 patients (268 HD and 38 PD) with
C. Freitas; M. Fructuoso; L. S. Martins; M. Almeida; S. Pedroso; L. Dias; A. C. Henriques; A. Cabrita
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
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.
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. PMID:10861820
Fang, B S; Sneller, M C; Straus, S E; Frenkel, L; Dale, J K; Rick, M E
Autoimmune Pancytopenia; Autoimmune Lymphoproliferative Syndrome (ALPS); Evans Syndrome; Idiopathic Thrombocytopenic Purpura; Anemia, Hemolytic, Autoimmune; Autoimmune Neutropenia; Lupus Erythematosus, Systemic; Inflammatory Bowel Disease; Rheumatoid Arthritis
This study was designed to determine the complete response (CR) rate, event-free survival (EFS) and overall survival (OS) in patients with metastatic breast cancer treated with an adriamycin-based induction regimen, high-dose chemotherapy consisting of cyclophosphamide and thiotepa with autologous bone marrow or stem cell reinfusion, followed by post-transplant 5-fluorouracil and cisplatin. Forty-eight consecutive patients were enrolled and 35 received two to four cycles of a cytoreductive chemotherapy regimen followed by high-dose chemotherapy which included cyclophosphamide and thiotepa. Thirty-three patients with non-progressive disease received at least one cycle of post-transplant 5-fluorouracil and cisplatin. Fifty percent of patients with evaluable disease responded to induction chemotherapy. Three of the 34 patients (9%) evaluable for response to high-dose chemotherapy achieved CR, eight (24%) achieved partial response (PR), 12 (35%) had stable disease (SD) and 11 (32%) had progressive disease (PD). The median time to neutrophil recovery was 11.5 days (range, 8 to 40 days) post- reinfusion. The median time to platelet independence was 14.5 days (range, 8 to 44 days). The median follow-up is 24.5 months (range, 1 to 96 months). The actuarial probability of EFS for all patients is 17% at 4 years. The EFS for patients receiving all four cycles of post-transplant chemotherapy is 27% at 4 years, compared to 36% at 1 year for patients not receiving any post-transplant chemotherapy. Ten of the 48 patients (21%) are alive, and seven of these (15%) have no evidence of disease. High-dose chemotherapy with autologous bone marrow or peripheral blood-derived stem cell transplantation followed by post-transplant consolidation chemotherapy in patients with metastatic breast cancer results in a proportion of patients without evidence of disease at 4 years. PMID:9384473
Tallman, M S; Rademaker, A W; Jahnke, L; Brown, S G; Bauman, A; Mangan, C; Kelly, C; Rubin, H; Kies, M S; Shaw, J; Kiel, K; Gordon, L I; Gradishar, W J; Winter, J N
The autoimmune lymphoproliferative syndrome (ALPS) affords novel insights into the mechanisms that regulate lymphocyte homeostasis and underlie the development of autoimmunity. This syndrome arises early in childhood in persons who inherit mutations in genes that mediate apoptosis, or programmed cell death. The timely deletion of lymphocytes is a way to prevent their accumulation and the persistence of cells that can react against the body's own antigens. In ALPS, defective lymphocyte apoptosis permits chronic, nonmalignant adenopathy and splenomegaly; the survival of normally uncommon "double-negative" CD3+ CD4- CD8- T cells; and the development of autoimmune disease. Most cases of ALPS involve heterozygous mutations in the lymphocyte surface protein Fas that impair a major apoptotic pathway. Detailed immunologic investigations of the cellular and cytokine profiles in ALPS show a prominent skewing toward a T-helper 2 phenotype; this provides a rational explanation for the humoral autoimmunity typical of patients with ALPS. Prospective evaluations of 26 patients and their families show an ever-expanding spectrum of ALPS and its major complications: hypersplenism, autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. Defective apoptosis may also contribute to a heightened risk for lymphoma. PMID:10189330
Straus, S E; Sneller, M; Lenardo, M J; Puck, J M; Strober, W
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
Oliveira, Joăo Bosco
Apoptosis of activated lymphocytes is critical to immune homeostasis. The cell surface receptor Fas is an important mediator of lymphocyte apoptosis; defective Fas expression causes accumulation of lymphocytes and autoimmune disease in mice. Apoptosis defects due to mutations of Fas have also been found in a rare human autoimmune lymphoproliferative syndrome (ALPS). Nine unrelated children with ALPS had lymphadenopathy, autoimmunity and expansion of a normally infrequent population of CD4-CD8-T cells. All nine exhibited impaired lymphocyte apoptosis in vitro, and eight had heterozygous Fas gene mutations. Thus genetic defects in apoptosis pathways are implicated in the pathogenesis of at least one human autoimmune disorder. PMID:9106310
Puck, J M; Sneller, M C
Hematopoietic cell transplantation (HCT) with non-myeloablative (NMA) conditioning for lymphoproliferative diseases (LD) includes fludarabine with and without low-dose TBI. Transplant outcomes were compared among patients aged ?40 years with LD who received a HCT with TBI (N=382) or no-TBI (N=515) NMA from 2001 to 2011. The groups were comparable except for donor, graft, prophylaxis for GVHD, disease status and year of HCT. Cumulative incidences of grades II-IV GVHD at 100 days were 29% and 20% (P=0.001) and of chronic GVHD at 1 year were 54% and 44% (P=0.004) for TBI and no-TBI, respectively. Multivariate analysis of progression/relapse, treatment failure and mortality showed no outcome differences by conditioning. Full donor chimerism at day 100 was observed in 82% vs 64% in the TBI and no-TBI groups, respectively (P=0.006). Subsets of the four most common conditioning/GVHD prophylaxis combinations demonstrated higher rates of grades II-IV acute (P<0.001) and chronic GVHD (P<0.001) among recipients of TBI-mycophenolate mofetil (MMF) compared with other combinations. TBI-based NMA conditioning induces faster full donor chimerism, but overall survival outcomes are comparable to no-TBI regimens. Combinations of TBI and MMF are associated with higher rates of GVHD without impact on survival outcomes in patients with LD.Bone Marrow Transplantation advance online publication, 1 December 2014; doi:10.1038/bmt.2014.269. PMID:25437248
Hong, S; Le-Rademacher, J; Artz, A; McCarthy, P L; Logan, B R; Pasquini, M C
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) in infected individuals after a long incubation period. To dissect the mechanisms of the development of the disease, we have previously established a rat model of ATL-like disease which allows examination of the growth and spread of HTLV-1 infected tumor cells, as well assessment of the effects of
TAKASHI OHASHI; SHINO HANABUCHI; HIROTOMO KATO; HIROMI TATENO; FUMIYO TAKEMURA; TOMONORI TSUKAHARA; YOSHIHIRO KOYA; ATSUHIKO HASEGAWA; TAKAO MASUDA; MARI KANNAGI
Autoimmune lymphoproliferative syndrome (ALPS) is caused by genetic defects decreasing Fas function and is characterized by lymphadenopathy/splenomegaly and expansion of CD4/CD8 double-negative T cells. This latter expansion is absent in the ALPS variant named Dianzani Autoimmune/lymphoproliferative Disease (DALD). In addition to the causative mutations, the genetic background influences ALPS and DALD development. We previously suggested a disease-modifying role for the perforin gene involved in familial hemophagocytic lymphohistiocytosis (FHL). The UNC13D gene codes for Munc13-4, which is involved in perforin secretion and FHL development, and thus, another candidate for a disease-modifying role in ALPS and DALD. In this work, we sequenced UNC13D in 21 ALPS and 20 DALD patients and compared these results with sequences obtained from 61 healthy subjects and 38 multiple sclerosis (MS) patients. We detected four rare missense variations in three heterozygous ALPS patients carrying p.Cys112Ser, p.Val781Ile, and a haplotype comprising both p.Ile848Leu and p.Ala995Pro. Transfection of the mutant cDNAs into HMC-1 cells showed that they decreased granule exocytosis, compared to the wild-type construct. An additional rare missense variation, p.Pro271Ser, was detected in a healthy subject, but this variation did not decrease Munc13-4 function. These data suggest that rare loss-of-function variations of UND13D are risk factors for ALPS development. PMID:23840885
Aricň, Maurizio; Boggio, Elena; Cetica, Valentina; Melensi, Matteo; Orilieri, Elisabetta; Clemente, Nausicaa; Cappellano, Giuseppe; Buttini, Sara; Soluri, Maria Felicia; Comi, Cristoforo; Dufour, Carlo; Pende, Daniela; Dianzani, Irma; Ellis, Steven R.; Pagliano, Sara; Marcenaro, Stefania; Ramenghi, Ugo; Chiocchetti, Annalisa; Dianzani, Umberto
Bracken (Pteridium aquilinum) has long been known to cause cancer in farm and laboratory animals. Ptaquiloside, a norsesquiterpene glycoside found in bracken, is considered its main carcinogenic toxin and is capable of inducing tumours in a variety of organ systems, but especially in the urinary bladder, depending on the animal species, the administration route employed and the duration of exposure. In the present study, 12 male CD-1 mice were intraperitoneally administered with 0.5 mg ptaquiloside weekly for 15 weeks, followed by 15 weeks without any treatment. Twelve animals used as controls were administered the vehicle solution (phosphate buffered saline). Two exposed animals died during the experimental work. On necropsy, blood and tissue samples (brain, eyes, thymus, heart, lungs, liver, digestive system, spleen, bladder, kidney, adrenal gland, urinary bladder, sexual accessory glands, testes, muscle, skin and femur) were collected for histological analysis. Leukograms were prepared from blood smears and total WBC counts obtained with a Neubauer chamber. Flow cytometry was used to assess blood T-(CD3(+)) and B-(CD19(+))-lymphocytes, medullary granulocytic (CD11b(+)/Ly-6G(-), CD11b(+)/Ly-6G(+)) and lymphocytic (CD19(+)/IgM(-), CD19+/IgM(+)) populations and thymic lymphoid (CD4(+), CD8(+), CD4(+)/CD8(+)) populations. Lymphoproliferative lesions were analysed immunohistochemically using antibodies against CD45R and CD3. All of the 10 surviving mice developed a lymphoproliferative malignancy. Lymphoproliferative disease was characterized by multifocal B-(CD45(+)/CD3(-))-lymphocytic renal (10/10 animals) and hepatic (2/10 animals) invasion, splenic white pulp hyperplasia (10/10) together with a significant increase in circulating B-(CD19(+))-lymphocytes and the appearance of circulating dysplastic lymphoid cells. Eight out of 10 ptaquiloside-exposed animals developed urothelial dysplasia (six low-grade dysplasia and two high-grade dysplasia). No lesions were detected in control mice. These results show that ptaquiloside is capable of inducing malignant transformation in mice and provide an in-depth characterisation of lymphoproliferative lesions. Furthermore, the urinary bladder is shown to be a target organ for this toxin in mice as well as in other animal species. PMID:21907228
Gil da Costa, Rui M; Oliveira, Paula A; Vilanova, Manuel; Bastos, Margarida M S M; Lopes, Célia C; Lopes, Carlos
The feasibility of allogeneic transplantation, without myeloablation or post-transplant immunosuppression, was tested using in vivo chemoselection of allogeneic hematopoietic stem cells (HSCs) after transduction with a novel tricistronic lentiviral vector (MGMTP140K-2A-GFP-IRES-TK (MAGIT)). This vector contains P140K-O6-methylguanine-methyltransferase (MGMTP140K), HSV-thymidine kinase (TKHSV), and enhanced green fluorescent protein (eGFP) enabling (i) in vivo chemoselection of HSC by conferring resistance to benzylguanine (BG), an inhibitor of endogenous MGMT, and to chloroethylating agents such as 1,3-bis(2-chloroethyl)nitrosourea (BCNU) and, (ii) depletion of proliferating cells such as malignant clones or transduced donor T cells mediating graft versus host disease (GVHD), by expression of the suicide gene TKHSV and Ganciclovir (GCV) administration. Non-myeloablative transplantation of transduced, syngeneic, lineage-depleted (Lin?) BM in neonates resulted in 0.67% GFP+ mononuclear cells in peripheral blood. BG/BCNU chemoselection, 4 and 8 weeks post-transplant, produced 50-fold donor cell enrichment. Transplantation and chemoselection of major histocompatibility complex (MHC)-mismatched MAGIT-transduced Lin? BM also produced similar expansion for >40 weeks. The efficacy of this allotransplant approach was validated in Hbbth3 heterozygous mice by correction of ?-thalassemia intermedia, without toxicity or GVHD. Negative selection, by administration of GCV resulted in donor cell depletion without graft ablation, as re-expansion of donor cells was achieved with BG/BCNU treatment. These studies show promise for developing non-ablative allotransplant approaches using in vivo positive/negative selection. PMID:22871662
Falahati, Rustom; Zhang, Jianqing; Flebbe-Rehwaldt, Linda; Shi, Yimin; Gerson, Stanton L; Gaensler, Karin ML
The feasibility of allogeneic transplantation, without myeloablation or post-transplant immunosuppression, was tested using in vivo chemoselection of allogeneic hematopoietic stem cells (HSCs) after transduction with a novel tricistronic lentiviral vector (MGMT(P140K)-2A-GFP-IRES-TK (MAGIT)). This vector contains P140K-O(6)-methylguanine-methyltransferase (MGMT(P140K)), HSV-thymidine kinase (TK(HSV)), and enhanced green fluorescent protein (eGFP) enabling (i) in vivo chemoselection of HSC by conferring resistance to benzylguanine (BG), an inhibitor of endogenous MGMT, and to chloroethylating agents such as 1,3-bis(2-chloroethyl)nitrosourea (BCNU) and, (ii) depletion of proliferating cells such as malignant clones or transduced donor T cells mediating graft versus host disease (GVHD), by expression of the suicide gene TK(HSV) and Ganciclovir (GCV) administration. Non-myeloablative transplantation of transduced, syngeneic, lineage-depleted (Lin(-)) BM in neonates resulted in 0.67% GFP(+) mononuclear cells in peripheral blood. BG/BCNU chemoselection, 4 and 8 weeks post-transplant, produced 50-fold donor cell enrichment. Transplantation and chemoselection of major histocompatibility complex (MHC)-mismatched MAGIT-transduced Lin(-) BM also produced similar expansion for >40 weeks. The efficacy of this allotransplant approach was validated in Hbb(th3) heterozygous mice by correction of ?-thalassemia intermedia, without toxicity or GVHD. Negative selection, by administration of GCV resulted in donor cell depletion without graft ablation, as re-expansion of donor cells was achieved with BG/BCNU treatment. These studies show promise for developing non-ablative allotransplant approaches using in vivo positive/negative selection. PMID:22871662
Falahati, Rustom; Zhang, Jianqing; Flebbe-Rehwaldt, Linda; Shi, Yimin; Gerson, Stanton L; Gaensler, Karin Ml
... Patients and Families Resources for Health Professionals What glossary definitions help with understanding XLP? apoptosis ; bone marrow ; ... many other terms in the Genetics Home Reference Glossary . See also Understanding Medical Terminology . References (11 links) ...
Epstein-Barr virus (EBV)–associated lymphoid proliferations are a well-recognized complication of congenital or acquired systemic immunosuppression. The CNS is a frequent site for development of such lymphoid proliferations. We describe the clinical, imaging, and pathologic observations of a CNS disorder histologically similar to posttransplantation lymphoproliferative disorder that occurred in four patients with autoimmune disease treated with mycophenolate mofetil (MM). Two patients had polymorphous lymphoplasmacytic infiltration of brain parenchyma, and two had monomorphous infiltrations consistent with diffuse large B-cell lymphoma. In situ hybridization for EBV-encoded RNA was positive in all four patients. All patients improved after MM withdrawal and the use of rituximab. Because of a favorable toxicity profile, MM is now being used as steroid-sparing immunomodulatory therapy in autoimmune disorders. Based on our experience presented herein, we recommend caution in patient selection for MM and strict surveillance of those patients with autoimmune disorders who receive MM. PMID:17522336
O’Neill, Brian Patrick; Vernino, Steven; Dogan, Ahmet; Giannini, Caterina
Summary Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of T cell dysregulation caused by defective Fas-mediated apoptosis. Patients with ALPS can develop a myriad of clinical manifestations including lymphadenopathy, hepatosplenomegaly, autoimmunity and increased rates of malignancy. ALPS may be more common that originally thought, and testing for ALPS should be considered in patients with unexplained lymphadenopathy, hepatosplenomegaly, and/or autoimmunity. As the pathophysiology of ALPS is better characterized, a number of targeted therapies are in preclinical development and clinical trials with promising early results. This review describes the clinical and laboratory manifestations found in ALPS patients, as well as the molecular basis for the disease and new advances in treatment. PMID:19930184
Teachey, David T.; Seif, Alix E.; Grupp, Stephan A.
Post-transplant renal function in the first year predicts long-term kidney transplant survival.BackgroundImprovements in long-term kidney graft survival have been recently noted. However, the reasons for this were unclear. This study examined post-transplant renal function within the first year as an independent variable influencing long-term survival.MethodsThe influence of demographic characteristics (age, sex, race); transplant variables (cadaver versus living donor, cold ischemia
Sundaram Hariharan; Maureen A Mcbride; Wida S Cherikh; Christine B Tolleris; Barbara A Bresnahan; Christopher P Johnson
Epidermal keratinocytes form a highly organized stratified epithelium and sustain a competent barrier function together with dermal and hematopoietic cells. The Notch signaling pathway is a critical regulator of epidermal integrity. Here, we show that keratinocyte-specific deletion of total Notch signaling triggered a severe systemic B-lymphoproliferative disorder, causing death. RBP-j is the DNA binding partner of Notch, but both RBP-j–dependent and independent Notch signaling were necessary for proper epidermal differentiation and lipid deposition. Loss of both pathways caused a persistent defect in skin differentiation/barrier formation. In response, high levels of thymic stromal lymphopoietin (TSLP) were released into systemic circulation by Notch-deficient keratinocytes that failed to differentiate, starting in utero. Exposure to high TSLP levels during neonatal hematopoiesis resulted in drastic expansion of peripheral pre- and immature B-lymphocytes, causing B-lymphoproliferative disorder associated with major organ infiltration and subsequent death, a previously unappreciated systemic effect of TSLP. These observations demonstrate that local skin perturbations can drive a lethal systemic disease and have important implications for a wide range of humoral and autoimmune diseases with skin manifestations. PMID:18507503
Demehri, Shadmehr; Liu, Zhenyi; Lee, Jonghyeob; Lin, Meei-Hua; Crosby, Seth D; Roberts, Christopher J; Grigsby, Perry W; Miner, Jeffrey H; Farr, Andrew G; Kopan, Raphael
Purpose of Review Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of disrupted lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway. Clinical manifestations include lymphadenopathy, splenomegaly, and autoimmune cytopenias. A number of new insights have improved the understanding of the genetics and biology of ALPS. These will be discussed in this review. Recent Findings A number of key observations have been made recently that better define the pathophysiology of ALPS, including the characterization of somatic FAS variant ALPS, the identification of haploinsufficiency as a mechanism of decreased Fas expression, and the description of multiple genetic hits in FAS in some families that may explain the variable penetrance of the disease. In addition, ALPS has been shown to be a more common condition, as patients diagnosed with other disorders, including Evans syndrome and common variable immune deficiency have been found to have ALPS. Finally, the treatment of the disease has changed as splenectomy and rituximab have been shown to have unexpected ALPS specific toxicities, and mycophenolate mofetil and sirolimus have been demonstrated to have marked activity against the disease. Summary Based on novel advances the diagnostic algorithm and recommended treatment for ALPS have changed significantly, improving quality of life for many patients. PMID:22157362
Teachey, David T.
Acute graft-versus-host disease (aGVHD) still remains the main cause of morbidity and mortality after allogeneic stem cell transplantation. Moreover, patients who did not respond to first-line treatment with glucocorticosteroids have a very poor outcome. Some studies suggested that alemtuzumab (a humanized monoclonal antibody against the CD52 antigen) might be effective for treatment of refractory aGVHD. Here we report a single-center experience with alemtuzumab in refractory gastrointestinal aGVHD. From September 2009 to April 2012 at the Grenoble medical university center, 24 patients who had presented a refractory gastrointestinal aGVHD to corticosteroid, or after another immunosuppressive drug, were retrospectively analyzed. Most patients (n = 19) presented stage 4 gastrointestinal aGVHD. Response to treatment (either complete or partial) was observed in 15 patients (62.4%). The overall survival rate at 1 year for all patients was 33.3% (95% confidence interval [CI], 15.9% to 51.9%) and for responders, 53.3% (95% CI, 26.3% to 74.4%). Two patients died from infection, 5 patients from recurrent GVHD, and 1 from an uncontrolled post-transplant lymphoproliferative disorder. PMID:24910381
Meunier, Mathieu; Bulabois, Claude Eric; Thiebaut-Bertrand, Anne; Itzykson, Raphaël; Carre, Martin; Carras, Sylvain; Garban, Fréderic; Cahn, Jean Yves
Background. Neurofibromatosis type 1 is a genetic disorder caused by loss-of-function mutations in a tumor suppressor gene (NF1) which codifies the protein neurofibromin. The frequent genetic alterations that modify neurofibromin function are deletions and insertions. Duplications are rare and phenotype in patients bearing duplication of NF1 gene is thought to be restricted to developmental abnormalities, with no reference to cancer susceptibility in these patients. We evaluated a patient who presented with few clinical signs of neurofibromatosis type 1 and a conspicuous personal and familiar history of different types of cancer, especially lymphoproliferative malignancies. The coding region of the NF-1 gene was analyzed by real-time polymerase chain reaction and direct sequencing. Multiplex ligation-dependent probe amplification was performed to detect the number of mutant copies. The NF1 gene analysis showed the following alterations: mosaic duplication of NF1, TRAF4, and MYO1D. Fluorescence in situ hybridization using probes (RP5-1002G3 and RP5-92689) flanking NF1 gene in 17q11.2 and CEP17 for 17q11.11.1 was performed. There were three signals (RP5-1002G3conRP5-92689) in the interphases analyzed and two signals (RP5-1002G3conRP5-92689) in 93% of cells. These findings show a tandem duplication of 17q11.2. Conclusion. The case suggests the possibility that NF1 gene duplication may be associated with a phenotype characterized by lymphoproliferative disorders. PMID:25580325
Fernandes, Gustavo; Souto, Mirela; Costa, Frederico; Oliveira, Edite; Garicochea, Bernardo
Abstract Background. Hepatitis B and C viruses’ infections are often associated with hematological disorders in evolution, suggesting that these viruses have a tropism for peripheral blood and/or bone marrow cells. Aim. To analyze the hematological parameters and bone marrow findings in a group of patients diagnosed with chronic lymphoproliferative disorders (CLD) and hepatitis viruses B, C, D infections, which were included in the research grant (acronym LIMFO-VIR) between December 2007 and May 2010 in the Hematology Department of the Emergency University Hospital of Bucharest. Methods and results. Patients were diagnosed by using immunopathology according to the WHO criteria. The analyzed group included 42 patients (both sexes), with the mean age of 60,35 years. The most frequent hematologic disease was non-Hodgkin’s lymphoma 30/42 (71,42%), followed by chronic lymphocytic leukemia (16,66%) and Hodgkin’s lymphoma (7,14%). Hepatitis viruses were distributed: 17/42 (40,47%) patients with HBV, 22/42 (52,38%) with HCV and 3/42 (7,14%) had a double/triple association of viruses. Most of the patients had an indolent type of disease - 27/42 (64,28%), whereas 15/42 (35,71%) had an aggressive one, pattern found both in the HBV and HCV infected groups. An abnormal bone marrow result was revealed in 32/42 (76,19%) patients, 19 (59,37%) of them being HCV infected. Myelodysplasia was found in 6/42(14,28%) patients, the majority being HCV infected, all having an indolent form of CLD. The antiviral therapy did not influence the hematological parameters (no significant differences were found between the groups with/without an antiviral therapy). Discussions. Patients with hepatitis virus infections may associate neutropenia and thrombocytopenia; the mechanisms are thought to involve hypersplenism, autoimmune processes and antiviral therapy. We excluded the influence of chemotherapy, as the study was performed before the treatment. In our group, patients whether HBV or HCV infected, presented an isolated cytopenia. The abnormal bone marrow cellularity (increased or decreased) and dysplasia were found especially in the HCV group. There are studies showing no association between myelodysplasia and hepatitis viruses; others found a strong relation of these. One of the mechanisms of myelodysplasia could be a dysregulation of the immune system. Conclusions. Bone marrow/peripheral blood features correlate with the type of viral infection and HCV is more prone to develop additional hematological changes than HBV. The degree of bone marrow involvement by CLDs influences these features. We considered mandatory to perform a bone marrow analysis at the diagnosis of CLDs to stage and to establish if other bone marrow changes were present, a crucial aspect for therapy and outcome of the disease. The association between the hepatitis viruses – myelodysplasia- autoimmunity seems to have a role in the lymphoproliferative disorders etiology. Abbreviations: CLD – chronic lymphoproliferative disorders; NHL- non-Hodgkin’s lymphoma, CLL- chronic lymphocytic leukemia, HL- Hodgkin’s lymphoma, MDS – myelodysplastic syndrome, AML – acute myeloid leukemia PMID:24868264
Ciufu, C; Arama, V; Bumbea, H; Dobrea, C; Ion, I; Vladareanu, AM
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-? gene rearrangement and positive EBV in situ hybridization. PMID:23169419
Lee, Hye Young; Baek, Jin Ok; Lee, Jong Rok; Park, Sang Hui; Jeon, In Sang; Roh, Joo Young
The incidence of lymphoproliferative disorders (LD) is increasing in developed countries. Patients with inflammatory bowel disease (IBD) exposed to thiopurines are at additional risk of three specific forms of LD: Epstein-Barr-Virus-related post-transplant like LD, hepato-splenic T-cell lymphoma and post-mononucleosis lymphoproliferation. The risk of the two latter forms of LD can be reduced when considering specific immunosuppressive strategies in young males. It is still unclear whether the risk of uterine cervix abnormalities is increased in IBD women, irrespective of the use of immunosuppressants. Given the excess risk demonstrated in various other contexts of immunosuppression, it is currently recommended that all women with IBD, particularly those receiving immunosuppressants, strictly adhere to a screening program of cervical surveillance and undergo vaccination against HPV, when appropriate. Patients with IBD receiving immunosuppressants are at increased risk of skin cancers. The risk of non-melanoma skin cancer is notably increased in patients receiving thiopurines. Recent data suggest that the risk of melanoma is mildly increased in patients exposed to anti-TNF therapy. All IBD patients should adhere to a program of sun protection and dermatological surveillance, whose details should take into account the other non-IBD-related risk factors. PMID:23721759
Magro, Fernando; Peyrin-Biroulet, Laurent; Sokol, Harry; Aldeger, Xavier; Costa, Antonia; Higgins, Peter D; Joyce, Joel C; Katsanos, Konstantinos H; Lopez, Anthony; de Xaxars, Teresa Mas; Toader, Elena; Beaugerie, Laurent
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…
Klein, Susan D.; Simmons, Roberta G.
To clarify the role of CD8+ effector T cells for infectious complications, 92 recipients were classified according to the hierarchical clustering of preoperative CD8+CD45 isoforms: Group I was naive, Group II was effector memory, and Group III was effector (E) T cell-dominant. The posttransplant infection rates progressively increased from 29% in Group I to 64.3% in Group III recipients. The posttransplant immune status was compared with the pretransplant status, based on the measure (% difference) and its graphical form (scatter plot). In Groups I and II, both approaches showed a strong upward deviation from pretransplant status upon posttransplant infection, indicating an enhanced clearance of pathogens. In Group III, in contrast, both approaches showed a clear downward deviation from preoperative status, indicating deficient cytotoxicity. The % E difference and scatter plot can be used as a useful indicator of a posttransplant infectious complication. PMID:18483571
Uemoto, Shinji; Ozawa, Kazue; Egawa, Hiroto; Takada, Yasutsugu; Sato, Hiroshi; Teramukai, Satoshi; Kasahara, Mureo; Ogawa, Kohei; Ono, Masako; Takai, Kenji; Fukushima, Masanori; Inaba, Kayo; Tanaka, Koichi
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance. Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis. Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which encode the intracellular portion of Fas. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonist monoclonal antibody. Similar defects were found in a Fas-negative cell line transfected with cDNAs bearing each of the mutations. In cotransfection experiments, Fas constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wild-type Fas. Two missense Fas variants, not restricted to patients with ALPS, were identified. Variant A(-1)T at the Fas signal-sequence cleavage site, which mediates apoptosis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles. Among the ALPS-associated Fas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the Fas receptor. Mutations causing disruption of the intracellular Fas death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS. PMID:10090885
Jackson, C E; Fischer, R E; Hsu, A P; Anderson, S M; Choi, Y; Wang, J; Dale, J K; Fleisher, T A; Middelton, L A; Sneller, M C; Lenardo, M J; Straus, S E; Puck, J M
Three field studies were conducted to determine the selectivity on leeks (Allium porrum L.) of early post-transplant herbicides and their efficacy on weed populations and crop yields. Herbicide treatments were cinmethylin, metolachlor, oxyfluorfen, prodiamine, and pendimethalin. Both a non-treated and a weed-free control were added. The most common species were the broadleaved weeds Eclipta alba (L.) Hassk., Rorippa teres (Michx.)
James P. Gilreath; Bielinski M. Santos; Phyllis R. Gilreath; Donald N. Maynard
Three field studies were conducted to determine the selectivity on leeks (Allium porrum L.) of early post-transplant herbicides and their efficacy on weed populations and crop yields. Herbicide treatments were cinmethylin, metolachlor, oxyfluorfen, prodiamine, and pendimethalin. Both a non-treated and a weed-free control were added. The most common species were the broadleaved weeds Eclipta alba (L.) Hassk., Rorippa teres (Michx.)
James P. Gilreath; Bielinski M. Santos; Phyllis R. Gilreath; Donald N. Maynard
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 TCR? 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
Huang, Wenting; Lv, Ning; Ying, Jianming; Qiu, Tian; Feng, Xiaoli
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
Ok, Chi Young; Li, Ling; Young, Ken H
X-linked chronic granulomatous disease (X-CGD) is an inherited immunodeficiency with absent phagocyte NADPH oxidase activity caused by defects in the gene encoding gp91phox. Here we evaluated strategies for less intensive conditioning for gene therapy of genetic blood disorders without selective advantage for gene correction, such as might be used in a human X-CGD protocol. We compared submyeloablative with ablative irradiation as conditioning in murine X-CGD, examining engraftment, oxidase activity and vector integration in mice transplanted with marrow transduced with a gamma-retroviral vector for gp91phox expression. The frequency of oxidase-positive neutrophils in the donor population was unexpectedly higher in many 300 cGy-conditioned mice compared to lethally irradiated recipients, as was the fraction of vector-marked donor secondary CFU-S12. Vector integration sites in marrow, spleen, and secondary CFU-S12 DNA from primary recipients were enriched for cancer-associated genes, including Evi1, and integrations in or near cancer-associated genes were more frequent in marrow and secondary CFU-S12 from 300 cGy-conditioned mice compared to fully ablated mice. These findings support the concept that vector integration can confer a selection bias, and suggest that intensity of the conditioning regimen may further influence the effects of vector integration on clonal selection in post-transplant engraftment and hematopoiesis. PMID:19657370
Sadat, Mohammed A.; Dirscherl, Sara; Sastry, Lakshmi; Dantzer, Jessica; Pech, Nancy; Griffin, Samantha; Hawkins, Troy; Zhao, Yiqiang; Barese, Cecilia N.; Cross, Scott; Orazi, Attilio; An, Caroline; Goebel, W. Scott; Yoder, Mervin C.; Li, Xiaoman; Grez, Manuel; Cornetta, Kenneth; Mooney, Sean D.; Dinauer, Mary C.
X-linked chronic granulomatous disease (X-CGD) is an inherited immunodeficiency with absent phagocyte NADPH-oxidase activity caused by defects in the gene-encoding gp91(phox). Here, we evaluated strategies for less intensive conditioning for gene therapy of genetic blood disorders without selective advantage for gene correction, such as might be used in a human X-CGD protocol. We compared submyeloablative with ablative irradiation as conditioning in murine X-CGD, examining engraftment, oxidase activity and vector integration in mice transplanted with marrow transduced with a gamma-retroviral vector for gp91(phox) expression. The frequency of oxidase-positive neutrophils in the donor population was unexpectedly higher in many 300 cGy-conditioned mice compared with lethally irradiated recipients, as was the fraction of vector-marked donor secondary CFU-S12. Vector integration sites in marrow, spleen and secondary CFU-S12 DNA from primary recipients were enriched for cancer-associated genes, including Evi1, and integrations in or near cancer-associated genes were more frequent in marrow and secondary CFU-S12 from 300 cGy-conditioned mice compared with fully ablated mice. These findings support the concept that vector integration can confer a selection bias, and suggest that the intensity of the conditioning regimen may further influence the effects of vector integration on clonal selection in post-transplant engraftment and hematopoiesis. PMID:19657370
Sadat, M A; Dirscherl, S; Sastry, L; Dantzer, J; Pech, N; Griffin, S; Hawkins, T; Zhao, Y; Barese, C N; Cross, S; Orazi, A; An, C; Goebel, W S; Yoder, M C; Li, X; Grez, M; Cornetta, K; Mooney, S D; Dinauer, M C
Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked over accumulation of mature lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS) in humans. To define the clinical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively evaluated with routine clinical studies, lymphocyte phenotyping, genotyping, and in vitro assays for lymphocyte apoptosis. Individual patients were followed up for 3 months to 6 years. ALPS was identified in 9 unrelated children as manifested by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD4- CD8- T cells that express the alpha/beta T-cell receptor (TCR). All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Fas-mediated lymphocyte apoptosis, but clinical features of ALPS were not present in the vast majority of these individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of lymphocyte apoptosis are associated with abnormal lymphoproliferation and autoimmunity. These findings provide evidence that apoptosis of activated lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans. Fas gene mutations account for impaired lymphocyte apoptosis in only a subset of patients with ALPS. PMID:9028957
Sneller, M C; Wang, J; Dale, J K; Strober, W; Middelton, L A; Choi, Y; Fleisher, T A; Lim, M S; Jaffe, E S; Puck, J M; Lenardo, M J; Straus, S E
Orthotopic and living related liver transplantation is an established mode of treatment of end-stage liver disease. One of the major causes of postoperative complications is vascular anastomotic stenosis. One such set of such complications relates to hepatic vein, inferior vena cava (IVC), or portal vein stenosis, with a reported incidence of 1-3%. The incidence of vascular complications is reported to be higher in living donor versus cadaveric liver transplants. We encountered a patient with hepatic venous outflow tract obstruction, where the hepatic vein had been previously stented, but the patient continued to have symptoms due to additional IVC obstruction. The patient required double-balloon dilatation of the IVC simultaneously from the internal jugular vein and IVC.
Kohli, Vikas, E-mail: email@example.com [Indraprastha Apollo Hospital, Pediatric Cardiology and Congenital Cardiac Surgery Unit (India); Wadhawan, Manav [Indraprastha Apollo Hospital, Department of Gastroenterology and Hepatology (India); Gupta, Subhash [Indraprastha Apollo Hospital, Department of Liver Transplant (India); Roy, Vipul [Indraprastha Apollo Hospital, Department of Cardiology (India)
Immunophenotypic characterization of leukemic cells has become essential for the diagnosis of acute leukemias (AL) and chronic lymphoproliferative disorders (CLPD). Immunophenotyping allows to classify AL according to (i) lineage assignement of the leukemic clone based on the degree of specificity (or “score”) of expressed markers, (ii) the différentiation level of the clone and (iii) the presence of irrelevant markers. In
R. Garand; N. Robillard
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...
We analyzed data from all consecutive kidney transplant patients at our institution between April 2003 and October 2006. We found 15 cases of late-onset cytomegalovirus (CMV) infection, two of which developed concurrent post-transplant diabetes mellitus (PTDM). In these two cases, PTDM was transient and normal glucose tolerance was achieved after an eight-wk therapeutic course of oral valganciclovir. These findings suggest that CMV infection after organ transplantation may be associated with concurrent PTDM. The distinct causative relationship is yet to be determined. PMID:18339147
Leung Ki, En-Ling; Venetz, Jean-Pierre; Meylan, Pascal; Lamoth, Fréderic; Ruiz, Juan; Pascual, Manuel
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. PMID:23928467
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
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. PMID:16771810
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
... soon after transplant Next Topic Other transplant issues Transplant problems that may show up later The type ... called Second Cancers Caused by Cancer Treatment . Post-transplant lymphoproliferative disorder Post-transplant lymphoproliferative ( lim -fo-pruh- ...
Twenty-six cases of B cell lymphoproliferative disorder (BLPD) were identified among 2395 patients following hematopoietic stem cell transplants (HSCT) for which an overall incidence of BLPD was 1.2%. The true incidence was probably higher, since 9\\/26 of the diagnoses were made at autopsy. No BLPD was observed following autologous HSCT, so risk factor analyses were confined to the 1542 allogeneic
TG Gross; M Steinbuch; T DeFor; RS Shapiro; P McGlave; NKC Ramsay; JE Wagner; AH Filipovich
Class III beta-tubulin (TUBB3) expression in carcinoma is associated with resistance to tubulin-binding chemotherapeutic agents. Recently, follicular dendritic cells (FDCs) were reported to express TUBB3 under physiologic conditions. We investigated TUBB3 expression in a wide range of lymphoproliferative disorders using immunohistochemistry. Dual immunostaining for Bcl-6 and TUBB3 revealed that some germinal center B cells also express TUBB3 in addition to FDCs. In Hodgkin lymphomas (HLs), 47.1% (40/85) expressed TUBB3 in the tumor cells with an all-or-none pattern. TUBB3 expression in HL was more common in mixed cellularity type than nodular sclerosis type (P=0.032). Among non-HLs, 79.3% (23/29) of anaplastic large cell lymphoma (ALCL), 8% (2/25) of extranodal natural killer/T-cell lymphoma, and 75% (21/28) of Burkitt lymphoma showed TUBB3 expression with an all-or-none pattern. Of diffuse large B-cell lymphoma, 15.2% (32/210) expressed TUBB3 in a heterogeneous pattern. In ALCL, TUBB3 expression was more common in systemic ALCL than in primary cutaneous ALCL (P=0.046). Diffuse large B-cell lymphomas with a germinal center B-like subgroup exhibited TUBB3 expression more frequently than non-GCB-like subgroup (P=0.01). Otherwise, none of the 18 angioimmunoblastic T-cell lymphomas; 18 peripheral T-cell lymphomas, not otherwise specified; 12 follicular lymphomas; 62 marginal zone lymphomas; 7 mantle cell lymphomas; 8 small lymphocytic lymphomas; or 2 FDC sarcomas expressed TUBB3. In angioimmunoblastic T-cell lymphoma and Castleman disease, TUBB3 was positive in immunoblasts corresponding to Epstein-Barr virus-infected or Kaposi sarcoma herpes virus-infected cells. A variety of neoplastic and non-neoplastic lymphoproliferative disorders exhibited characteristic TUBB3 expression patterns; these results suggest potential for diagnostic utility, some insight into the pathobiology of TUBB3 expression, and potential therapeutic implications. PMID:20220512
Yoon, Sun Och; Kim, Wook Youn; Go, Heounjeong; Paik, Jin Ho; Kim, Ji Eun; Kim, Young A; Huh, Joo R; Jeon, Yoon Kyung; Kim, Chul-Woo
The translocation t(14;18) and its t(2;18) and t(18,22) variants, which involve the BCL2 genetic hallmark for follicular lymphoma (FL), have been reported in several cases of chronic B-cell lymphoproliferative disease (CLPD) and frequently in chronic lymphocytic leukaemia (CLL). We describe here the clinical, morphological, immunological, cytogenetic and molecular findings from 37 cases of t(14;18)-positive CLPD, identified from our series of non-FL B-cell neoplasms (n=993) that were routinely analysed in peripheral blood by conventional cytogenetics analyses. The FL diagnosis was excluded by morphology and immunology (the samples were CD10 negative in all cases). The BCL2 translocations were observed in 22 CLL cases, including 7 monoclonal B-cell lymphocytosis (MBL) cases re-classified according to the new International Workshop on CLL criteria, six small lymphocytic lymphoma (SLL) cases, 1 splenic marginal zone lymphoma (SMZL) case and eight cases of unclassifiable CLPD with overlapping CLL/MZL features. In the CLL cases, the IGH/BCL2 fusion was remarkably associated with trisomy 12 (13/22) and mutated IGHV status (20/21) and did not affect the outcome. Moreover, most of these CLLs harboured a low mutation load of BCL6 gene and unmutated FAS (CD95) loci, which points to a post-germinal-centre cellular origin. PMID:22686190
Baseggio, Lucile; Geay, Marie-Odile; Gazzo, Sophie; Berger, Françoise; Traverse-Glehen, Alexandra; Ffrench, Martine; Hayette, Sandrine; Callet-Bauchu, Evelyne; Verney, Aurélie; Morel, Dominique; Jallades, Laurent; Magaud, Jean-Pierre; Salles, Gilles; Felman, Pascale
Lymphadenopathy in children for which no infectious or malignant cause can be ascertained constitutes a challenging diagnostic dilemma. Autoimmune lymphoproliferative syndrome (ALPS) is a human genetic disorder of lymphocyte apoptosis resulting in an accumulation of lymphocytes and childhood onset chronic lymphadenopathy, splenomegaly, multilineage cytopenias, and an increased risk of B-cell lymphoma. In 1999, investigators at the National Institutes of Health (NIH) suggested criteria to establish the diagnosis of ALPS. Since then, with approximately 500 patients with ALPS studied worldwide, significant advances in our understanding of the disease have prompted the need for revisions to the existing diagnostic criteria and classification scheme. The rationale and recommendations outlined here stem from an international workshop held at NIH on September 21 and 22, 2009, attended by investigators from the United States, Europe, and Australia engaged in clinical and basic science research on ALPS and related disorders. It is hoped that harmonizing the diagnosis and classification of ALPS will foster collaborative research and better understanding of the pathogenesis of autoimmune cytopenias and B-cell lymphomas. PMID:20538792
Bleesing, Jack J.; Dianzani, Umberto; Fleisher, Thomas A.; Jaffe, Elaine S.; Lenardo, Michael J.; Rieux-Laucat, Frederic; Siegel, Richard M.; Su, Helen C.; Teachey, David T.
Accurate diagnosis of lymphoma includes the assessment of lineage-specific markers. Hematopoietic and lymphoid tissues express PAX5 exclusively in pro-B-cell to mature B-cell stages. However, some mature PAX5+ T-cell lymphomas have been reported. We report three cases of primary cutaneous CD30+ T-cell lymphoproliferative disorders (LPDs) with PAX5 expression: one cutaneous anaplastic large cell lymphoma (ALCL) and two cases of lymphomatoid papulosis (LyP). The three patients were 26 years old and female, 75 years old and female, and 65 years old and male. In all cases, Hodgkin's and Reed-Sternberg-like large lymphoid cells were present, positive for CD30, fascin, and PAX5, and negative for CD3, CD4, CD8, CD20, CD45RO, CD56, cytotoxic markers, and Epstein-Barr virus. The ALCL was accompanied by lymphadenopathy; the patient died of progressive disease 5 months after diagnosis. The LyP cases were localized in the skin with spontaneous regression. One case was diagnosed during pregnancy, transformed to ALCL, and ended in death 32 months after diagnosis despite multi-agent chemotherapy. This study is the first to address the clinical significance of PAX5+ primary cutaneous CD30+ T-cell LPDs. These cases were distinct regarding PAX5 expression and a relatively aggressive clinical course versus conventional primary cutaneous CD30+ T-cell LPDs. PMID:22449230
Hagiwara, Masahiro; Tomita, Akihiro; Takata, Katsuyoshi; Shimoyama, Yoshie; Yoshino, Tadashi; Tomita, Yasushi; Nakamura, Shigeo
After monolateral dual kidney transplantation, a 69 years old male patient developed symptomatic lymphocele with mild hydroureteronephrosis, impaired renal function, and right inferior limb oedema. A percutaneous ultrasound-guided drainage of the fluid collection was planned, but the complex mutual relations between the collection and the renal hilus did not allow to identify a suitable route for a safe drainage insertion during conventional ultrasound examination. A retrograde cystography using echographic contrast agent was, therefore, performed, and it clarified the position of both ureters and the renal vessels, permitting an harmless ultrasound-guided percutaneous lymphocele drainage. In conclusion contrast-enhanced ultrasound retrograde cystography may be helpful in percutaneous drainage of complex posttransplant lymphocele. PMID:22606639
Di Domenico, Stefano; Patti, Valentina; Fazio, Federico; Moggia, Elisabetta; Fontana, Iris; Valente, Umberto
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 decade from Taiwan, adds to the understanding of these rare diseases with variable clinical and histopathological presentations. PMID:24966953
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
Marek’s disease (MD) is a lymphoproliferative disease of chickens that is caused by a highly cell-associated oncogenic alpha-herpesvirus, Marek’s disease virus (MDV). The role of cytokines and other related proteins in MD pathogenesis and immunity is poorly understood. The aim of this study was to...
Marek’s disease virus (MDV) is an alphaherpesvirus that causes Marek’s disease (MD), a lymphoproliferative disease in chickens. Pathotyping has become an increasingly important assay for monitoring shifts in virulence of field strains, however, it is time-consuming and expensive and alternatives are...
Marek’s disease (MD) is a contagious lymphoproliferative disease of domestic chickens caused by a highly cell-associated alpha-herpesvirus, Marek’s disease virus (MDV). MDV replicates in chicken lymphocytes and establishes a latent infection within CD4+ T cells. Mechanisms of viral pathogenesis, r...
In-utero exposure to HIV-1 may affect the immune system of the developing child and may induce HIV-1-specific immune responses, even in the absence of HIV-1 infection. We evaluated lymphoproliferative capacity at birth among 40 HIV-1-uninfected infants born to HIV-1-infected mothers and 10 infants who had acquired HIV-1 in utero. Cord blood mononuclear cells were assayed using [(3) H]-thymidine incorporation for proliferation in response to HIV-1 p55-gag and the control stimuli phytohaemagglutinin (PHA), Staphylococcus enterotoxin B (SEB) and allogeneic cells. In response to HIV-1 p55-gag, eight (20%) HIV-1-exposed, uninfected (EU) infants had a stimulation index (SI) ??2 and three (30%) in-utero?HIV-1 infected infants had SI ?2. The frequency and magnitude of responses to HIV-1 p55-gag were low overall, and did not differ statistically between groups. However, proliferative responses to control stimuli were significantly higher in EU infants than in infants infected in utero, with a median SI in response to PHA of 123 [interquartile range (IQR) 77-231] versus 18 (IQR 4-86) between EU and infected infants, respectively (P?0·001). Among infected infants, gestational maturity was associated with the strength of HIV-1 p55-gag response (P?0·001); neither maternal nor infant HIV-1 viral load was associated. In summary, EU and HIV-1-infected infants mounted HIV-1-specific lymphoproliferative responses at similar rates (20-30%), and although global immune function was preserved among EU infants, neonatal immune responses were significantly compromised by HIV-1 infection. Such early lymphoproliferative compromise may, in part, explain rapid progression to AIDS and death among HIV-1-infected infants. PMID:24853045
Lohman-Payne, B; Sandifer, T; OhAinle, M; Crudder, C; Lynch, J; Omenda, M M; Maroa, J; Fowke, K; John-Stewart, G C; Farquhar, C
Plasmablastic transformation of low-grade B-cell lymphoproliferative disorders is rarely reported, particularly in cases with clonal evolution. Moreover, the relationship of these 2 morphologically and immunophenotypically distinctive neoplasms remains elusive. Here, we report 2 exceptional cases of plasmablastic transformation with apparently direct transformation from their preceding low-grade B-cell lymphoproliferative disorder. In both cases, the plasmablastic transformation and low-grade lymphoproliferative disorder shared the same immunoglobulin heavy chain gene rearrangements and an identical chromosomal translocation. Notably, both plasmablastic transformation cases also carried MYC gene rearrangements on chromosome 8q24, which have been frequently identified in de novo plasmablastic lymphoma. Therefore, our data suggest that dysregulation of MYC gene may play a critical role in the pathogenesis of plasmablastic transformation. PMID:23791008
Pan, Zenggang; Xie, Qingmei; Repertinger, Susan; Richendollar, Bill G; Chan, Wing C; Huang, Qin
Post-transplant diabetes among renal transplant recipients is more prevalent in the African-American population. However, it is unknown if methylprednisolone (a commonly prescribed glucocorticoid in transplant patients) pharmacokinetics is altered among African-American renal allograft recipients compared to Caucasian counterparts. Therefore, the objectives of this study were to identify the occurrence of post-transplant diabetes in our clinic population and to characterize the pharmacokinetics of methylprednisolone among our African-American and Caucasian renal transplant recipients. A retrospective chart survey was done on African-American and Caucasian recipients with stable renal function and no history of diabetes pre-transplantation in order to characterize the occurrence of post-transplant diabetes in our clinical population. The survey was conducted from January 1985 to January 1992 in recipients with graft survival of at least 3 months. Post-transplant diabetes was defined as two fasting glucose serum concentrations greater than 140 mg/dl or one random serum glucose concentration greater than 200 mg/dl which was confirmed by a fasting serum glucose value greater than 140 mg/dl and a 2 hour post-prandial greater than 200 mg/dl. A 24-hour pharmacokinetic evaluation was conducted in a sub-group of African-American and Caucasian patients after intravenous administration of methylprednisolone. Over the survey period, 75 renal transplants (30 females; 45 males) were performed and 50 of these transplant recipients (24 females; 26 males) were not diabetic prior to the allograft placement. Of these 50 patients, 22 males and 17 females fulfilled the inclusion criteria established for the retrospective survey.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7579735
Tornatore, K M; Biocevich, D M; Reed, K A; Tousley, K; Gray, V; Singh, J P; Murray, B M; Venuto, R C
Lymphoproliferative syndrome with well differentiated lymphocytes and moderate lymphocytosis in the peripheral blood includes a heterogeneous group of disorders, that present often difficulties in classification. We have studied the lymphocyte markers (ER, EMR, sIg and T3, T4, T8 antigens) in 36 cases who had lymphocytic infiltration in the bone marrow and peripheral lymphocyte counts less than 15 X 10(9) l-1. Four cases (11.1%) had the characteristics of T8 lymphocytosis and 31 had a B cell monoclonal proliferation in the peripheral blood. Of these, four were sIg-, EMR+, 19 were sIg+, EMR+ and 8 were sIg+, EMR-. Most patients (17/32) had the clinical picture of stage 0 and I B-CLL. Six cases presented as pure splenomegalic form of CLL, three had the features of immunocytic lymphoma and five had the features of lymphocytic lymphoma. It is concluded that the majority of lymphoproliferative disorders presenting with moderate lymphocytosis represent early forms of B-CLL. Occasionally cases of lymphocytic or immunocytic lymphoma may present problems of differential diagnosis since there may be a dissociation of phenotypic characteristics of lymphocytes between tissues and peripheral blood. PMID:3490873
Economidou, J.; Choremi, H.; Konstantinidou, N.; Kofina, A.; Psarra, K.; Stefanoudaki, K.; Papayannis, A.; Economopoulos, F.; Dervenoulas, J.; Vlachos, J.
Cancer has been a serious complication of kidney transplantation ever since the outcome of this procedure improved. The incidence of cancer among kidney transplant (KT) recipients is increasing, and these patients have a higher risk of developing cancer than the general population. The present retrospective cohort study compared the cancer rate of kidney recipients in a single transplantation center in Korea with that in healthy Korean individuals using the standardized incidence ratio (SIR). The medical records of all 2365 patients who underwent renal transplantation between 1989 and 2009 were reviewed retrospectively. During the study period, 136 renal allograft recipients developed 140 malignancies. The cumulative cancer incidence one, five, 10, and 15 yr post-transplantation was 0.60%, 3.24%, 5.69%, and 8.90%, respectively. Non-Hodgkin lymphoma (NHL) and thyroid cancer were the most common cancers after renal transplantation, occurring significantly more frequently than in the general Korean population. The SIR of all cancers was 1.9 (women: 2.4; men: 1.6). Comparison with similar studies in Korea and other countries suggests transplant center-related differences dictate post-transplant malignancy incidence more strongly than ethnic or geographic factors. Early surveillance programs for de novo malignancies after kidney transplantation focusing on kidney-transplantation-related tumors and postoperative time period should be established. PMID:24750289
Kim, Ji Hyun; Kim, Seon-Ok; Han, Duck Jong; Park, Su-Kil
Marek’s disease (MD) is a lymphoproliferative disease of chickens caused by MD virus and has an important impact on the poultry industry worldwide.There have been reports showing different physiological characteristics between MD susceptible and resistant chickens. However, little is known about whe...
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 ...
The authors have developed a panel of monoclonal antibodies (MCA) of IPO series (Institute of Problems of Oncology, Kiev). RPMI-1788 cell line, Daudi, as well as splenocytes of a patient with hairy-cell leukemia were used for immunization of mice. It has been shown that IPO-3, IPO-10 and IPO-24 MCA are directed against differentiation antigens of human B-lymphocytes. IPO-4 MCA reveal the antigen of activated T- and B-cells. IPO-5 and IPO-20 MCA recognize HLA-ABC, while IPO-37 a common leucocytic antigen. IPO-38 MCA are directed against the nuclear antigen. The possibilities of using IPO MCA in hematology have been discussed. PMID:2373343
Sidorenko, S P; Vetrova, E P; Iurchenko, O V; Shlapatskaia, L N; Berdova, A G; Elenskaia, A M; Bal'shin, M D; Gluzman, D F
Summary Alemtuzumab is a humanized IgG1 antibody targetting the CD52 antigen which is primarily present on normal and neoplastic lymphoid\\u000a cells. In a number of studies, its therapeutic efficacy was shown in the treatment of certain lymphomas including chronic\\u000a lymphocytic leukaemia (B-CLL). In this indication, it was registered in 2001 with patients refractory towards fludarabine.\\u000a In 2007, it was also registered
M. Fiegl; G. Gastl; G. Hopfinger; K. Eigenberger; A. Zabernigg; T. Schenk; F. Falkner; A. Falkner; S. Sodia; M. Doubek; Y. Brychtova; A. Panovska; R. Greil; J. Mayer
Bleeding and thrombosis are important complications in patients with malignant lymphomas. They may be due to direct actions of the lymphoma, such as venous compression or bone marrow infiltration, but they may also be caused by paraneoplastic phenomena, which are immune-mediated in most of the cases. The most important paraneoplastic immune-mediated disorders in lymphomas causing bleeding are autoimmune thrombocytopenia, acquired hemophilia A and acquired von Willebrand syndrome. In addition, there are a variety of other less common immune-mediated bleeding conditions, such as acquired thrombasthenia, acquired factor X-, V-, XI-, XII-, or prothrombin deficiency. The presence of antiphospholipid antibodies is a rare condition predisposing to venous and arterial thrombosis and there are other very uncommon conditions, which predispose exclusively to arterial thrombosis such as hyperlipidemic xanthomatosis. Interestingly, there is hardly any correlation between the histological type and the aggressiveness of lymphoma and the type and prevalence of the immune-mediated conditions. Successful treatment of the underlying lymphoma is often associated with definite and sustained resolution of the immune-mediated disorder. PMID:24615692
Lechner, Klaus; Pabinger, Ingrid; Obermeier, Hanna Lena; Knoebl, Paul
Marek's disease (MD) is a contagious lymphoproliferative and neurotropic disease of poultry caused by Marek's disease virus (MDV), an oncogenic alphaherpesvirus. Despite the use of vaccines, the field strains of MDV continue to evolve, resulting in unpredictable disease outbreaks. Therefore, underst...
Introductiont The increased disparity between organ supply and need has led to the use of extended criteria donors (ECD) and donation-after-cardiac-death (DCD) donors with other comorbidities. Methods We have examined the pre-implantation transcriptome of 112 kidney transplant recipient (KTRs) samples from 100 deceased donor (DD) kidneys by microarray profiling. Subject groups were segregated based on estimated glomerular filtration rate at 1-month post-transplantation (post-KTx): the GFR-high group (N=74) included patients with eGFR >45 mL/min/1.73m2 while the GFR-low group (N=35) included patients with eGFR ?45 mL/min/1.73m2. Results Gene expression profiling identified higher expression of 160 probesets (140 genes) in the GFR-low group while expression of 37 probesets (33 genes) was higher in the GFR-high group (p<0.01, FDR<0.2). Four genes (CCL5, CXCR4, ITGB2, and EGF) were selected based on fold change and p-value and further validated using an independent set of samples. A random forest analysis identified three of these genes (CCL5, CXCR4, and ITGB2) as important predictors of graft function post-transplant. Conclusions Inclusion of pre-transplant molecular gene expression profiles in donor quality assessment systems may provide the necessary information for better donor organ selection and function prediction. These biomarkers would further allow a more objective and complete assessment of procured renal allografts at pre transplantation time. PMID:22992769
Scian, Mariano J; Maluf, Daniel G; Archer, Kellie J; Turner, Stephen D; Suh, Jihee L; David, Krystle G; King, Anne L; Posner, Marc P; Brayman, Kenneth L; Mas, Valeria R
Human islet isolation is associated with adverse conditions inducing apoptosis and necrosis. The aim of the present study was to assess whether antiapoptotic preconditioning can improve in vitro and posttransplant function of isolated human islets. A dose-finding study demonstrated that 200 ?mol/L of the caspase-3 inhibitor Ac-DEVD-CMK was most efficient to reduce the expression of activated caspase-3 in isolated human islets exposed to severe heat shock. Ac-DEVD-CMK-pretreated or sham-treated islets were transplanted into immunocompetent or immunodeficient diabetic mice and subjected to static glucose incubation to measure insulin and proinsulin secretion. Antiapoptotic pretreatment significantly deteriorated graft function resulting in elevated nonfasting serum glucose when compared to sham-treated islets transplanted into diabetic nude mice (p < 0.01) and into immunocompetent mice (p < 0.05). Ac-DEVD-CMK pretreatment did not significantly change basal and glucose-stimulated insulin release compared to sham-treated human islets but increased the proinsulin release at high glucose concentrations (20 mM) thus reducing the insulin-to-proinsulin ratio in preconditioned islets (p < 0.05). This study demonstrates that the caspase-3 inhibitor Ac-DEVD-CMK interferes with proinsulin conversion in preconditioned islets reducing their potency to cure diabetic mice. The mechanism behind this phenomenon is unclear so far but may be related to the ketone CMK linked to the Ac-DEVD molecule. Further studies are required to identify biocompatible caspase inhibitors suitable for islet preconditioning. PMID:23536200
Brandhorst, Daniel; Brandhorst, Heide; Maataoui, Vidya; Maataoui, Adel; Johnson, Paul R V
Marek’s disease (MD) is a serious economic disease of chickens which occurs worldwide. MD can present as one of several forms, with the most commonly occurring forms being the lymphoproliferative diseases. Under experimental conditions, an early mortality syndrome has been recognized following infec...
Marek’s disease (MD), a lymphoproliferative disease of chicken is caused by a highly cell-associated alpha-herpesvirus, Marek’s disease virus (MDV). MDV replicates in chicken lymphocytes and establishes a latent infection within CD4+ T cells. The expression analysis of limited viral and host transc...
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...
Marek’s disease (MD), a lymphoproliferative disease of chicken is caused by a highly cell-associated alpha-herpesvirus, Marek’s disease virus (MDV). MDV replicates in chicken lymphocytes and establishes a latent infection within CD4+ T cells. The expression analysis of limited viral transcripts ha...
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...
In this report, we present a case of peripheral T-cell leukemia/lymphoma having mostly small- to medium-sized cells with abundant clear cytoplasmic vacuoles. The presentation at the time of diagnosis was one of leukemia/lymphoma. The phenotype of the leukemic cells of the peripheral blood was T1+, T11+, TQ1+, interleukin-2+, T3-, T4-, and T8-. The cells in the peripheral blood as well as those obtained from lymph node biopsy were strongly periodic acid-Schiff positive; the positivity was diastase sensitive. Electron microscopy confirmed the presence of glycogen in the cytoplasmic vacuoles. Serologic tests were negative for human T-cell lymphotropic virus type 1 antibody. The data presented in this article support the existence of a vacuolated variant of peripheral T-cell leukemia/lymphoma and further expand the morphological spectrum of T-cell lymphoproliferative disorders. PMID:2787977
Krauss, J S; Pantazis, C G; Spurlock, B O; Price, L M; Neeley, A E
Monoclonal gammopathy of undetermined significance (MGUS) is a common phenomenon in kidney transplant patients that might be a prestage of posttransplant lymphoproliferative disease (PTLD). Because the role of Epstein-Barr virus (EBV) for PTLD development is well established, we wondered about the association between EBV and MGUS. Thus, B-cells from kidney transplant patients (25 with and 100 without MGUS) and from
N. Babel; F. Schwarzmann; A. Pruss; H.-D. Volk; P. Reinke
Hematologic malignancies are relatively uncommon neoplasms of abdominal soft tissue. This article discusses the clinical and imaging features of pancreatic lymphoma, pancreatic extraosseous multiple myeloma, granulocytic sarcoma (chloroma), posttransplant lymphoproliferative disorder, and Castleman disease. The combination of imaging findings and the appropriate clinical presentation should allow the radiologist to raise a provisional diagnosis of hematologic malignancy. PMID:25120155
Sandrasegaran, Kumar; Tomasian, Anderanik; Elsayes, Khaled M; Nageswaran, Harris; Shaaban, Akram; Shanbhogue, Alampady; Menias, Christine O
Because survival of recipients of allogeneic hematopoietic stem cell transplantation (HSCT) has improved, long-term complications become more important. We studied the incidence and risk factors of chronic kidney disease in these patients and evaluated associated posttransplant complications and mortality. We performed a retrospective cohort study of 266 adults who received myeloablative allogeneic HSCT and who survived for >6 months in
Sabina Kersting; Ronald J. Hené; Hein A. Koomans; Leo F. Verdonck
Donor genotype for polymorphisms near IFNL3 influences hepatitis C virus (HCV) therapy responsiveness. This relationship has not been studied in a sample of HCV-infected living donor liver transplantation (LDLT) recipients in the United States (US). We investigated the association of donor and recipient genotypes near the IFNL3 gene at a large US liver transplant center. Recipient homozygosity for rs12979860 C was associated with increased sustained virologic response (SVR) in antiviral treatment-experienced patients pretransplant (P=0.055). Consistently, donor homozygosity for rs12979860 C was also associated with increased SVR in patients who received post-transplant antiviral therapy (P=0.048). Transplantation of an rs12979860 CC graft confers a favorable post-transplant antiviral response among HCV-positive recipients in an LDLT setting. Recipients with the favorable rs12979860 genotype receiving antiviral therapy before transplant are also more likely to achieve SVR. The effect of genotype status in the era of direct-acting antiviral agents will require future study. PMID:25343304
Monaghan, Kristin G; Gonzalez, Humberto C; Levin, Albert M; Abouljoud, Marwan S; Gordon, Stuart C
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...
Marek's disease virus (MDV) is an alpha-herpesvirus and the causative agent for Marek's disease, a lymphoproliferative disease of chickens. The MDV UL41 gene has significant protein sequence identity with the varicella-zoster (33%), pseudorabies (42%), and herpes simplex (29%) virion host shutoff (v...
Objective Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of apoptosis, often presenting in childhood. Similarly, MRL/lpr?/? mice homozygous for Fas mutations develop an ALPS-like disease with autoimmunity, lymphadenopathy, splenomegaly, and expansion of double negative T (DNT) cells. Currently, there are no proven therapies with adequate safety margins for sustained abolition of the lymphoproliferation associated with ALPS. We sought to test the ability of valproic acid (VPA), a histone deacetylase inhibitor, to induce apoptosis and inhibit lymphoproliferation. Methods Human peripheral blood mononuclear cells (PBMCs) from patients with ALPS and normal controls were tested in vitro to determine the efficacy of VPA at inducing cell death. VPA was used in vivo to control lymphoproliferation in MRL/lpr?/? mice, a model for ALPS. Results VPA induced cell death in vitro, and was partially inhibited by the pan caspase inhibitor, Z-VAD-FMK. MRL/lpr?/? mice treated with VPA for 8 weeks showed significant reductions in spleen and lymph node weights and cellularity compared to controls. A concomitant decrease in DNT cells was observed in the spleen, lymph nodes, and peripheral blood. Serum levels of VPA peaked 1 hour after injection, and a 2.5 fold increase in histone acetylation was observed in the spleen at 4 hours after injection. Conclusion Based on our data, VPA is effective at reducing lymphoproliferation in mice, and is currently being studied in a clinical trial as a lympholytic agent in patients with ALPS. PMID:19217201
Dowdell, Kennichi C; Pesnicak, Lesley; Hoffmann, Victoria; Steadman, Kenneth; Remaley, Alan T.; Cohen, Jeffrey I.; Straus, Stephen E; Rao, V. Koneti
The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations. PMID:25349176
Velusamy, Thirunavukkarasu; Kiel, Mark J; Sahasrabuddhe, Anagh A; Rolland, Delphine; Dixon, Catherine A; Bailey, Nathanael G; Betz, Bryan L; Brown, Noah A; Hristov, Alexandra C; Wilcox, Ryan A; Miranda, Roberto N; Medeiros, L Jeffrey; Jeon, Yoon K; Inamdar, Kedar V; Lim, Megan S; Elenitoba-Johnson, Kojo S J
Cyclin-dependent protein kinase 6 (CDK6), in cooperation with cyclin Ds, drives cell cycle progression from G1 to S phase through phosphorylation and subsequent inactivation of Retinoblastoma 1 protein (Rb). Alteration of this pathway results in both non-hematologic and hematologic malignancies, which include a small subset of B-cell lymphoproliferative disorders (BLPDs). We identified 5 cases of BLPD that carried CDK6 chromosomal translocations and characterized their clinical, pathologic, immunophenotypic, and genetic features. Common clinical characteristics included marked neoplastic lymphocytosis, systemic lymphadenopathy, splenomegaly, and bone marrow involvement. Three patients were diagnosed with low-grade B-cell lymphoma and had an indolent clinical course, and 2 patients (one who transformed to large B-cell lymphoma and another who was initially diagnosed with a high-grade B-cell lymphoma) had an aggressive clinical course. Immunophenotypically, the neoplastic B-cells expressed CD5, CDK6, and cytoplasmic Rb in all cases, expressed phospho-RB, p27kip1, and cyclin D2 in most cases, and uniformly lacked expression of all other cyclins. In four cases, the CDK6 translocation partner was kappa immunoglobulin light-chain gene (IGK); and in the fifth case, the CDK6 translocation partner was unknown. These distinct clinicopathologic and cytogenetic features distinguish the CDK6 translocation-associated BLPDs (CDK6-BLPDs) from other mature B-cell lymphomas. PMID:19145199
Chen, Dong; Law, Mark E.; Theis, Jason D.; Gamez, Jeffrey D.; Caron, Lynn B.; Vrana, Julie A.; Dogan, Ahmet; Remstein, Ellen D.
T-cell lymphoproliferative disorders are a heterogeneous group of neoplasms with distinct clinical-biological properties. The normal cellular counterpart of these processes has been postulated based on functional and immunophenotypic analyses. However, T lymphocytes have been proven to be remarkably capable of modulating their properties, adapting their function in relationship with multiple stimuli and to the microenvironment. This impressive plasticity is determined by the equilibrium among a pool of transcription factors and by DNA chromatin regulators. It is now proven that the acquisition of specific genomic defects leads to the enforcement/activation of distinct pathways, which ultimately alter the preferential activation of defined regulators, forcing the neoplastic cells to acquire features and phenotypes distant from their original fate. Thus, dissecting the landscape of the genetic defects and their functional consequences in T-cell neoplasms is critical not only to pinpoint the origin of these tumors but also to define innovative mechanisms to re-adjust an unbalanced state to which the tumor cells have become addicted and make them vulnerable to therapies and targetable by the immune system. In our review, we briefly describe the pathological and clinical aspects of the T-cell lymphoma subtypes as well as NK-cell lymphomas and then focus on the current understanding of their pathogenesis and the implications on diagnosis and treatment. PMID:25510275
Inghirami, Giorgio; Chan, Wing C; Pileri, Stefano
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder associated with heritable defects in lymphocyte apoptosis that result in chronic nonmalignant lymphadenopathy, splenomegaly, and autoimmunity. To examine the prevalence, mechanisms, and potential implications of eosinophilia in ALPS, we reviewed data retrospectively from 187 consecutive ALPS patients and their family members studied at the National Institutes of Health. ALPS patients with eosinophilia were compared with ALPS patients without eosinophilia with respect to their clinical and immunologic phenotype. Potential mechanisms for the eosinophilia, including abnormal Fas-mediated eosinophil apoptosis, increased production of eosinophilopoietic cytokines, and presence of anti-eosinophilic autoantibodies were also explored in a small number of patients from whom samples were available. Analysis of data from 68 ALPS patients and 119 of their relatives identified a distinct subgroup of patients with prominent and persisting eosinophilia that proved to be associated with increased numbers of peripheral blood leukocytes (PBL) of multiple lineages and a trend towards increased serum IgE levels. Eosinophilic ALPS patients also had a significantly higher risk of death due to infectious complications. Although the specific etiology of the eosinophilia in these patients remains uncertain, it does not appear to be associated with an altered serum cytokine profile, increased survival responsiveness of eosinophils to IL-5, defective Fas-mediated eosinophil apoptosis, or anti-eosinophil antibodies. Eosinophilia defines a distinct subgroup of ALPS patients with increased serum IgE levels, increased numbers of PBL of multiple lineages, and higher mortality from infectious complications. PMID:17266055
Kim, Yae-Jean; Dale, Janet K; Noel, Pierre; Brown, Margaret R; Nutman, Thomas B; Straus, Stephen E; Klion, Amy D
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by childhood onset of lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, elevated numbers of double-negative T (DNT) cells, and increased risk of lymphoma. Most cases of ALPS are associated with germline mutations of the FAS gene (type Ia), whereas some cases have been noted to have a somatic mutation of FAS primarily in their DNT cells. We sought to determine the proportion of patients with somatic FAS mutations among a group of our ALPS patients with no detectable germline mutation and to further characterize them. We found more than one-third (12 of 31) of the patients tested had somatic FAS mutations, primarily involving the intracellular domain of FAS resulting in loss of normal FAS signaling. Similar to ALPS type Ia patients, the somatic ALPS patients had increased DNT cell numbers and elevated levels of serum vitamin B12, interleukin-10, and sFAS-L. These data support testing for somatic FAS mutations in DNT cells from ALPS patients with no detectable germline mutation and a similar clinical and laboratory phenotype to that of ALPS type Ia. These findings also highlight the potential role for somatic mutations in the pathogenesis of nonmalignant and/or autoimmune hematologic conditions in adults and children. PMID:20360470
Niemela, Julie E.; Price, Susan; Davis, Joie; Hornung, Ronald L.; Oliveira, Joăo Bosco; Puck, Jennifer M.; Jaffe, Elaine S.; Pittaluga, Stefania; Cohen, Jeffrey I.; Fleisher, Thomas A.; Rao, V. Koneti
Background Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder characterized by defective function of Fas, autoimmune manifestations that predominantly involve blood cells, polyclonal accumulation of lymphocytes in the spleen and lymph nodes with lymphoadenomegaly and/or splenomegaly, and expansion of TCR??+ CD4/CD8 double-negative (DN) T cells in the peripheral blood. Most frequently, it is due to Fas gene mutations, causing ALPS type Ia (ALPS-Ia). However, other mutations, namely of the FasL gene (ALPS-Ib) and the caspase-10 gene (ALPS-II) are occasionally detected, whereas some patients do not present any known mutations (ALPS-III). Recently, mutations of the NRAS gene have been suggested to cause ALPS-IV. Results This work reports two patients that are combined heterozygous for single nucleotide substitutions in the Fas and caspase-10 genes. The first patient carried a splice site defect suppressing allele expression in the Fas gene and the P501L substitution in caspase-10. The second had a mutation causing a premature stop codon (Q47X) in the Fas gene and the Y446C substitution in caspase-10. Fas expression was reduced and caspase-10 activity was decreased in both patients. In both patients, the mutations were inherited from distinct healthy parents. Conclusion These data strongly suggest that co-transmission of these mutation was responsible for ALPS. PMID:17999750
Cerutti, Elisa; Campagnoli, Maria F; Ferretti, Massimo; Garelli, Emanuela; Crescenzio, Nicoletta; Rosolen, Angelo; Chiocchetti, Annalisa; Lenardo, Michael J; Ramenghi, Ugo; Dianzani, Umberto
Caspases are cysteine proteases that mediate programmed cell death in phylogenetically diverse multicellular organisms. We report here two kindreds with autoimmune lymphoproliferative syndrome (ALPS) type II, characterized by abnormal lymphocyte and dendritic cell homeostasis and immune regulatory defects, that harbor independent missense mutations in Caspase 10. These encode amino acid substitutions that decrease caspase activity and interfere with death receptor-induced apoptosis, particularly that stimulated by Fas ligand and TRAIL. These results provide evidence that inherited nonlethal caspase abnormalities cause pleiotropic apoptosis defects underlying autoimmunity in ALPS type II. PMID:10412980
Wang, J; Zheng, L; Lobito, A; Chan, F K; Dale, J; Sneller, M; Yao, X; Puck, J M; Straus, S E; Lenardo, M J
This study investigates PCR analysis of immunoglobulin heavy chain (IgH) and T cell receptor (TCR) gene rearrangements on paraffin-embedded tissue sections and bone marrow aspirates of patients suspected to have lymphoproliferative disorders but with inconclusive diagnosis in histopathological examination. 130 samples of patients with inconclusive immunohistochemistry results were evaluated for clonal rearrangement of IgH and TCR genes. Based on histopathology examination, the patients were divided into three groups: the first group without any definite diagnosis of lymphoproliferative disorders (60 cases, 46.2 %), the second group suspected to have a lymphoproliferative disorder but in favor of benign disorders (19 cases, 14.6 %) and the third group suspect to lymphoproliferative disorders but relatively in favor of malignant disorders (51 cases, 39.2 %). After DNA extraction and quality control, semi-nested PCR was performed using consensus primers for amplification of TCR-? and CDR-3 regions of IgH genes. PCR products were analyzed after heteroduplex analysis using polyacrylamide gel electrophoresis, and were subject to silver staining. Totally, in over half of the cases (55.4 %), a monoclonal pattern was found in IgH or TCR-? genes rearrangements. Monoclonal IgH gene rearrangement was detected in 48.1 % of patients, whereas monoclonal TCR-? gene rearrangement was found in 33.6 % of them, which was not statistically significant (P = 0.008). Only in 32 patients (24.6 %) were the results of TCR-? and IgH gene rearrangements consistent with respect to the presence (2.3 %) or absence (22.3 %) of monoclonality. Finally, PCR analysis of TCR-? and IgH gene rearrangements led to definite diagnosis in 105 patients (80.8 %), and only 25 cases (19.2 %) remained inconclusive. Our results emphasize the usefulness of gene rearrangement study in cases without a definite diagnosis in immunohistochemistry studies. Multiple PCR analysis results when combined with patient's clinical course and immunohistochemistry can lead to early diagnosis and subsequent therapy. PMID:25548443
Poopak, Behzad; Valeshabad, Ali Kord; Elahi, Fazel; Rezvani, Hamid; Khosravipour, Gelareh; Jahangirpour, Mohammad Ali; Bolouri, Shirin; Golkar, Tolou; Salari, Fatemeh; Shahjahani, Mohammad; Saki, Najmaldin
Castleman's disease (CD) is a rare lymphoproliferative disorder of uncertain cause. The most common site of involvement is the mediastinum. Endotracheal CD is extremely rare. We report a case of unicentric, hyaline-vascular type CD presenting as an obstructive tracheal mass. The tumor was successfully managed by rigid bronchoscopy with argon plasma coagulation. There was no recurrence at the 2-month follow-up visit. PMID:24792274
Yu, Jin Yeong; Oh, In Jae; Kim, Kyu Sik; Kim, Yu Il; Lim, Sung Chul; Kim, Young Chul; Choi, Yoo Duk; Kwon, Yong Soo
The etiology of chronic large granular lymphocyte proliferations is largely unknown. Although these disorders are characterized by the expansion of different cell types (T and natural killer) with specific genetic features and abnormalities, several lines of evidence suggest a common pathogenetic mechanism. According to this interpretation, we speculated that in patients with natural killer-type chronic lymphoproliferative disorder, together with natural killer cells, also T lymphocytes undergo a persistent antigenic pressure, possibly resulting in an ultimate clonal T-cell selection. To strengthen this hypothesis, we evaluated whether clonal T-cell populations were detectable in 48 patients with killer immunoglobulin-like receptor-restricted natural killer-type chronic lymphoproliferative disorder. At diagnosis, in half of the patients studied, we found a clearly defined clonal T-cell population, despite the fact that all cases presented with a well-characterized natural killer disorder. Follow-up analysis confirmed that the TCR gamma rearrangements were stable over the time period evaluated; furthermore, in 7 patients we demonstrated the appearance of a clonal T subset that progressively matures, leading to a switch between killer immunoglobulin-like receptor-restricted natural killer-type disorder to a monoclonal T-cell large granular lymphocytic leukemia. Our results support the hypothesis that a common mechanism is involved in the pathogenesis of these disorders. PMID:25193965
Gattazzo, Cristina; Teramo, Antonella; Passeri, Francesca; De March, Elena; Carraro, Samuela; Trimarco, Valentina; Frezzato, Federica; Berno, Tamara; Barilŕ, Gregorio; Martini, Veronica; Piazza, Francesco; Trentin, Livio; Facco, Monica; Semenzato, Gianpietro; Zambello, Renato
The Ikaros gene encodes a Krüppel-like zinc-finger transcription factor involved in hematopoiesis regulation. Ikaros has been established as one of the most clinically relevant tumor suppressors in several hematological malignancies. In fact, expression of dominant negative Ikaros isoforms is associated with adult B-cell acute lymphoblastic leukemia, myelodysplastic syndrome, acute myeloid leukemia and adult and juvenile chronic myeloid leukemia. Here, we report the isolation of a novel, non-canonical Ikaros splice variant, called Ikaros 11 (Ik11). Ik11 is structurally related to known dominant negative Ikaros isoforms, due to the lack of a functional DNA-binding domain. Interestingly, Ik11 is the first Ikaros splice variant missing the transcriptional activation domain. Indeed, we demonstrated that Ik11 works as a dominant negative protein, being able to dimerize with Ikaros DNA-binding isoforms and inhibit their functions, at least in part by retaining them in the cytoplasm. Notably, we demonstrated that Ik11 is the first dominant negative Ikaros isoform to be aberrantly expressed in B-cell lymphoproliferative disorders, such as chronic lymphocytic leukemia. Aberrant expression of Ik11 interferes with both proliferation and apoptotic pathways, providing a mechanism for Ik11 involvement in tumor pathogenesis. Thus, Ik11 could represent a novel marker for B-cell lymphoproliferative disorders. PMID:23874502
Mancarelli, Maria Michela; Verzella, Daniela; Fischietti, Mariafausta; Di Tommaso, Ambra; Maccarone, Rita; Plebani, Sara; Di Ianni, Mauro; Gulino, Alberto; Alesse, Edoardo
Summary Owing to the need of lifelong immunosuppression, solid-organ transplant recipients are known to have an increased risk of posttransplant malignancies including lung cancer. Posttransplant neoplastic transformation of donor-derived cells giving rise to hematopoietic malignancies, Kaposi sarcoma, and basal cell carcinoma in nongraft tissues has been reported. The goal of this study was to assess the cell origin (donor versus recipient derived) of posttransplant non–small cell lung carcinomas (NSCLCs) in kidney and heart transplant recipients. An institutional database search identified 2557 kidney and heart transplant recipients in 8 consecutive years. Among this cohort, 20 (0.8%) renal and 18 (0.7%) heart transplant recipients developed NSCLC. The study cohort comprised 6 of 38 NSCLCs arising in donor-recipient sex-mismatched transplant patients. The tumor cell origin was evaluated by chromogenic in situ hybridization with Y-chromosome probe on formalin-fixed, paraffin-embedded tissues. Y-chromosome was identified in 97% ± 1% (range from 92% to 99%) of all types of nucleated cells in male control tissues. In all 5 NSCLCs from male recipients of female donor organ, Y-chromosome was identified in 97% ± 2% (range from 92% to 100%) of tumor cells, statistically equivalent to normal control (P < .001). No Y-chromosome was identified in NSCLC cells from a female recipient of male kidney. These findings suggest a recipient derivation of NSCLC arising in kidney and heart transplant recipients. A combination of histologic evaluation and chromogenic in situ hybridization with Y-chromosome analysis allows reliable determination of tissue origin in sex-mismatched solid-organ transplant recipients and may aid in management of posttransplant malignancy in such cases. PMID:24746212
Chen, Wei; Brodsky, Sergey V.; Zhao, Weiqiang; Otterson, Gregory A.; Villalona-Calero, Miguel; Satoskar, Anjali A.; Hasan, Ayesha; Pelletier, Ronald; Ivanov, Iouri; Ross, Patrick; Nadasdy, Tibor; Shilo, Konstantin
Owing to the need of lifelong immunosuppression, solid-organ transplant recipients are known to have an increased risk of posttransplant malignancies including lung cancer. Posttransplant neoplastic transformation of donor-derived cells giving rise to hematopoietic malignancies, Kaposi sarcoma, and basal cell carcinoma in nongraft tissues has been reported. The goal of this study was to assess the cell origin (donor versus recipient derived) of posttransplant non-small cell lung carcinomas (NSCLCs) in kidney and heart transplant recipients. An institutional database search identified 2557 kidney and heart transplant recipients in 8 consecutive years. Among this cohort, 20 (0.8%) renal and 18 (0.7%) heart transplant recipients developed NSCLC. The study cohort comprised 6 of 38 NSCLCs arising in donor-recipient sex-mismatched transplant patients. The tumor cell origin was evaluated by chromogenic in situ hybridization with Y-chromosome probe on formalin-fixed, paraffin-embedded tissues. Y-chromosome was identified in 97% ± 1% (range from 92% to 99%) of all types of nucleated cells in male control tissues. In all 5 NSCLCs from male recipients of female donor organ, Y-chromosome was identified in 97% ± 2% (range from 92% to 100%) of tumor cells, statistically equivalent to normal control (P < .001). No Y-chromosome was identified in NSCLC cells from a female recipient of male kidney. These findings suggest a recipient derivation of NSCLC arising in kidney and heart transplant recipients. A combination of histologic evaluation and chromogenic in situ hybridization with Y-chromosome analysis allows reliable determination of tissue origin in sex-mismatched solid-organ transplant recipients and may aid in management of posttransplant malignancy in such cases. PMID:24746212
Chen, Wei; Brodsky, Sergey V; Zhao, Weiqiang; Otterson, Gregory A; Villalona-Calero, Miguel; Satoskar, Anjali A; Hasan, Ayesha; Pelletier, Ronald; Ivanov, Iouri; Ross, Patrick; Nadasdy, Tibor; Shilo, Konstantin
An international group of researchers investigating the molecular, cellular, immunological, and clinical aspects of Autoimmune Lymphoproliferative Syndrome (ALPS) met in Bethesda, Maryland on September 21–22, 2009 to discuss advances made over the past 15 years. Their discussions yielded ten broad messages applicable to genetic and immunological investigations of human disease. PMID:20346767
Lenardo, Michael J.; Oliveira, Joăo B.; Zheng, Lixin; Rao, V. Koneti
Posttransplant metabolic syndrome (PTMS)-obesity, hypertension, elevated triglycerides, low HDL and glucose intolerance-is a major contributor to morbidity after adult liver transplant. This analysis of the Withdrawal of Immunosuppression in Pediatric Liver Transplant Recipients (WISP-R) pilot trial is the first prospective study of PTMS after pediatric liver transplant. Twenty children were enrolled in WISP-R, at median age 8.5 years (IQR 6.4-10.8), and weaned from calcineurin-inhibitor monotherapy. The 12 children who tolerated complete immunosuppression withdrawal were compared to matched historical controls. At baseline, 45% of WISP-R subjects and 58% of controls had at least one component of PTMS. Calcineurin-inhibitor withdrawal in the WISP-R subjects did not impact the prevalence of PTMS components compared to controls. At 5 years, despite weaning off of immunosuppression, 92% of the 12 tolerant WISP-R subjects had at least one PTMS component and 58% had at least two; 33% were overweight or obese, 50% had dyslipidemia, 33% glucose intolerance and 42% systolic hypertension. Overweight/obesity increased the risk of hypertension in all children. Compared to controls, WISP-R tolerant subjects had similar GFR at baseline but did have higher GFR at 2, 3 and 4 years. Further study of PTMS and immunosuppression withdrawal after pediatric liver transplant is warranted. PMID:25648649
Perito, E R; Mohammad, S; Rosenthal, P; Alonso, E M; Ekong, U D; Lobritto, S J; Feng, S
The association of anemia with chronic renal disease is well known. The striking hematologic improvement following a successful renal allotransplantation led to the present study. Using radioactive 59Fe, ferrokinetic measurements were carried out in nine uremic patients (seven with and two without anemia), four post-allotransplant cases, three patients with iron deficiency anemia and a group of five normal subjects. Erythrocyte life-span was calculated by 51Cr-labelled, autotransfused red cells in all patients who had had transplants and in three patients with renal anemia. The results showed that in patients with renal anemia the plasma radioiron clearance was slightly delayed but the 59Fe incorporation into the circulating erythrocytes was significantly decreased. Red cell life-span was moderately shortened in two out of three uremic patients investigated. The findings constitute evidence of ineffective erythropoiesis in patients with renal anemia. By comparison, the four transplant patients showed normal 59Fe plasma clearance and red cell incorporation; the 51Cr erythrocyte survival was normal in all four patients. PMID:4931770
Farooki, M. S.; Kimber, R. W.
Lymphoproliferative disorders (LPDs) are a serious side effect of immunosuppression after liver transplantation, and the introduction on the market of a new immunosuppressive drug has been associated with an increased risk of these disorders. To compare the effect of cyclosporine A (CSA) and FK506 in a clinical setting, the incidence of monoclonal or oligoclonal gammopathies known to often precede the appearance of LPDs was evaluated. A total of 88 adult patients was analyzed, 46 were prospectively randomized to CSA and 42 to FK506 for immunosuppression. None of these patients had gammopathy before transplantation. All the patients were tested for immunoglobulin abnormalities five to nine times during a period of 1 year and then two to four times per year thereafter from December 1990 until March 1997. The same incidence of serum immunoglobulin (Ig) abnormalities was observed in both groups (13%) with a mean delay of appearance of 11.1 +/- 5.9 versus 7.6 +/- 3.6 months for CSA and FK506, respectively (P > .05). In each group, the gammopathies were transient in 3 patients and persisted in 2. The class of Ig involved was IgG, and a monoclonal component was documented in 2 patients treated with CSA and in 3 patients with FK506. One patient treated with FK506 developed an LPD localized to the lymph nodes 8 months after the occurrence of serum protein abnormalities. The lymphoproliferative lesions subsequently disappeared with the reduction of immunosuppression. In this study, an immunosuppressive regimen of FK506 has not shown an increased incidence of lymphoproliferation compared with CSA in adult liver transplant patients. PMID:9516567
Pham, H; Lemoine, A; Salvucci, M; Azoulay, D; Frenoy, N; Samuel, D; Reynčs, M; Bismuth, H; Debuire, B
Epstein-Barr virus (EBV)-associated posttransplant lymphoma (PTLD) is a major cause of morbidity/mortality after hematopoietic stem cell (SCT) or solid organ (SOT) transplant. Adoptive immunotherapy with EBV-specific cytotoxic lymphocytes (CTLs), although effective in SCT, is less successful after SOT where lifelong immunosuppression therapy is necessary. We have genetically engineered EBV-CTLs to render them resistant to calcineurin (CN) inhibitor FK506 through retroviral transfer of a calcineurin A mutant (CNA12). Here we examined whether or not FK506-resistant EBV-CTLs control EBV-driven tumor progression in the presence of immunosuppression in a xenogeneic mouse model. NOD/SCID/IL2r?(null) mice bearing human B-cell lymphoma were injected with autologous CTLs transduced with either CNA12 or eGFP in the presence/absence of FK506. Adoptive transfer of autologous CNA12-CTLs induced dramatic lymphoma regression despite the presence of FK506, whereas eGFP-CTLs did not. CNA12-CTLs persisted longer, homed to the tumor, and expanded more than eGFP-CTLs in mice treated with FK506. Mice receiving CNA12-CTLs and treated with FK506 survived significantly longer than control-treated animals. Our results demonstrate that CNA12-CTL induce regression of EBV-associated tumors in vivo despite ongoing immunosuppression. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy. PMID:25185261
Ricciardelli, Ida; Blundell, Michael Patrick; Brewin, Jennifer; Thrasher, Adrian; Pule, Martin; Amrolia, Persis J
Epstein-Barr virus (EBV)-associated posttransplant lymphoma (PTLD) is a major cause of morbidity/mortality after hematopoietic stem cell (SCT) or solid organ (SOT) transplant. Adoptive immunotherapy with EBV-specific cytotoxic lymphocytes (CTLs), although effective in SCT, is less successful after SOT where lifelong immunosuppression therapy is necessary. We have genetically engineered EBV-CTLs to render them resistant to calcineurin (CN) inhibitor FK506 through retroviral transfer of a calcineurin A mutant (CNA12). Here we examined whether or not FK506-resistant EBV-CTLs control EBV-driven tumor progression in the presence of immunosuppression in a xenogeneic mouse model. NOD/SCID/IL2r?null mice bearing human B-cell lymphoma were injected with autologous CTLs transduced with either CNA12 or eGFP in the presence/absence of FK506. Adoptive transfer of autologous CNA12-CTLs induced dramatic lymphoma regression despite the presence of FK506, whereas eGFP-CTLs did not. CNA12-CTLs persisted longer, homed to the tumor, and expanded more than eGFP-CTLs in mice treated with FK506. Mice receiving CNA12-CTLs and treated with FK506 survived significantly longer than control-treated animals. Our results demonstrate that CNA12-CTL induce regression of EBV-associated tumors in vivo despite ongoing immunosuppression. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy. PMID:25185261
Ricciardelli, Ida; Blundell, Michael Patrick; Brewin, Jennifer; Thrasher, Adrian; Pule, Martin
This study focused on the efficacy of IDEC-C2B8 (chimeric anti-CD20) immunotherapy relative to specific subtypes of low-grade lymphoproliferative disorders/non-Hodgkin's lymphomas (LPD/NHL). Forty-eight patients with resistant or relapsed disease completed the IDEC-C2B8 infusion schedule of 375 mg/m2/wk x 4 wk. The LPD/NHL subtypes included: (a) follicular centre cell lymphoma (FCC) in 22 patients; (b) mantle cell lymphoma (MCL) in 10; (c) 1 diffuse large cell lymphoma (DLCL); and (d) the category of small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL) and related disorders in 15 patients. No patient obtained a complete remission. Ten patients (21%) achieved partial remission: 6 FCC, 2 MCL, 1 DLCL and 1 patient from the SLL/CLL group. Twenty-eight patients had stable disease and 10 progressed during immunotherapy. In patients with CLL and MCL in leukaemic phase, there was no correlation between the marked decrease in circulating neoplastic cells following antibody infusions and amelioration of the tumour burden. The results suggest that the subtype of LPD/NHL and the intensity of CD20 on the tumour cells influence the effectiveness of IDEC-C2B8. The antibody was most efficacious against FCC lymphoma. The efficacy (at the dose schedule of 375 mg/m2/wk x 4) against MCL and SLL/CLL appeared to be limited, however. PMID:10052709
Nguyen, D T; Amess, J A; Doughty, H; Hendry, L; Diamond, L W
Acquired angioedema is often associated with significant morbidity. An underlying lymphatic malignancy, autoimmune disorder, adenocarcinoma, or other malignancy may be present. Screening for these disorders should occur in all patients with acquired angioedema as treatment may result in resolution of angioedema. PMID:25506230
Kaur, Ravdeep; Williams, Aerik Anthony; Swift, Catherine Baker; Caldwell, Jason W
Background: Rituximab has been associated with hepatitis B virus reactivation (HBV-R). However, the characteristics and scope of this association remain largely undefined. Methods: We completed a comprehensive literature search of all published rituximab-associated HBV-R cases and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) MedWatch database. Literature and FDA cases were compared for completeness, and a meta-analysis was completed. Results: One hundred and eighty-three unique cases of rituximab-associated HBV-R were identified from the literature (n = 27 case reports, n = 156 case series). The time from last rituximab to reactivation was 3 months (range 0–12), although 29% occurred >6 months after last rituximab. Within FDA data (n = 118 cases), there was a strong signal for rituximab-associated HBV-R [proportional reporting ratio = 28.5, 95% confidence interval (CI) 23.9–34.1; Empiric Bayes Geometric Mean = 26.4, 95% CI 21.4–31.1]. However, the completeness of data in FDA reports was significantly inferior compared with literature cases (P < 0.0001). Among HBV core antibody (HBcAb(+)) series, the pooled effect of rituximab-based therapy showed a significantly increased risk of HBV-R compared with nonrituximab-treated patients (odds ratio 5.73, 95% CI 2.01–16.33; Z = 3.33, P = 0.0009) without heterogeneity (?2 = 2.12, P = 0.5473). Conclusions: The FDA AERS provided strong HBV-R safety signals; however, literature-based cases provided a significantly more complete description. Furthermore, meta-analysis of HBcAb(+) series identified a more than fivefold increased rate of rituximab-associated HBV-R. PMID:21115603
Evens, A. M.; Jovanovic, B. D.; Raisch, D. W.; Ganger, D.; Belknap, S. M.; Dai, M.-S.; Chiu, B.-C. C.; Fintel, B.; Cheng, Y.; Chuang, S.-S.; Lee, M.-Y.; Chen, T.-Y.; Kuo, C.-Y.
Angiotensin II type 1 receptor antibodies (AT,Rab) are associated with a significantly lower graft survival and a higher risk of acute rejection after kidney transplantation. This study aimed to evaluate graft function and biopsy proven acute rejection (BPAR) during the first year post-transplant in adult renal transplant recipients (RTR), between 03/2009 and 08/2012. Pre-transplant sera were screened for AT1Rab (via enzyme linked immunosorbent assay) and donor specific anti-human leukocyte antigen antibodies (HLA-DSA, via Luminex). Three groups were analyzed: AT1Rab only (n=13); HLA-DSA only (n=8); and no AT1Rab or HLA-DSA (n=90). No differences were observed in clinical characteristics across groups. A higher percentage of BPAR was observed in the AT1Rab positive group, but this difference was not significant. RTR with AT1Rab had a lower median estimated glomerular filtration rate (eGFR=20 ml/min/1.73m2) when compared to RTR with no antibodies at 12 months. A significant difference in eGFR was observed since the first month post-transplant. Multivariate analysis showed four factors independently and significantly associated with eGFR at 12 months post-transplant: BPAR (beta -18.7, 95% CI -28.2 to -9.26, p<0.001), AT,Rab (beta -10.51, 95% CI -20.9 to -0.095 p=0.048), donor age (beta -0.42, 95% CI -0.75 to -0.103, p=0.010), and recipient age (3 -0.36, 95% CI -0.67 to -0.048, p= 0.024). In this study, AT1Rab in pre-transplant sera from RTR was an independent and significant risk factor contributing to a lower eGFR at 12 months posttransplant. This finding deserves to be confirmed in a larger RTR population. PMID:25095527
Hernández-Méndez, Erick Alejandro; Arreola-Guerra, José Manuel; Morales-Buenrostro, Luis E; Ramírez, Julia B; Calleja, Said; Castelán, Natalia; Salcedo, Isaac; Vilatobá, Mario; Contreras, Alan G; Gabilondo, Bernardo; Granados, Julio; Alberú, Josefina
PSTEIN-BARR VIRUS (EBV) plays a causative role E in infectious mononucleosis and in the immunoblastic lymphoproliferative diseases that arise in certain congenital and acquired immunodeficiencies. High endemic Burkitt lymphoma (BL) is EBV-DNA positive in 97% of the cases. EBV genomes were recently also found in a number of T-cell-derived leukemias and in the T-cell-derived lethal midline granuloma.' The virus is
Adoptive T-cell therapy has definite clinical benefit in relapsed leukaemia after allogeneic transplant and in Epstein–Barr virus-associated post-transplant lymphoproliferative disease. However, the majority of tumour targets are weakly immunogenic self-antigens and success has been limited in part by inadequate persistence and expansion of transferred T cells and by tumour-evasion strategies. Adoptive immunotherapy presents the opportunity to activate, expand and genetically
Siok-Keen Tey; Catherine M Bollard; Helen E Heslop
Here, the influence of T vs T and B cell depletion on the incidence of EBV-associated lymphoproliferative disorder (EBV-LPD) after bone marrow transplantation (BMT) from a matched unrelated donor (MUD) is analyzed. From 1982 to 1997 the soy bean agglutinin\\/sheep red blood cell (SBA\\/SRBC) method was used for T cell depletion. This technique is well established, but the use of
E Meijer; ICM Slaper-Cortenbach; SFT Thijsen; AW Dekker; LF Verdonck
Castleman's disease (CD) is a rare, localized or generalized, lymphoproliferative disorder with a frequent mediastinal location, but possible in any lymph node or extra nodal site. It usually appears in young adults whilst it rarely occurs in childhood. There are only about 100 pediatric cases published, five of them in Italy. We report 3 cases of localized Castleman's disease, investigated in our Department in a 3 years period and reviewed the literature. PMID:22014148
Farruggia, Piero; Trizzino, Antonino; Scibetta, Nunzia; Cecchetto, Giovanni; Guerrieri, Patrizia; D'Amore, Emanuele S G; D'Angelo, Paolo
Rosai-Dorfman Disease (RDD) is a rare, idiopathic lymphoproliferative disorder. Central nervous system (CNS) involvement in this disorder is an uncommon manifestation. The clinical and radiographic appearance of CNS RDD is variable, and may mimic more common diseases. Treatment is controversial, and spontaneous remission is common. Positive outcomes have been reported with radiation therapy, or corticosteroid administration, or surgical excision. Our case is unusual in that the extracranial sites of involvement responded to corticosteroid therapy while the intracranial masses progressed. PMID:19659569
Walker, Robert N; Nickles, Thomas P; Lountzis, Nektarios I; Jacobs, Darren L; Nawaz, Nava K
Pseudomonas aeruginosa exotoxin A (PE) represents a microbial superantigen that requires processing by accessory cells in order to induce the proliferation of V beta 8-bearing murine T lymphocytes. In this study, we have observed that PE requires intracellular processing by a protease in order to induce lymphoproliferation. Pepstatin A, an inhibitor of acid proteases, inhibited PE-induced lymphoproliferation, whereas leupeptin, an inhibitor of serine and thiol proteases, had no effect on PE-induced lymphoproliferation. A number of mutant forms of PE were examined for their ability to induce lymphoproliferation. The mutant form which lacks amino acids 5 to 224 of the receptor-binding domain, PE43, was capable of inducing murine thymocytes to proliferate in the presence of accessory cells. However, neither PEgly276, a mutant toxin which undergoes a different intracellular processing pattern than wild-type PE, nor PE589, a mutant toxin which lacks amino acids 590 to 613 at the carboxyl terminus, was able to induce thymocyte proliferation. In addition, the lymphoproliferation induced by the PE43 mutant form of PE could also be inhibited by pepstatin A. Therefore, our data indicate that intracellular processing by a proteolytic enzyme which is inhibited by pepstatin A is critical for PE-induced lymphoproliferation. Furthermore, the lymphoproliferative activity of PE is associated with the carboxyl-terminal portion of PE. PMID:1548056
Legaard, P K; LeGrand, R D; Misfeldt, M L
Lymphomas were studied in kindreds with autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte homeostasis usually associated with germline Fas mutations. Fas (CD95/APO-1) is a cell surface receptor that initiates programmed cell death, or apoptosis, of activated lymphocytes. Lymphoma phenotype was determined by immunohistochemistry, frequency of CD3(+)CD4(-)CD8(-) T-cell-receptor alpha/beta cells by flow cytometry, nucleotide sequences of the gene encoding Fas (APT1, TNFRSF6), and the percentage of lymphocytes undergoing apoptosis in vitro. Of 223 members of 39 families, 130 individuals possessed heterozygous germline Fas mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected (each P <.001). Investigation of these 10 patients and their relatives with Fas mutations revealed that all had defective lymphocyte apoptosis and most had other features of ALPS. The tumor cells retained the heterozygous Fas mutations found in the peripheral blood and manifested defective Fas-mediated killing. These data implicate a role for Fas-mediated apoptosis in preventing B-cell and T-cell lymphomas. Inherited defects in receptor-mediated lymphocyte apoptosis represent a newly appreciated risk factor for lymphomas. PMID:11418480
Straus, S E; Jaffe, E S; Puck, J M; Dale, J K; Elkon, K B; Rösen-Wolff, A; Peters, A M; Sneller, M C; Hallahan, C W; Wang, J; Fischer, R E; Jackson, C M; Lin, A Y; Bäumler, C; Siegert, E; Marx, A; Vaishnaw, A K; Grodzicky, T; Fleisher, T A; Lenardo, M J
Johne's disease in ruminants is a chronic infection of the intestines caused by Mycobacterium avium subsp. paratuberculosis. An important strategy to control disease is early detection, and a potentially efficient method for early detection is measurement of cell-mediated immune responses developed by the host in response to exposure or infection. One method is to measure lymphoproliferation and cytokine release from the host cells when exposed to the organism or parts of the organism. In this study, 10 recombinant M. avium subsp. paratuberculosis proteins known to be upregulated under in vitro stress conditions were evaluated by examining their ability to evoke memory as a result of exposure by vaccination or oral challenge with live Mycobacterium avium subsp. paratuberculosis. Out of 10 proteins, MAP2698c was found to induce higher cell-mediated immune responses in vaccinated and challenged sheep in comparison to healthy controls. The findings suggest that not all stress-regulated proteins have the diagnostic potential to detect cell-mediated immune responses in ovine paratuberculosis. PMID:24695774
Gurung, Ratna B.; Begg, Douglas J.; Purdie, Auriol C.; de Silva, Kumudika; Bannantine, John P.
The number of Hematopoietic Stem Cell Transplantations has globally taken off in the past decade. However, this increase in transplantation activity has put in the spotlight the need to create a special transplantation-skilled population of nurses. This type of specialisation allocated solely to this activity has not existed within the French nursing community until now. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) sets up its forth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille. Here we report our results and recommendations regarding the implementation of a transplant nurse status for post-transplant follow-up care. PMID:24972456
Cornillon, J; Peffault de Latour, R; Apaza, S; Bourg, M-A; Courbon, C; Evard, S; Guiraud, M; Le Bars, L; Petit, S; Magro, L; Schmitt, S; Tardieu, L; Samsonova, O; Tipton, R; Yakoub-Agha, I
Acute kidney injury (AKI) affects roughly 25% of all recipients of deceased donor organs. The prevention of post-transplant AKI is still an unmet clinical need. We prospectively collected zero-hour, indication as well as protocol kidney biopsies from 166 allografts between 2011 and 2013. In this cohort eight cases with AKI and ten matched allografts without pathology serving as control group were identified with a follow-up biopsy within the first twelve days after engraftment. For this set the zero-hour and follow-up biopsies were subjected to genome wide microRNA and mRNA profiling and analysis, followed by validation in independent expression profiles of 42 AKI and 21 protocol biopsies for strictly controlling the false discovery rate. Follow-up biopsies of AKI allografts compared to time-matched protocol biopsies, further baseline adjustment for zero-hour biopsy expression level and validation in independent datasets, revealed a molecular AKI signature holding 20 mRNAs and two miRNAs (miR-182-5p and miR-21-3p). Next to several established biomarkers such as lipocalin-2 also novel candidates of interest were identified in the signature. In further experimental evaluation the elevated transcript expression level of the secretory leukocyte peptidase inhibitor (SLPI) in AKI allografts was confirmed in plasma and urine on the protein level (p<0.001 and p?=?0.003, respectively). miR-182-5p was identified as a molecular regulator of post-transplant AKI, strongly correlated with global gene expression changes during AKI. In summary, we identified an AKI-specific molecular signature providing the ground for novel biomarkers and target candidates such as SLPI and miR-182-5p in addressing AKI. PMID:25093671
Wilflingseder, Julia; Sunzenauer, Judith; Toronyi, Eva; Heinzel, Andreas; Kainz, Alexander; Mayer, Bernd; Perco, Paul; Telkes, Gábor; Langer, Robert M.; Oberbauer, Rainer
Currently, clinical laboratories face increasing demand for flow cytometry testing combined with limited funding. Therefore, many laboratories search for panels that would provide sufficient immunophenotyping information and meet economical requirements. At the Flow Cytometry Laboratory, University Health Network, Toronto, ON, Canada, we apply two 10-color tubes of surface markers for diagnosis of lymphoproliferative disorders (LPDs). These tubes contain most of the mandatory B- and T-cell markers according to European Leukemia Net (www.leukemia-net.org) recommendations. The B-cell-oriented panel includes the following antibodies: Kappa-FITC/lambda-PE/CD19-ECD/CD38-PC5.5/CD20-PC7/CD34-APC/CD23 APC-AF700/CD10 APC-AF750/CD5-PB/CD45-KO. A different combination is applied to detect cytoplasmic Ig light chain expression and aberrant immunophenotype of plasma cells. The T-cell panel allows enumeration of various T- and NK-cell subsets: CD57-FITC/CD11c-PE/CD8-ECD/CD3-PC5.5/CD2-PC7/CD56-APC/CD7-APC-AF700/CD4-APC-AF750/CD5-PB/CD45-KO. The reported overall incidence of B-cell chronic LPDs presenting with more than one aberrant population is approximately 5%. Multicolor analysis facilitates the detection of multiple aberrant populations in the same sample because expression of multiple antigens can be studied simultaneously in each defined population. Examples of LPDs with multiple aberrant populations are presented. PMID:23590655
Rosai-Dorfman disease is a rare non-neoplastic lymphoproliferative condition. It commonly affects individuals between third and fifth decades, most common presentation being in the form of massive painless cervical lymphadenopathy with fever, weight loss and malaise. Isolated intracranial involvement is rare seen in less than 5% of patients with extranodal involvement. We present a patient with isolated contiguous cranio-spinal involvement who presented to us with remitting symptoms. PMID:20825289
Ambekar, Sudheer; Somanna, Sampath; Bhat, Dhananjaya Ishwar; Ranjan, Manish
Gnotobiotic pigs were orally inoculated with virulent Wa strain (G1P1A) human rotavirus (group 1), attenuated Wa rotavirus (group 2) or diluent (controls) and were challenged with virulent Wa rotavirus 21 days later. On various postinoculation or postchallenge days, virus-specific responses of systemic (blood and spleen) and intestinal (mesenteric lymph node and ileal lamina propria) mononuclear cells (MNC) were assessed by lymphoproliferative assays (LPA). After inoculation, 100% of group 1 pigs and 6% of group 2 pigs shed virus. Diarrhea occurred in 95, 12, and 13% of group 1, group 2, and control pigs, respectively. Only groups 1 and 2 developed virus-specific LPA responses prior to challenge. Group 1 developed significantly greater mean virus-specific LPA responses prior to challenge and showed no significant changes in tissue mean LPA responses postchallenge, and 100% were protected against virulent virus challenge. By comparison, both group 2 and controls had significantly lower LPA responses at challenge and both groups showed significant increases in mean LPA responses postchallenge. Eighty-one percent of group 2 and 100% of control pigs shed challenge virus, and both groups developed diarrhea that was similar in severity postchallenge. The virus-specific LPA responses of blood MNC mirrored those of intestinal MNC, albeit at a reduced level and only at early times postinoculation or postchallenge in all pigs. In a separate study evaluating antibody-secreting-cell responses of these pigs (L. Yuan, L.A. Ward, B.I. Rosen, T.L. To, and L.J. Saif, J. Virol. 70:3075-3083, 1996), we found that the magnitude of a tissue's LPA response positively correlated with the numbers of virus-specific antibody-secreting cells for that tissue, supporting the hypothesis that the LPA assesses T-helper-cell function. The magnitude of LPA responses in systemic and intestinal tissues also strongly correlated with the degree of protective immunity elicited by the inoculum (p = 0.81). We conclude that blood may provide a temporary "window" for monitoring intestinal T cells and that the LPA can be used to assess protective immunity to human rotaviruses. PMID:8705681
Ward, L A; Yuan, L; Rosen, B I; Tô, T L; Saif, L J
CD27, a tumor necrosis factor receptor family member, interacts with CD70 and influences T-, B- and NK-cell functions. Disturbance of this axis impairs immunity and memory generation against viruses including Epstein Barr virus (EBV), influenza, and others. CD27 is commonly used as marker of memory B cells for the classification of B-cell deficiencies including common variable immune deficiency. Flow cytometric immunophenotyping including expression analysis of CD27 on lymphoid cells was followed by capillary sequencing of CD27 in index patients, their parents, and non-affected siblings. More comprehensive genetic analysis employed single nucleotide polymorphism-based homozygosity mapping and whole exome sequencing. Analysis of exome sequencing data was performed at two centers using slightly different data analysis pipelines, each based on the Genome Analysis ToolKit Best Practice version 3 recommendations. A comprehensive clinical characterization was correlated to genotype. We report the simultaneous confirmation of human CD27 deficiency in 3 independent families (8 patients) due to a homozygous mutation (p. Cys53Tyr) revealed by whole exome sequencing, leading to disruption of an evolutionarily conserved cystein knot motif of the transmembrane receptor. Phenotypes varied from asymptomatic memory B-cell deficiency (n=3) to EBV-associated hemophagocytosis and lymphoproliferative disorder (LPD; n=3) and malignant lymphoma (n=2; +1 after LPD). Following EBV infection, hypogammaglobulinemia developed in at least 3 of the affected individuals, while specific anti-viral and anti-polysaccharide antibodies and EBV-specific T-cell responses were detectable. In severely affected patients, numbers of iNKT cells and NK-cell function were reduced. Two of 8 patients died, 2 others underwent allogeneic hematopoietic stem cell transplantation successfully, and one received anti-CD20 (rituximab) therapy repeatedly. Since homozygosity mapping and exome sequencing did not reveal additional modifying factors, our findings suggest that lack of functional CD27 predisposes towards a combined immunodeficiency associated with potentially fatal EBV-driven hemo-phagocytosis, lymphoproliferation, and lymphoma development. PMID:22801960
Salzer, Elisabeth; Daschkey, Svenja; Choo, Sharon; Gombert, Michael; Santos-Valente, Elisangela; Ginzel, Sebastian; Schwendinger, Martina; Haas, Oskar A.; Fritsch, Gerhard; Pickl, Winfried F.; Förster-Waldl, Elisabeth; Borkhardt, Arndt; Boztug, Kaan; Bienemann, Kirsten; Seidel, Markus G.
Patients with light-chain deposition disease (LCDD) frequently do not meet criteria for myeloma. In such cases, despite low tumor burden, the circulating monoclonal immunoglobulins cause renal damage, are responsible for post-transplant recurrence, and are rightly categorized as monoclonal gammopathy of renal significance (MGRS) requiring chemotherapy. A 65-year male with uncharacterized nodular glomerulopathy presented with proteinuria 3 years postrenal transplant. His allograft biopsies were diagnostic of light-chain deposition disease (likely recurrent), and in the absence of myeloma, he was labeled as MGRS. Based on the limited literature available, he was treated with bortezomib which resulted in normalization of serum-free light-chain ratios and resolution of proteinuria. He, however, later succumbed to complications of chemotherapy. This case highlights the diagnostic difficulties in LCDD, the importance of an accurate pretransplant diagnosis, and treatment of the malignant clone, in the absence of which post-transplant management of recurrence is challenging with poor outcomes. PMID:25441103
Nambirajan, Aruna; Bhowmik, Dipankar; Singh, Geetika; Agarwal, Sanjay Kumar; Dinda, Amit Kumar
Diseases caused by the Epstein-Barr virus are of great significance among organ transplant recipients. One of these diseases, post-transplant lymphoproliferative disease, is a major complication among organ transplant recipients. Management of this entity is problematic due to the difficulties with laboratory surveillance, diagnosis, prevention and treatment. A group of Canadian and American experts was assembled to discuss these aspects of Epstein-Barr virus diseases in Canadian organ transplant recipients. This report summarizes the relevant background literature and levels of evidence in relation to the outcomes of the deliberations and recommendations by the expert panel. PMID:18159378
Allen, Upton; Alfieri, Caroline; Preiksaitis, Jutta; Humar, Atul; Moore, Dorothy; Tapiero, Bruce; Tellier, Raymond; Green, Michael; Davies, Dele; Hébert, Diane; Weitzman, Sheila; Petric, Martin; Jacobson, Kevan
Allogeneic hematopoietic stem cell transplantation (SCT) offers the best chance for cure and/or long-term survival for a broad range of diseases, including many high-risk hematologic malignancies, bone marrow failure states and subsets of inherited metabolic diseases and hemoglobinopathies. Clinical advances in allogeneic SCT have resulted in dramatically improved clinical outcomes over the past two decades, resulting in a significant expansion of transplant utilization to many recipients who would previously have been excluded from consideration, including elderly recipients and individuals lacking matched sibling or unrelated donors. Despite these advances, significant clinical challenges remain, including delayed immune reconstitution and the frequent occurrence of acute and chronic graft-versus-host disease, especially in the unrelated donor transplant setting. Translational laboratory efforts, facilitated by technical advances in our ability to measure thymopoiesis and functional T cell subsets in humans, have resulted in an improved understanding of immune recovery and have provided novel insights that may lead to more rational and selective immunosuppression. PMID:24242818
Komanduri, Krishna V; Wieder, Eric D; Benjamin, Cara L; Levy, Robert B
Evidence-based practice in medicine promotes the performance of medicine based upon proven and validated practice. The CARE-PARTNER system presented here is a computerized knowledge-support system for stem-cell post-transplant long-term follow-up (LTFU) care on the WWW, which means that it monitors the quality of the knowledge both of its own knowledge-base and of its users. Its aim is to support the evidence-based practice of the LTFU clinicians and of the home-town physicians who actually care for the transplanted patients. Currently, three fundamental characteristics of CARE-PARTNER are accountable for its knowledge-support function: the quality of its knowledge-base, its availability on the WWW, and its learning from experience capability. As a matter of fact, the integration of a case-based reasoner in the reasoning framework enables the system to introspectively study its results, and to learn from its successes and failures, thus confronting the quality of the guidelines and pathways it reuses to the reality and complexity of the clinical cases. PMID:9929247
Bichindaritz, I; Siadak, M F; Jocom, J; Moinpour, C; Kansu, E; Donaldson, G; Bush, N; Chapko, M; Bradshaw, J M; Sullivan, K M
Evidence-based practice in medicine promotes the performance of medicine based upon proven and validated practice. The CARE-PARTNER system presented here is a computerized knowledge-support system for stem-cell post-transplant long-term follow-up (LTFU) care on the WWW, which means that it monitors the quality of the knowledge both of its own knowledge-base and of its users. Its aim is to support the evidence-based practice of the LTFU clinicians and of the home-town physicians who actually care for the transplanted patients. Currently, three fundamental characteristics of CARE-PARTNER are accountable for its knowledge-support function: the quality of its knowledge-base, its availability on the WWW, and its learning from experience capability. As a matter of fact, the integration of a case-based reasoner in the reasoning framework enables the system to introspectively study its results, and to learn from its successes and failures, thus confronting the quality of the guidelines and pathways it reuses to the reality and complexity of the clinical cases. Images Figure 4 Figure 5 PMID:9929247
Bichindaritz, I.; Siadak, M. F.; Jocom, J.; Moinpour, C.; Kansu, E.; Donaldson, G.; Bush, N.; Chapko, M.; Bradshaw, J. M.; Sullivan, K. M.
Relapse remains a leading cause of death after allogeneic hematopoietic cell transplantation (HCT) for patients with high-risk leukemias. The potentially beneficial donor T-cell-mediated graft-versus-leukemia (GVL) effect is often mitigated by concurrent graft versus host disease (GVHD). Providing T-cells that can selectively target Wilms’ Tumor Antigen 1 (WT1), a transcription factor over-expressed in leukemias that contributes to the malignant phenotype, represents a potential opportunity to promote anti-leukemic activity without inducing GVHD. HLA A*0201-restricted WT1-specific donor-derived CD8+ cytotoxic T-cell (CTL) clones were administered post-HCT to 11 relapsed or high-risk leukemia patients without any evidence of on-target toxicity. The last four treated patients received CTL clones generated with exposure to IL-21 as a means to prolong in vivo CTL survival, as IL-21 can limit terminal differentiation of antigen-specific T-cells generated in vitro. Transferred cells exhibited direct evidence of anti-leukemic activity in 2 patients: a transient response in one patient with advanced progressive disease and the induction of a prolonged remission in a patient with minimal residual disease (MRD). Additionally, three treated patients at high risk for relapse post-HCT survive without leukemia relapse, GVHD or additional anti-leukemic treatment. CTL generated in the presence of IL-21, which were transferred in these latter three patients and the patient with MRD, all remained detectable long-term and maintained/acquired in vivo phenotypic and functional characteristics associated with long-lived memory CD8+ T-cells. This study supports expanding efforts to immunologically target WT1, and provides insights into the requirements necessary to establish potent persistent T-cell responses in patients. PMID:23447018
Chapuis, A.G.; Ragnarsson, G. B.; Nguyen, H. N.; Chaney, C. N.; Pufnock, J. S.; Schmitt, T. M.; Duerkopp, N.; Roberts, I. M.; Pogosov, G. L.; Ho, W. Y.; Ochsenreither, S.; Wölfl, M.; Bar, M.; Radich, J. P.; Yee, C; Greenberg, P. D.
Autoimmune diseases affect a significant segment of the population and are typically thought to be multifactorial in etiology. Autoimmune diseases due to single gene defects are rare, but offer an invaluable window into understanding how defects in the immune system can lead to autoimmunity. In this review, we will focus on autoimmune polyendocrinopathy syndrome type 1 and recent advances in our understanding of this disease. We will also discuss two other monogenic autoimmune diseases: immunodysregulation, polyendocrinopathy, and enteropathy, X-linked and Autoimmune lymphoproliferative syndrome. Importantly, the knowledge and principles gained from studying these diseases have been applicable to more common autoimmune diseases and have opened the door to better diagnostic and therapeutic modalities. PMID:19190526
SU, MAUREEN A.; ANDERSON, MARK S.
In order to test for improved survival following autologous transplantation (ASCT), we conducted a prospective clinical trial of post-ASCT thalidomide therapy in Japanese patients with multiple myeloma (MM). Twenty-five newly diagnosed patients received double or single ASCT with high-dose melphalan (200 mg/m(2)). Two months after stem cell infusion, if the patients failed to achieve a near-complete response, thalidomide was administered at 200 mg/day until disease progression or occurrence of intolerable adverse events. Seventeen patients were in partial response or minimal response after ASCT and received thalidomide alone. Their median progression-free survival (PFS) from ASCT was 17.4 months, and the median overall survival (OS) was 42.9 months. Some patients with normal karyotype experienced durable disease stabilization for over 5 years. Five patients who exhibited high-risk chromosomal changes such as t(4;14) or deletion of chromosome 13 or 17 showed very short PFS and OS compared with those who did not. Observed grade 3 or 4 toxicities included infection in three patients, hematological toxicities in three, and gastrointestinal toxicities in two, but there was no grade 3 or higher peripheral neuropathy, probably due to appropriate dose modifications. This long-term prospective study is the first to demonstrate the feasibility of post-ASCT thalidomide therapy in Japanese patients with MM. PMID:22949139
Ueda, Tomoki; Iino, Rioko; Yokoyama, Kenji; Okamoto, Shinichiro; Asakura, Keiko; Tsukada, Yuiko; Ishizawa, Jo; Matsuki, Eri; Ikeda, Yasuo; Hattori, Yutaka
The vascular endothelium regulates blood flow in response to physiological needs. Endothelial dysfunction is closely related to atherosclerosis and its risk factors, and it constitutes an intermediate step on the progression to adverse events throughout the natural history of coronary artery disease (CAD), often affecting clinical outcomes. Understanding the relation of endothelial function with CAD provides an important pathophysiological insight, which can be useful both in clinical and research management. In this review, we summarize the current knowledge on endothelial dysfunction and its prognostic influence throughout the natural history of CAD, from early atherosclerosis to post-transplant management. PMID:24014385
Gutiérrez, Enrique; Flammer, Andreas J.; Lerman, Lilach O.; Elízaga, Jaime; Lerman, Amir; Fernández-Avilés, Francisco
Rosai-Dorfman disease is a rare lymphoproliferative disorder that can have nodal and extranodal manifestations. In the absence of established guidelines for the management of this condition, various therapeutic modalities are used, including radiotherapy. Radiation dosages and fractionation schedules have not been reported in all instances. We present a case in which glottic and subglottic Rosai-Dorfman lesions causing airway obstruction in a frail steroid-refractory patient were put into complete remission using radiotherapy. The lesions responded transiently to a course of prednisone, but responded completely to external-beam radiation, with minimal side effects to the patient. PMID:21655154
Toguri, D; Louie, A V; Rizkalla, K; Franklin, J; Rodrigues, G; Venkatesan, V
Rosai–Dorfman disease is a rare lymphoproliferative disorder that can have nodal and extranodal manifestations. In the absence of established guidelines for the management of this condition, various therapeutic modalities are used, including radiotherapy. Radiation dosages and fractionation schedules have not been reported in all instances. We present a case in which glottic and subglottic Rosai–Dorfman lesions causing airway obstruction in a frail steroid-refractory patient were put into complete remission using radiotherapy. The lesions responded transiently to a course of prednisone, but responded completely to external-beam radiation, with minimal side effects to the patient. PMID:21655154
Toguri, D.; Louie, A.V.; Rizkalla, K.; Franklin, J.; Rodrigues, G.; Venkatesan, V.
Methotrexate sodium use in the management of various immunologic disorders has increased--as have the number of reported adverse effects associated with this therapy. While methotrexate has helped combat various autoimmune and cancerous disorders, the paradoxical risk of causing an often fatal malignancy may still occur as a result of the drug's effect on suppressing immune function. We present a case of methotrexate-induced Hodgkin disease in a 48-year-old man with a history of systemic lupus erythematosus (SLE). Discontinuation of methotrexate facilitated Hodgkin disease reversal. In addition, we review other lymphoproliferative hematologic malignancies caused by methotrexate. PMID:19556391
Sliesoraitis, Sarunas; Khan, Rizwan; Rothman, Jan
The mediation of the T cell lymphoproliferative response to streptococcal blastogen A by non-T mononuclear cells was studied in patients with rheumatic heart disease (RHD) and control subjects. Non-T cells are essential for T cell response to blastogen A. Non-T cells from RHD patients were less effective in enabling the T lymphocyte response to blastogen A than control non-T cells though no consistent difference was observed in the response to phytohaemagglutinin. The results suggest that a functional alteration is present in the non-T cells from RHD patients which might be related to the pathogenesis of the disease. PMID:6982139
Gray, E D; Regelmann, W E; Wannamaker, L W; El Kholy, A; Abdin, Z H
Lymphoproliferative disorders are more likely to occur in transplant patients compared to the general population. Typically in these patients, lymphomas occur within 6-10 months following transplant and are Epstein-Barr virus (EBV) positive. We report a biclonal apparently EBV negative lymphoma occurring in a patient ten years after renal transplant, with karyotypes XX,t(14;18) and XY,t(11;14). Though the biclonal populations also had different sex chromosome compositions, complete evaluation showed that both clones most likely evolved from the patient's native lymphocytes. PMID:17321331
Dennis, Katie L; Wallentine, Steven L; Vanveldhuizen, Peter J; Persons, Diane L; Mathur, Sharad C
It is well established that patients with immunosuppression have a higher risk of development of lymphoproliferative disorders (LPDs), and Epstein-Barr virus (EBV) is associated with development of LPDs. Aplastic anemia (AA) is an immune-mediated hematological disorder, and immunosuppression therapy (IST), such as antithymocyte globulin (ATG), is widely used for treatment of AA. However, occurrence of LPD without bone marrow transplantation has been extremely rarely documented in patients with IST for AA. Herein, we report the 6th documented case of EBV-associated LPD after IST for AA and review the clinicopathological features of this extremely rare complication. A 46-year-old Japanese female was admitted for evaluation of progressive pancytopenia. Bone marrow biopsy revealed fatty marrow with marked decrease of trilineage cells, and bone marrow aspiration demonstrated no dysplastic changes. IST with rabbit ATG was administered, after which, she developed high fever. Bone marrow aspiration showed increase of atypical plasma cells with mildly enlarged nuclei and irregular nuclear contour. These atypical plasma cells were EBER-positive. Accordingly, a diagnosis of EBV-positive plasmacytic LPD was made. Most cases of LPDs are B-cell origin, and plasmacytic LPD is a rare subtype. The current report is the second case of plasmacytic LPD in patients with IST for AA. Therefore, detailed histopathological and immunohistochemical analyses are needed for correct diagnosis and treatment, and additional studies are needed to clarify the clinicopathological features of EBV-LPD after IST for AA. PMID:24817974
Nakanishi, Ryota; Ishida, Mitsuaki; Hodohara, Keiko; Okuno, Hiroko; Yoshii, Miyuki; Horinouchi, Akiko; Shirakawa, Ayaka; Harada, Ayumi; Iwai, Muneo; Yoshida, Keiko; Kagotani, Akiko; Yoshida, Takashi; Okabe, Hidetoshi
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
Fujiwara, Shigeyoshi; Matsuda, Go; Imadome, Ken-Ichi
Subacute necrotizing lymphadenitis or Kikuchi-Fujimoto disease is a benign pathological entity diagnosed chiefly in young adults. We report a case in a 20-year-old woman who presented with swollen lymph nodes and a fever. Disseminated lymphadenopathy with nodes measuring up to 6 cm in diameter was found upon physical examination. The erythrocyte sedimentation rate was elevated to 40 mm/h and the lactic dehydrogenase level to 593 IU/l. Findings were negative from serological tests for rubella, hepatitis B, hepatitis C, HIV, and toxoplasmosis, as well as from tests for tuberculosis. A biopsy of a cervical lymph node showed nonsuppurative necrosis, karyorrhexis, and a marked histiocytic reaction consistent with Kikuchi-Fujimoto disease. No treatment was given, and a full recovery was achieved within 3 months. In this patient, the disseminated lymphadenopathy and constitutional symptoms strongly suggested a hematological malignancy and more specifically a lymphoproliferative disease. PMID:16495107
Mseddi, Sondes; Makni, Salwa; Elloumi, Moez; Boudawara, Tahia; Frikha, Mounir; Souissi, Taoufik
Childhood multicentric Castleman disease (MCD) is a rare and unexplained lymphoproliferative disorder. We report a human herpesvirus-8 (HHV-8)-infected child, born to consanguineous Comorian parents, who displayed isolated MCD in the absence of any known immunodeficiency. We also systematically review the clinical features of the 32 children previously reported with isolated and unexplained MCD. The characteristics of this patient and the geographic areas of origin of most previous cases suggest that pediatric MCD is associated with HHV-8 infection. Moreover, as previously suggested for Kaposi sarcoma, MCD in childhood may result from inborn errors of immunity to HHV-8 infection. PMID:22157133
Moshous, Despina; Cassar, Olivier; Reguerre, Yves; Byun, Minji; Pedergnana, Vincent; Canioni, Danielle; Gessain, Antoine; Oksenhendler, Eric; Fieschi, Claire; Mahlaoui, Nizar; Rivičre, Jean-Pierre; Herbigneaux, Rose-Marie; Muszlak, Matthias; Arnaud, Jean-Pierre; Fischer, Alain; Picard, Capucine; Blanche, Stéphane; Plancoulaine, Sabine
Rosai-Dorfman disease (RDD) is a rare lymphoproliferative disorder with nodal and extranodal involvements. Here we report a case of RDD in a 15-year-old female who presented with epigastric pain, fatigue, Raynaud phenomenon in fingers, submandibular lymphadenopathy, proptosis, hepatosplenomegaly, and round shape painless patches on the extensor surfaces. Histological examination of the submandibular lymph nodes and skin biopsy demonstrated evidences of RDD. Patient was treated with prednisone and thereafter, with azathioprine. After one year, prednisone was discontinued and all of the symptoms and signs, except proptosis, were resolved. This report highlights the extranodal manifestations of RDD. The presentation, differential diagnosis, and treatment are discussed. PMID:22973396
Najafi-Sani, Mehri; Saneian, Hossein; Mahjoub, Fatemeh
It is well recognized that patients with immunodeficiency have a high risk of development of lymphoproliferative disorders (LPDs), and Epstein-Barr virus (EBV) is associated with the occurrence of LPDs. Methotrexate (MTX) is one of the common cause of iatrogenic-associated LPD, and approximately 40-50% of MTX-related LPD cases occur in extranodal sites. However, the occurrence of MTX-related LPD in the gingiva is extremely rare. Herein, we report the fourth documented case of MTX-related EBV-associated LPD occurring in the gingiva of a patient with rheumatoid arthritis (RA). A 76-year-old Japanese female with a 10-year history of RA, who was treated with MTX and infliximab, presented with a tumorous lesion in the gingiva. Biopsy of the gingiva tumor revealed diffuse proliferation of large-sized lymphoid cells with cleaved nuclei containing conspicuous nucleoli. These lymphoid cells were CD20- and EBER-positive. Therefore, a diagnosis of MTX-related EBV-associated LPD showing features of diffuse large B-cell lymphoma (DLBCL) that occurred in the gingiva was made. Although the occurrence of LPD in the oral region, as seen in the present case, is rare, the prevalence of this disorder may be on the rise due to the increased number of patients undergoing immunosuppression therapy. Moreover, immunosenescence can also be a cause of EBV-associated LPD. Therefore, recognition of the occurrence of this disorder in the oral cavity and consideration of the clinical history can facilitate the correct diagnosis. PMID:24133604
Ishida, Mitsuaki; Hodohara, Keiko; Yoshii, Miyuki; Okuno, Hiroko; Horinouchi, Akiko; Nakanishi, Ryota; Harada, Ayumi; Iwai, Muneo; Yoshida, Keiko; Kagotani, Akiko; Yoshida, Takashi; Okabe, Hidetoshi
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, as 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.
Tait, R.C.; Burnett, A.K.; Robertson, A.G.; McNee, S.; Riyami, B.M.; Carter, R.; Stevenson, R.D. (Department of Haematology, Royal Infirmary, Glasgow (Scotland))
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
Schulze, P. Christian; Kitada, Shuichi; Clerkin, Kevin; Jin, Zhezhen; Mancini, Donna M.
Murine AIDS (MAIDS) is induced by a replication-defective virus (BM5d). In susceptible mice (C57BL/6J), inoculation with LP-BM5 murine leukemia virus, which consists of the BM5d virus and replication-competent B-tropic ecotropic (BM5e) and milk cell focus-inducing (BM5-MCF) helper viruses results in the polyclonal proliferation of T and B cells, immunodeficiency, and the expansion of B cells containing the BM5d provirus followed by the development of B-cell lymphomas. Several strains of mice that are resistant to LP-BM5-induced murine AIDS have been identified, and major histocompatibility complex genes as well as non-major histocompatibility complex genes were shown to play a role in this resistance. In the present study, we have examined and compared the replication of the BM5d and BM5e viruses after inoculation of LP-BM5 into sensitive (C57BL/6J) and resistant (C57BL/KSJ) mice. Using a specific polymerase chain reaction, we could detect the BM5d and BM5e proviruses as early as 1 week postinfection in the sensitive mice, and the levels of both viruses increased significantly with the progression of the disease. In contrast, in the resistant C57BL/KSJ mice, replication of BM5d and BM5e was restricted and no BM5d and only very low levels of the BM5e provirus could be detected either at early or late times postinoculation with the LP-BM5 virus mixture. Inoculation with LP-BM5 did not lead to the production of antibodies that could recognize the BM5d-encoded Pr60gag in either the sensitive or resistant mice; however, production of antibodies recognizing the env-related proteins of the helper virus was detected in the resistant but not in the sensitive mice at late times postinfection. Interestingly, inoculation with LP-BM5 increased polyclonal stimulation of spleen cells and decreased mitogen stimulation in both strains of mice. This stimulation of splenocytes persisted in the sensitive mice but decreased after a few weeks in the resistant mice. These results show an early block in BM5d and BM5e replication in the resistant C57BL/KSJ mice and indicate that resistance is a consequence of the inhibition of an onset of the BM5d virus infection and its expansion. However, initial responses to virus infection such as proliferation of spleen cells and response to mitogen are similar in both strains of mice and are therefore not necessarily related to the development of the disease. PMID:8380473
Pozsgay, J M; Reid, S; Pitha, P M
Murine AIDS (MAIDS) is induced by a replication-defective virus (BM5d). In susceptible mice (C57BL/6J), inoculation with LP-BM5 murine leukemia virus, which consists of the BM5d virus and replication-competent B-tropic ecotropic (BM5e) and milk cell focus-inducing (BM5-MCF) helper viruses results in the polyclonal proliferation of T and B cells, immunodeficiency, and the expansion of B cells containing the BM5d provirus followed by the development of B-cell lymphomas. Several strains of mice that are resistant to LP-BM5-induced murine AIDS have been identified, and major histocompatibility complex genes as well as non-major histocompatibility complex genes were shown to play a role in this resistance. In the present study, we have examined and compared the replication of the BM5d and BM5e viruses after inoculation of LP-BM5 into sensitive (C57BL/6J) and resistant (C57BL/KSJ) mice. Using a specific polymerase chain reaction, we could detect the BM5d and BM5e proviruses as early as 1 week postinfection in the sensitive mice, and the levels of both viruses increased significantly with the progression of the disease. In contrast, in the resistant C57BL/KSJ mice, replication of BM5d and BM5e was restricted and no BM5d and only very low levels of the BM5e provirus could be detected either at early or late times postinoculation with the LP-BM5 virus mixture. Inoculation with LP-BM5 did not lead to the production of antibodies that could recognize the BM5d-encoded Pr60gag in either the sensitive or resistant mice; however, production of antibodies recognizing the env-related proteins of the helper virus was detected in the resistant but not in the sensitive mice at late times postinfection. Interestingly, inoculation with LP-BM5 increased polyclonal stimulation of spleen cells and decreased mitogen stimulation in both strains of mice. This stimulation of splenocytes persisted in the sensitive mice but decreased after a few weeks in the resistant mice. These results show an early block in BM5d and BM5e replication in the resistant C57BL/KSJ mice and indicate that resistance is a consequence of the inhibition of an onset of the BM5d virus infection and its expansion. However, initial responses to virus infection such as proliferation of spleen cells and response to mitogen are similar in both strains of mice and are therefore not necessarily related to the development of the disease. Images PMID:8380473
Pozsgay, J M; Reid, S; Pitha, P M
The inextricable link between the heart and the kidneys predestines that significant cardiovascular disease ensues in the face of end stage renal disease (ESRD). As a point of fact, the leading cause of mortality of patients on dialysis is still from cardiovascular etiologies, albeit differing in particular types of disease from the general population. For example, sudden cardiac death outnumbers coronary artery disease in patients with ESRD, which is the reverse for the general population. In this review, we will focus on the pathophysiology and treatment options of important traditional and non-traditional risk factors for cardiovascular disease in ESRD patients such as hypertension, anemia, vascular calcification, hyperparathyroidism, uremia, and oxidative stress. The evidence of erythropoietin-stimulating agents, phosphate binders, calcimimetics, and dialysis modalities will be presented. We will then discuss how these risk factors may be changed and perhaps exacerbated after renal transplantation. This is largely due to the immunosuppressive agents that are both crucial yet potentially detrimental in the post-transplant state. Calcineurin inhibitors, corticosteroids, and mTOR inhibitors, the mainstay of transplant immunosuppresion, are all known to increase the risks of developing new onset diabetes as well as the metabolic syndrome. Thus, we need to carefully negotiate between patients' cardiovascular profile and their risks of rejection. Finally, we end by considering strategies by which we may minimize cardiovascular disease in the transplant population, as this modality still confers the highest chance of survival in patients with ESRD. PMID:25420053
Ghanta, Mythili; Kozicky, Mark; Jim, Belinda
Mikulicz's disease (MD) has been included within the diagnosis of primary Sjögren's syndrome (SS), but it represents a unique condition involving persistent enlargement of the lacrimal and salivary glands characterized by few autoimmune reactions and good responsiveness to glucocorticoids, leading to the recovery of gland function. Mikulicz's disease was recently reported to be associated with elevated immunoglobulin G4 (IgG4) concentrations in the serum and prominent infiltration of plasmacytes expressing IgG4 into the lacrimal and salivary glands. The following features were used for diagnosis: (1) visual confirmation of symmetrical and persistent swelling in more than two lacrimal and major salivary glands; (2) prominent mononuclear cell infiltration of lacrimal and salivary glands; and (3) exclusion of other diseases that present with glandular swelling, such as sarcoidosis and lymphoproliferative disease. These features are not observed in most SS cases. The complications of MD include autoimmune pancreatitis, retroperitoneal fibrosis, tubulointerstitial nephritis, autoimmune hypophysitis, and Riedel's thyroiditis, all of which show IgG4 involvement in their pathogenesis. Mikulicz's disease thus differs from SS and may be a systemic IgG4-related plasmacytic disease. PMID:17164992
Yamamoto, Motohisa; Takahashi, Hiroki; Ohara, Mikiko; Suzuki, Chisako; Naishiro, Yasuyoshi; Yamamoto, Hiroyuki; Shinomura, Yasuhisa; Imai, Kohzoh
Kikuchi-Fujimoto disease, also known as histiocytic necrotizing lymphadenitis, is a self-limiting, benign, and rare systemic lymphadenitis with unknown etiology. The cardinal symptoms are fever, lymphadenopathy and night sweat; consequently, it is first necessary to rule out infectious, lymphoproliferative, and connective tissue diseases such as systemic lupus erythematosus. Histology can allow diagnosis by demonstrating necrotizing histiocyte lymphadenitis. Disease, which has no specific treatment, self-limits itself in 1 to 6 months clinically. However, non-steroid anti-inflammatory agents can be given for symptomatic treatment and there are reports using corticosteroids and antibiotics in complicated cases. This article concerns a 32-years-old female who diagnosed Kikuchi-Fujimoto disease and treated with glucocorticoid. PMID:21869892
Yalcin, Selim; Toprak, Selami Kocak; Erismis, Betul; Altundag, Ozden; Ozdemir, Handan; Topcuoglu, Nuray
Castleman’s disease (CD) is a rare lymphoproliferative disorder of unknown etiology. Clinically, it occurs as a localized (unicentric) disease or as a systemic (multicentric) disease. Unicentric Castleman’s disease (UCD) presents as a solitary mass and primarily affects the mediastinal, retroperitoneal, and cervical lymph nodes. In contrast to multicentric CD, which involves peripheral lymphadenopathy and numerous systemic symptoms, UCD is not typically associated with generalized symptoms. Three main distinct histologic variants are recognized: hyaline-vascular type, plasma cell type, and mixed type. Extranodal CD is rare. Specifically, UCD exclusively in the spleen is extremely rare, with only 2 cases described in the literature to date. Here, we describe an asymptomatic 75-year-old man with a 5.7 cm × 4.5 cm sized heterogenous enhanced mass located in the spleen. He underwent surgical resection for diagnosis and treatment. A pathologic examination indicated the hyaline-vascular type of CD. In this patient, the preoperative diagnosis was difficult to determine, and therefore, invasive procedures were required. PMID:25663790
Lee, Hee-Jeong; Jeon, Ho-Jong; Park, Sang-Gon; Park, Chi-Young
Objective: Cutaneous Rosai-Dorfman disease is rare, and there is a lack of literature on clinical evidence for treatment options. The objective of this report is to illustrate that acitretin may be effective in treating cutaneous Rosai-Dorfman disease. Design: A patient with cutaneous Rosai-Dorfman disease refractory to antibiotics, steroids, and surgical excision was treated with acitretin for a period of four months and was closely monitored for improvement in the lesion. Setting: This was a patient in the authors’ medical dermatology clinic. Participants: A single patient was involved. Results: The patient had continuous improvement in her cutaneous Rosai-Dorfman disease throughout a four-month treatment course with softening of the plaque and decreased erythema. She chose to discontinue treatment after four months due to hair loss with acitretin. Conclusion: Cutaneous Rosai-Dorfman disease is a rare, benign, generally self-limited, lymphoproliferative disease of unknown etiology. It typically occurs as histiocyte-rich inflammatory infiltrates, manifesting as red papules and plaques in older women, without predilection for site. Treatment is usually unnecessary, unless the lesions persist and are bothersome to the patient or cause functional deficits. Treatments are based on case reports and include surgery, radiation, and medical options. Our experience with a patient with a case of cutaneous Rosai-Dorfman disease persisting after surgical excision demonstrates that acitretin may be an effective therapeutic option for cutaneous Rosai-Dorfman disease. PMID:20877523
Fening, Katherine; Peters, Sara; Zirwas, Matthew; Darabi, Kamruz
Dynamic International Prognostic Scoring System scores, pre-transplant therapy and chronic graft-versus-host disease determine outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis
Background Myelofibrosis is a myeloproliferative stem cell disorder curable exclusively by allogeneic hematopoietic stem cell transplantation and is associated with substantial mortality and morbidity. The aim of this study was to assess disease-specific and transplant-related risk factors that influence post-transplant outcome in patients with myelofibrosis. Design and Methods We retrospectively assessed 76 consecutive patients with primary (n=47) or secondary (n=29) myelofibrosis who underwent bone marrow (n=6) or peripheral blood stem cell (n=70) transplantation from sibling (n=30) or unrelated (n=46) donors between January 1994 and December 2010. The median follow-up of surviving patients was 55±7.5 months. Results Primary graft failure occurred in 5% and the non-relapse mortality rate at 1 year was 28%. The relapse-free survival rate was 50% with a relapse rate of 19% at 5 years. The use of pharmacological pre-treatment and the post-transplant occurrence of chronic graft-versus-host disease were significant independent unfavourable risk factors for post-transplant survival in multivariate analysis. Using the Dynamic International Prognostic Scoring System for risk stratification, low-risk patients had significantly better overall survival (P=0.014, hazard ratio 1.4) and relapse-free survival (P=0.02, hazard ratio 1.3) compared to the other risk groups of patients. The additional inclusion of thrombocytopenia, abnormal karyotype and transfusion need (Dynamic International Prognostic Scoring System Plus) resulted in a predicted 5-year overall survival of 100%, 51%, 54% and 30% for low, intermediate-1, intermediate-2 and high-risk groups, respectively. The relapse incidence was significantly higher in the absence of chronic graft-versus-host disease (P=0.006), and pharmacological pre-treatment (n=43) was associated with reduced relapse-free survival (P=0.001). Conclusions The data corroborate a strong correlation between alloreactivity and long-term post-transplant disease control and confirm an inverse relationship between disease stage, pharmacotherapy and outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis. The Dynamic International Prognostic Scoring System was demonstrated to be useful for risk stratification of patients with myelofibrosis who are to undergo hematopoietic stem cell transplantation. PMID:22491742
Ditschkowski, Markus; Elmaagacli, Ahmet H.; Trenschel, Rudolf; Gromke, Tanja; Steckel, Nina K.; Koldehoff, Michael; Beelen, Dietrich W.
Autologous hematopoietic stem cell transplantation is a valid alternative to immunosuppressive treatment in patients with auto-immune disease; however, the role of this approach remains subject to debate. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. In this article we give an overview regarding the indications of autologous stem cell transplantation in auto-immune diseases as well as recommendations regarding post-transplant follow-up of patients. PMID:25017794
Farge, D; Terriou, L; Badoglio, M; Cras, A; Desreumaux, P; Hadj-Khelifa, S; Marjanovic, Z; Moisan, A; Dulery, R; Faucher, C; Hij, A; Martin, T; Vermersch, P; Yakoub-Agha, I
We observed a patient in whom graft-versus-host disease (GVHD) appeared to induce a positive effect. This 32-year-old male with Philadelphia chromosome-positive acute lymphoblastic leukemia received a bone marrow transplant (BMT) from an HLA-identical sibling donor. We analyzed the bone marrow with the reverse transcriptase-polymerase chain reaction to screen for the minor bcr/abl transcript, which indicates the presence of minimal residual disease (MRD). MRD was present in the pre- and post-transplant phases. There was no evidence of acute GVHD by post-transplant day 45. We abruptly discontinued the immunosuppressive therapy in an attempt to eliminate MRD by inducing an antileukemic reaction during GVHD. GVHD associated with diarrhea and liver dysfunction developed on day 64. On day 105, MRD disappeared and GVHD was treated with prednisolone and cyclosporin. The disappearance of MRD may have been due to the graft-versus-leukemia (GVL) effect mediated by the alloimmune response of donor T lymphocytes. These findings suggest that induction of the GVL effect may be useful for eliminating MRD after BMT in leukemia patients at high risk of recurrence of the disease. PMID:9249945
Kanamori, H; Sasaki, S; Yamazaki, E; Ueda, S; Hattori, M; Fukawa, H; Tamura, T; Harano, H; Matsuzaki, M; Ogawa, K; Mohri, H; Okubo, T
Parainfluenza virus type 3 (PIV-3) can cause severe respiratory illness among hematopoietic cell transplantation (HCT) recipients. Factors associated with PIV-3–specific antibody level, and the association between PIV-3 antibody levels and clinical outcomes in HCT recipients who acquire PIV-3 infection, are unknown. We evaluated PIV-3-specific hemagglutination inhibition antibody levels and clinical outcomes among 172 patients with PIV-3 infection following HCT. In a multivariable linear regression model, high post-transplantation antibody levels were independently associated with higher pre-transplantation recipient titer (mean difference 0.38 [95% CI, 0.26, 0.50], p<0.001). Significant associations between pre-HCT antibody titers in both patients and donors and occurrence of lower respiratory tract disease (LRD) after HCT were not observed. In conclusion, low pre-transplantation titers are associated with low antibody levels after HCT. The relationship between PIV-3 antibody levels and outcomes remain uncertain. Further study is needed to prospectively evaluate the dynamics of PIV-3–specific antibody responses and the relative contribution of PIV-3–specific antibody to protection from infection acquisition and progression to LRD. PMID:24978141
Seo, Sachiko; Xie, Hu; Karron, Ruth A.; Thumar, Bhagvanji; Englund, Janet A.; Leisenring, Wendy M.; Stevens-Ayers, Terry; Boeckh, Michael; Campbell, Angela P.
The clinicopathologic findings in eight Mexican patients with immunoproliferative small intestinal disease (IPSID) are analyzed. Four of these cases have been previously reported and the remainder were found in a retrospective review of 42 lymphoproliferative disorders of the small bowel (9.5% of the cases at our institution). There were six male and two female patients with an average age of 30 years. Laparotomy with intestinal resection was performed in seven cases. Malignant lymphoma was documented in five and the early phase of IPSID in two patients. The remaining case was diagnosed by means of several endoscopic biopsies. It is concluded that although IPSID seems to be a rare disease in the mestizo population of our country, it may not be exceptional and its diagnosis has probably been overlooked. PMID:8113590
Arista-Nasr, J; González-Romo, M A; Mantilla-Morales, A; Lazos-Ochoa, M; Ortiz-Hidalgo, C
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
Restrepo, Carlos S; Chen, Melissa M; Martinez-Jimenez, Santiago; Carrillo, Jorge; Restrepo, Catalina
Most guidelines for pre-transplant screening recommend enhanced screening among patients with potential exposure to such pathogens as Strongyloides stercoralis and Trypanosoma cruzi, the cause of Chagas disease. The incidence of these diseases in the Hispanic immigrant population has not been extensively studied. Transplant candidates who were evaluated by our program's Hispanic Transplant Program were referred for expanded infectious disease screening including Mycobacterium tuberculosis, S. stercoralis, Leishmania, and T. cruzi. Between December 2006 and December 2008, 83 patients were screened. Most were from Mexico but we also screened patients from Ecuador, Puerto Rico, and Peru. Most patients lived in urban locations before moving to the United States. Latent tuberculosis infection (LTBI) was found in 20%, and 6.7% had serologic evidence of S. stercoralis infection. These patients underwent treatment of latent infection without difficulty. To date, 14 patients have undergone living-donor kidney transplantation. Two of these patients had positive Leishmania titers and are being followed clinically, 1 was treated for S. stercoralis, and 2 were treated for LTBI pre-transplant. All have done well without evidence of screened pathogens an average of 348 days (range 65-766 days) post transplant. Expanded screening identifies endemic infections in the Hispanic immigrant population that can be treated before transplant, thereby minimizing post-transplant infectious complications. PMID:20534036
Fitzpatrick, M A; Caicedo, J C; Stosor, V; Ison, M G
Background X-linked lymphoproliferative syndrome (XLP) is a rare inherited immunodeficiency by an extreme vulnerability to Epstein-Barr virus (EBV) infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP are now divided into type 1 (XLP-1) and type 2 (XLP-2), which are caused by mutations of SH2D1A/SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis protein (XIAP) genes, respectively. The diagnosis of XLP in individuals with EBV-associated HLH (EBV-HLH) is generally difficult because they show basically similar symptoms to sporadic EBV-HLH. Although EBV-infected cells in sporadic EBV-HLH are known to be mainly in CD8+ T cells, the cell-type of EBV-infected cells in EBV-HLH seen in XLP patients remains undetermined. Methods EBV-infected cells in two patients (XLP-1 and XLP-2) presenting EBV-HLH were evaluated by in EBER-1 in situ hybridization or quantitative PCR methods. Results Both XLP patients showed that the dominant population of EBV-infected cells was CD19+ B cells, whereas EBV-infected CD8+ T cells were very few. Conclusions In XLP-related EBV-HLH, EBV-infected cells appear to be predominantly B cells. B cell directed therapy such as rituximab may be a valuable option in the treatment of EBV-HLH in XLP patients. PMID:22325832
Patients with end-stage liver disease often reveal significant protein-energy malnutrition, which may deteriorate after listing for transplantation. Since malnutrition affects post-transplant survival, precise assessment must be an integral part of pre- and post-surgical management. While there is wide agreement that aggressive treatment of nutritional deficiencies is required, strong scientific evidence supporting nutritional therapy is sparse. In practice, oral nutritional supplements are preferred over parenteral nutrition, but enteral tube feeding may be necessary to maintain adequate calorie intake. Protein restriction should be avoided and administration of branched-chain amino acids may help yield a sufficient protein supply. Specific problems such as micronutrient deficiency, fluid balance, cholestasis, encephalopathy, and comorbid conditions need attention in order to optimize patient outcome. PMID:18254884
Stickel, Felix; Inderbitzin, Daniel; Candinas, Daniel
The incidence of renovascular hypertension in the transplanted kidney is reported to range between 5 and 15%. A review of 391 consecutive renal transplant patients revealed 16 patients (5.4%) with hypertension secondary to partial obstruction of renal arterial blood flow. The clinical course of this group of patients was marked by early normotension followed by progressive diastolic pressure elevation, with improving renal function and loss of accumulated excess volume. Five etiologic factors are responsible for impaired arterial flow in this group of patients. Indication for operation was based on hypertension and/or impaired renal function. Patch angioplasty using saphenous veins was the procedure of choice in most instances. The average blood pressure was 185 mmHg; systolic/125 mmHg; diastolic preoperatively, compared with 140 mmHg; systolic/90 mmHg: diastolic postoperatively. Twelve of 16 patients had good results, and improvement in renal function was observed in eight patients. Serum renin levels did not correlate well with the operative findings. The use of meticulous technique, combined with maximum use of autogenous tissue, is emphasized. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 6. PMID:7002070
Dickerman, R M; Peters, P C; Hull, A R; Curry, T S; Atkins, C; Fry, W J
The identification of patients at high risk of relapse is a critical goal of modern translational research in oncohematology. Minimal residual disease (MRD) detection by polymerase chain reaction-based methods is routinely employed in the management of patients with acute lymphoblastic leukemia. Current knowledge indicates that it is also a useful prognostic tool in several mature lymphoproliferative disorders and particularly in follicular lymphoma (FL). Based on this evidence clinical trials employing MRD-based risk stratification are currently ongoing in FL. In this review the ‘state of the art’ of MRD evaluation in FL is discussed. A short description of technical issues and recent methodological advances is provided. Then, the bulk of the review focuses on critical take-home messages for clinicians working in the field. Finally, we discuss future perspectives of MRD detection and more generally outcome prediction in FL. PMID:23730496
Lobetti-Bodoni, Chiara; Mantoan, Barbara; Monitillo, Luigia; Genuardi, Elisa; Drandi, Daniela; Barbero, Daniela; Bernocco, Elisa; Boccadoro, Mario
... information Autoimmune diseases fact sheet Diabetes fact sheet Hashimoto's disease fact sheet Illnesses and disabilities Lupus fact sheet ... of overactive thyroid. It is closely related to Hashimoto's disease, another autoimmune disease affecting the thyroid. Return to ...
Minimal residual disease (MRD) after allogeneic stem cell transplantation (SCT) for Ph+ acute lymphoblastic leukemia (ALL) is predictive of relapse. Imatinib administration subsequent to SCT may prevent relapse, but the role of scheduling and its impact on outcome are not known. In a prospective, randomized multicenter trial, we compared the tolerability and efficacy of post-transplant imatinib administered either prophylactically (arm A; n=26) or following detection of MRD (arm B; n=29). Prophylactic imatinib significantly reduced the incidence of molecular recurrence after SCT compared with MRD-triggered imatinib (40% vs 69%; P=0.046). Median duration of PCR negativity was 26.5 and 6.8 months, respectively (P=0.065). Five-year survival in both interventional groups was high (80 and 74.5%), despite premature discontinuation of imatinib in the majority of patients because of poor tolerability. Relapse probability was significantly higher in patients who became MRD positive (P=0.017). In conclusion, post-transplant imatinib results in a low relapse rate, durable remissions and excellent long-term outcome in patients with BCR-ABL1-positive ALL irrespective of whether it is given prophylactically or MRD-triggered. Reappearance of BCR-ABL1 transcripts early after SCT or at higher levels identifies a small subset of patients who do not benefit sufficiently from imatinib, and in whom alternative approaches should be explored. PMID:23212150
Pfeifer, H; Wassmann, B; Bethge, W; Dengler, J; Bornhäuser, M; Stadler, M; Beelen, D; Vucinic, V; Burmeister, T; Stelljes, M; Faul, C; Dreger, P; Kiani, A; Schäfer-Eckart, K; Schwerdtfeger, R; Lange, E; Kubuschok, B; Horst, H A; Gramatzki, M; Brück, P; Serve, H; Hoelzer, D; Gökbuget, N; Ottmann, O G
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
Okano, M; Thiele, G M; Davis, J R; Grierson, H L; Purtilo, D T
X-linked Inhibitor of Apoptosis (XIAP) is an essential ubiquitin ligase for pro-inflammatory signalling downstream of the nucleotide-binding oligomerization domain containing (NOD)-1 and -2 pattern recognition receptors. Mutations in XIAP cause X-linked lymphoproliferative syndrome type-2 (XLP2), an immunodeficiency associated with a potentially fatal deregulation of the immune system, whose aetiology is not well understood. Here, we identify the XIAP baculovirus IAP repeat (BIR)2 domain as a hotspot for missense mutations in XLP2. We demonstrate that XLP2-BIR2 mutations severely impair NOD1/2-dependent immune signalling in primary cells from XLP2 patients and in reconstituted XIAP-deficient cell lines. XLP2-BIR2 mutations abolish the XIAP-RIPK2 interaction resulting in impaired ubiquitylation of RIPK2 and recruitment of linear ubiquitin chain assembly complex (LUBAC) to the NOD2-complex. We show that the RIPK2 binding site in XIAP overlaps with the BIR2 IBM-binding pocket and find that a bivalent Smac mimetic compound (SMC) potently antagonises XIAP function downstream of NOD2 to limit signalling. These findings suggest that impaired immune signalling in response to NOD1/2 stimulation is a general defect in XLP2 and demonstrate that the XIAP BIR2-RIPK2 interaction may be targeted pharmacologically to modulate inflammatory signalling. The X-linked lymphoproliferative syndrome type-2 is an immunodeficiency disease caused by mutations in the XIAP gene. BIR2 domain mutations in patients impair RIPK2 binding and NOD2-dependent innate immune signaling, explaining some of the pathology. PMID:23818254
Damgaard, Rune Busk; Fiil, Berthe Katrine; Speckmann, Carsten; Yabal, Monica; zur Stadt, Udo; Bekker-Jensen, Simon; Jost, Philipp J; Ehl, Stephan; Mailand, Niels; Gyrd-Hansen, Mads
Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy (SHML), is an uncommon benign idiopathic lymphoproliferative disorder. The histologic hallmark of RDD is the finding of emperipolesis displayed by lesional histiocytes. While RDD most commonly affects lymph nodes, extranodal involvement of multiple organs has been reported, including the central nervous system (CNS). However, CNS involvement in RDD is rare and is not well characterized. As a result, therapeutic approaches to CNS involvement in RDD are not well established. Herein we report 6 cases of RDD with isolated CNS involvement and review the literature on RDD with CNS involvement. One of the presented cases exhibited intramedullary involvement of the spinal cord--a very rare form of RDD with CNS involvement. PMID:24797172
Sandoval-Sus, Jose D; Sandoval-Leon, Ana C; Chapman, Jennifer R; Velazquez-Vega, Jose; Borja, Maria J; Rosenberg, Shai; Lossos, Alexander; Lossos, Izidore S
Human herpesvirus-6 (HHV-6) was initially isolated in 1986 from patients with lymphoproliferative disorders (Ablashi et al. 1987). Since that time, two genetically distinct variants were sequenced, HHV-6A and HHV-6B (Ablashi and Balachandran 1991). Both variants have been linked with neurologic disease (Crawford et al. 2007). HHV-6 encephalitis has been well described in literature, typically presenting with confusion, coma, seizure, and headache. The majority of HHV-6 encephalitis has been limited to post-transplant recipients (Singh and Paterson 2000). Encephalitis due to HHV-6 infection has been reported in two liver transplant recipients (Massih and Razonable 2009 and Montejo et al. 2002). Although there has been in vitro studies regarding the potential resistance patterns for HHV-6 virus, there has been only one clinic case report supporting these findings (Isegawa et al. 2009). We describe the first case of ganciclovir-resistant HHV-6 encephalitis in a post-liver transplant patient. PMID:21287317
We report on a small bowel transplant patient, donor/recipient seropositive (D+/R+) for cytomegalovirus (CMV), with a clinical course complicated by CMV disease. Anti-CMV prophylaxis was given for 100 days. Immunosuppression consisted of alemtuzumab, tacrolimus, mycophenolate mofetil and prednisolone. Five months posttransplant, CMV tissue invasive disease of the upper gastrointestinal tract was evident without the presence of viremia, tested by quantitative polymerase chain reaction (PCR). Complete viral load suppression was achieved with intravenous ganciclovir, followed by valganciclovir for secondary prophylaxis. Mycophenolate mofetil and prednisolone were discontinued. Shortly thereafter the patient presented with recurrent CMV and candida esophagitis. While on ganciclovir and caspofungin, the patient developed CMV tissue invasive disease of the ileal graft, with persistent absence of viremia. Foscarnet and CMV immunoglobulin were added. Viral load declined to undetectable levels; however, clinical improvement did not occur due to occurrence of graft rejection. Despite infliximab and high dose prednisolone, graft rejection was progressive, requiring surgical explantation of the graft. This case highlights the importance of additional diagnostic tools such as endoscopy including PCR analysis of tissue samples. Extension of primary antiviral prophylaxis interval up to 6 months and prolonged retreatment for recurrent CMV disease may be useful to avoid severe CMV-related complications. PMID:24703746
Avsar, Yesim; Cicinnati, Vito R; Kabar, Iyad; Wolters, Heiner; Anthoni, Christoph; Schmidt, Hartmut H J; Beckebaum, Susanne
NINDS Kennedy's Disease Information Page Synonym(s): Bulbospinal Muscular Atrophy, X-Linked Spinal and Bulbar Muscular Atrophy Table of Contents (click ... is being done? Clinical Trials Organizations What is Kennedy's Disease? Kennedy's disease is an inherited motor neuron disease ...
The modern history of the prion diseases is one of novel microbes, anthropological intrigue, and food safety mishaps. The\\u000a prion diseases, also called the transmissible spongiform encephalopathies, are fatal neurodegenerative diseases that can be\\u000a sporadic, inherited, or acquired. These multiple origins are unique among human disease. The basis of all prion diseases is\\u000a the misfolding of the host prion protein
Qingzhong Kong; Richard A. Bessen
Alcoholic cirrhosis remains the second most common indication for liver transplantation. A comprehensive medical and psychosocial evaluation is needed when making a decision to place such patients on the transplant list. Most transplant centers worldwide need a minimum of 6 mo of alcohol abstinence for listing these patients. Patients with alcohol dependence are at high risk for relapse to alcohol use after transplantation (recidivism). These patients need to be identified and require alcohol rehabilitation treatment before transplantation. Recidivism to the level of harmful drinking is reported in about 15%-20% cases. Although, recurrent cirrhosis and graft loss from recidivism is rare, occurring in less than 5% of all alcoholic cirrhosis-related transplants, harmful drinking in the post-transplant period does impact the long-term outcome. The development of metabolic syndrome with cardiovascular events and de novo malignancy are important contributors to non liver-related mortality amongst transplants for alcoholic liver disease. Surveillance protocols for earlier detection of de novo malignancy are needed to improve the long-term outcome. The need for a minimum of 6 mo of abstinence before listing makes transplant a nonviable option for patients with severe alcoholic hepatitis who do not respond to corticosteroids. Emerging data from retrospective and prospective studies has challenged the 6 mo rule, and beneficial effects of liver transplantation have been reported in select patients with a first episode of severe alcoholic hepatitis who are unresponsive to steroids. PMID:24106395
Singal, Ashwani K; Chaha, Khushdeep S; Rasheed, Khalid; Anand, Bhupinderjit S
We report the association in a 10-year-old boy of an angiomatoid malignant fibrous histiocytoma (AMFH) of the left thigh with ipsilateral inguinal, pelvic and extensive retroperitoneal lymphadenopathy, and severe systemic manifestations. These include growth retardation, fever, severe anemia, hypergammaglobinemia, and hypoalbuminemia. At ultrastructural level the tumor was characterized by an abundance of myofibroblasts, occasional histiocytes, and small vessels with marked reduplication of the basal lamina. Biopsies of the inguinal and abdominal lymph nodes showed follicular hyperplasia and massive plasmacytosis indistinguishable from Castleman's disease (giant lymph node hyperplasia) of plasma cell type. The radical surgical excision of the primary tumor in the thigh resulted in the disappearance of the abdominal lymphadenopathy and a marked reduction in size of the pelvic lymph nodes with marked decrease of the gammaglobulins, thus proving that the nodal lesions were the expression of a reactive process to the tumor rather than a coincidental independent lymphoproliferative disorder. Retroperitoneal and pelvic node dissection was performed 1 year after the radical excision of the thigh tumor because of persistent pelvic lymphadenopathy and failure of serum immunoglobulins M and A to return to normal level, with a recent peak of IgA to twofolds that of normal value. Metastatic AMFH was found in the three pelvic nodes. One month postoperatively IgA returned to near normal level whereas IgM remained slightly elevated. PMID:3029740
Seo, I S; Frizzera, G; Coates, T D; Mirkin, L D; Cohen, M D
Rosai-Dorfman disease (RDD)-sinus histiocytosis with massive lymphadenopathy-represents a peculiar proliferation of histiocyte-like cells in patients. The condition was described by Rosai and Dorfman in 1969, after examining 4 cases, as an idiopathic histiocytic disorder. In 1972, they studied an additional 30 cases of patients with RDD. A histioproliferative disorder, RDD is characterized by bilateral, painless, cervical lymphadenopathy in 81% of patients. Fever, leukocytosis, elevated sedimentation rate, and polyclonal hypergammaglobulinemia may also be found. In 30% of patients, extranodal involvement is present and may include the skin, eye orbit, upper respiratory tract, or testes. Cases involving the central nervous system are rare and account for < 5% of patients with RDD. We report on a 78-year-old woman presenting with new-onset headache, dizziness, and imbalance, which had been present for a few weeks prior to admission. Magnetic resonance imaging of the brain showed 2 enhancing lesions within the right and left cerebellar hemispheres. Biopsy of the mass demonstrated a lymphohistiocytic infiltrate involving the cerebellum with foci of emperipolesis (phagocytosed lymphocytes). The adjacent cerebellum showed myelinated nerve fibers with reactive gliosis. A thorough work-up and histopathologic exam of the biopsied mass demonstrated lymphohistiocytic infiltrate with foci of emperipolesis (phagocytosed lymphocytes) consistent with RDD. Other differential considerations, such as primary or secondary neoplasms, infections, lymphoproliferative disorders, granulomatoses, Langerhans cell histiocytosis, and lymphocyte-rich meningioma were ruled out by additional histopathologic exam. PMID:24145594
Autoimmune diseases may reveal or occur during the course of a neoplasia or its treatment. Autoimmune cytopenia, especially haemolytic anaemia, is common in lymphoproliferative disorders such as chronic lymphoid leukemia. The link between cancer and myositis is well established. Dermatomyositis is associated with an increased relative risk of cancer of 3.4 to 4.4. A combination of detection of antibodies against p155 and TEP-computed tomography may be the best approach to ascertain the presence of occult malignancy in patients with dermatomyositis. A cutaneous or a systemic vascularitis may reveal a cancer, most often a haematological malignancy such as hairy cell leukemia. Paraneoplastic polyarthritis have been described in particular with adenocardinoma of the lungs. Underlying neoplasia should be considered in male smokers patients with new onset polyarthritis and poor health status. The prevalence of autoimmune conditions in myelodysplastic syndromes is 10 to 30%. Vasculitis and relapsing polychondritis are the most commonly reported manifestations. Immune manifestations can also be related to treatment. The most common treatment complications are autoimmune haemolytic anaemia with fludarabine and thyroiditis related to interferon and cervical radiotherapy. PMID:25106665
Pasquet, F; Pavic, M; Ninet, J; Hot, A
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 Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell 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; Recurrent/Refractory Childhood Hodgkin Lymphoma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage III Multiple Myeloma; Testicular Lymphoma; Waldenström Macroglobulinemia
B-cell Adult Acute Lymphoblastic Leukemia; 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 Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma
Post-transplant Lymphoproliferative Disorder; 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; Waldenström Macroglobulinemia
Post-transplant Lymphoproliferative Disorder; 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; Waldenström Macroglobulinemia
Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Central nervous system metastasis is a very rare complication portending a very poor prognosis. We report a rare case of follicular lymphoma presenting with leptomeningeal involvement achieving a complete remission after initial therapy. PMID:25544910
Costa, Ricardo; Costa, Renata
Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Central nervous system metastasis is a very rare complication portending a very poor prognosis. We report a rare case of follicular lymphoma presenting with leptomeningeal involvement achieving a complete remission after initial therapy. PMID:25544910
Costa, Rubens; Costa, Ricardo; Costa, Renata
... properly regulate the number of immune system cells (lymphocytes). ALPS is characterized by the production of an abnormally large number of lymphocytes (lymphoproliferation). Accumulation of excess lymphocytes results in enlargement ...
Mucolipidosis type II (MLII), or I-cell disease, is a rare but severe disorder affecting localization of enzymes to the lysosome, generally resulting in death before the 10th birthday. Although hematopoietic stem cell transplantation (HSCT) has been used to successfully treat some lysosomal storage diseases, only 2 cases have been reported on the use of HSCT to treat MLII. For the first time, we describe the combined international experience in the use of HSCT for MLII in 22 patients. Although 95% of the patients engrafted, overall survival was low, with only 6 patients (27%) alive at last follow-up. The most common cause of death post-transplant was cardiovascular complications, most likely due to disease progression. Survivors were globally delayed in development and often required complex medical support, such as gastrostomy tubes for nutrition and tracheostomy with mechanical ventilation. Although HSCT has demonstrated efficacy in treating some lysosomal storage disorders, the neurologic outcome and survival for patents with MLII were poor. Therefore, new medical and cellular therapies should be sought for these patients. PMID:25016194
Lund, Troy C; Cathey, Sara S; Miller, Weston P; Eapen, Mary; Andreansky, Martin; Dvorak, Christopher C; Davis, Jeffrey H; Dalal, Jignesh D; Devine, Steven M; Eames, Gretchen M; Ferguson, William S; Giller, Roger H; He, Wensheng; Kurtzberg, Joanne; Krance, Robert; Katsanis, Emmanuel; Lewis, Victor A; Sahdev, Indira; Orchard, Paul J
Background: Behçet's disease is a multisystem disease that is rare in the United States.Objective: The purpose of our study was to assess the characteristics and treatment of a series of patients with Behçet's disease in the United States.Methods: A retrospective clinical review of 25 patients with Behçet's disease was performed, and histopathologic findings and therapeutic modalities were reviewed.Results: All patients
Heidi C. Mangelsdorf; Wain L. White; Joseph L. Jorizzo
This overview of the public health significance of Lyme disease includes the microbiological specifics of the infectious spirochete, the entomology and ecology of the ticks which are the primary disease carrier, the clinical aspects and treatment stages, the known epidemiological patterns, and strategies for disease control and for expanded public…
Taylor, George C.
... years of age and the sixth leading cause of death for all people in the United States. Most people live 4 to 8 years after being diagnosed with Alzheimer’s disease. Some live with the disease for up ... of Alzheimer’s disease? The Alzheimer’s Association has identified 10 ...
Background and Purpose—Acute cerebral ischemia has been described in different diseases of the thyroid gland, and not only as a result of thyrotoxic atrial fibrillation and cardioembolic stroke. The purpose of this review is to summarize the studies on the relationship between thyroid diseases and cerebrovascular diseases, discussing the main findings for overt hyperthyroidism and hypothyroidism, as well as for
A. Squizzato; V. E. A. Gerdes; D. P. M. Brandjes; H. R. Buller; J. Stam
In general, the development of civilization is viewed as a positive step for the well-being of the human species, leading to an increased duration and quality of life. The accelerated progress of civilization (mainly industrialization, urbanization and nutrition) has lead to new possibilities for adverse effects on human health. In former high civilization--like old Egypt, Greece, Roman, Chinese, Indian, Maya civilizations--the "modem civilization diseases" were unknown. Modem science through improved sanitation, vaccination and antibiotics as well as improved social and economical conditions, has eliminated the threat of death from most infectious diseases. In the years after World War II the social, economic and health conditions changed. Most deaths have resulted from heart disease, stroke, cancer and other diseases as a result of an inappropriate relationship of people with their environment and changed lifestyle. Lifestyle diseases are different from other diseases because they are potentially preventable and can be lowered with changes in diet, lifestyle and environment. PMID:18350729
Coagulopathy in cirrhosis is a composite condition where liver synthetic deficit rebalances coagulation to a parallel reduction of both pro- and anticoagulant factors. Cirrhosis is therefore no longer considered a hypocoagulable state but rather a more unstable hemostatic balance with a lower threshold for tipping toward thrombosis or bleeding. Tendency to bleeding in cirrhosis is due to the reduction in the synthesis of procoagulants and a low platelet count as well as hyperfibrinolysis. Variceal hemorrhage is a frequent bleeding complication in decompensated cirrhosis. However, the possible contribution of coagulopathy as a precipitant or an aggravating factor is poorly documented and further data are required to clarify its real contributing role. Moreover, apart from the gastrointestinal tract, the occurrence of spontaneous and procedure-related bleeding elsewhere in the body, whilst not uncommon, is less than would be expected. By contrast, a large-scale population-based study has shown the propensity towards venous thrombosis in patients with liver diseases. Portal vein thrombosis (PVT) is a critical but frequent event occurring in up to 40% of patients with liver cirrhosis. PVT causes deterioration of the clinical course, the complications of portal hypertension and an increase in post-transplant mortality. The pathogenesis of PVT includes both local alterations, like blood flow reduction and endothelial activation, and systemic derangement. Systemic prohemostatic alterations include high von Willebrand factor, low ADAMTS-13, low levels of anticoagulants (antithrombin, proteins C and S) and increases in procoagulants like factor VIII. Low-molecular-weight heparin such as enoxaparin has proven to be safe and effective in both the treatment and prevention of PVT. In addition, patients in prophylaxis with enoxaparin showed a lower rate of decompensation and a better survival without bleeding complications. In such patients, circulating bacterial DNA, endotoxemia and markers of inflammation were attenuated compared to controls. These results therefore suggest a possible connection between enoxaparin, decrease of endotoxemia and reduction of portal hypertension. The approach to the coagulopathy in patients with liver diseases is changing: while the main goal for clinicians so far has been to reduce the risk of bleeding, the results of these new studies highlight the importance of preventing or treating thrombophilic disorders like PVT to avoid microcirculatory damage and eventually liver decompensation. PMID:25034295
Bianchini, Marcello; De Pietri, Lesley; Villa, Erica
Prion Diseases is one of a set of lecture notes for Virology 335 by Shaun Heaphy of Leicester University (UK). It contains detailed information on its topic, along with selected links. Although prion research has been going on for over 25 years, the scientific and medical communities have only recently acknowledged the existence of prions and there remains serious debate over their role in a variety of neurological diseases. The name "prion" is derived from "proteinaceous infectious particles," and was coined by Dr. Stanley Prusiner, who discovered the agents and who recently received the Nobel Prize for Medicine for his work. Prions are thought to be the first transmissible and heritable disease-causing agents that lack DNA and RNA. They are composed solely of protein and appear to be the cause of such diseases as kuru and Creutzfeldt-Jakob disease in humans, and bovine spongiform encephalopathies, mad cow disease, and scrapie in sheep and goats.
In assigning health priorities, skin diseases are sometimes thought of, in planning terms, as small-time players in the global league of illness compared with diseases that cause signif- icant mortality, such as HIV\\/AIDS, community-acquired pneu- monias, and tuberculosis. However, skin problems are generally among the most common diseases seen in primary care settings in tropical areas, and in some regions
Roderick Hay; Sandra E. Bendeck; Suephy Chen; Roberto Estrada; Anne Haddix; Tonya McLeod; Antoine Mahé
A little microorganism called a spirochete causes Lyme disease, which can cause extremely severe symptoms, including neck stiffness, acute headaches, neurological damage, and rheumatoid arthritis-like problems. Lyme disease is transmitted by ticks and so is tied to the ticks' life cycle. Lyme disease is also seen by veterinarians, largely in dogs, for whom it can be fatal. Lyme research is ongoing on numerous fronts.
Dr. Leslie Nader (MSMR)
Huntington's disease (HD) is the most common inherited neurodegenerative disease and is characterized by uncontrolled excessive motor movements and cognitive and emotional deficits. The mutation responsible for HD leads to an abnormally long polyglutamine (polyQ) expansion in the huntingtin (Htt) protein, which confers one or more toxic functions to mutant Htt leading to neurodegeneration. The polyQ expansion makes Htt prone to aggregate and accumulate, and manipulations that mitigate protein misfolding or facilitate the clearance of misfolded proteins tend to slow disease progression in HD models. This article will focus on HD and the evidence that it is a conformational disease. PMID:21441583
Hepatitis C virus (HCV) infection is highly prevalent among chronic kidney disease (CKD) subjects under hemodialysis and in kidney transplantation (KT) recipients, being an important cause of morbidity and mortality in these patients. The vast majority of HCV chronic infections in the hemodialysis setting are currently attributable to nosocomial transmission. Acute and chronic hepatitis C exhibits distinct clinical and laboratorial features, which can impact on management and treatment decisions. In hemodialysis subjects, acute infections are usually asymptomatic and anicteric; since spontaneous viral clearance is very uncommon in this context, acute infections should be treated as soon as possible. In KT recipients, the occurrence of acute hepatitis C can have a more severe course, with a rapid progression of liver fibrosis. In these patients, it is recommended to use pegylated interferon (PEG-IFN) in combination with ribavirin, with doses adjusted according to estimated glomerular filtration rate. There is no evidence suggesting that chronic hepatitis C exhibits a more aggressive course in CKD subjects under conservative management. In these subjects, indication of treatment with PEG-IFN plus ribavirin relies on the CKD stage, rate of progression of renal dysfunction and the possibility of a preemptive transplant. HCV infection has been associated with both liver disease-related deaths and cardiovascular mortality in hemodialysis patients. Among those individuals, low HCV viral loads and the phenomenon of intermittent HCV viremia are often observed, and sequential HCV RNA monitoring is needed. Despite the poor tolerability and suboptimal efficacy of antiviral therapy in CKD patients, many patients can achieve sustained virological response, which improve patient and graft outcomes. Hepatitis C eradication before KT theoretically improves survival and reduces the occurrence of chronic graft nephropathy, de novo glomerulonephritis and post-transplant diabetes mellitus. PMID:25593456
Carvalho-Filho, Roberto J; Feldner, Ana Cristina CA; Silva, Antonio Eduardo B; Ferraz, Maria Lucia G
Castleman's disease is a rare B cell lymphoproliferative disorder related to excess interleukin-6 (IL-6)-like activity. Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8), which encodes a functional cytokine (vIL-6), has been found in some patients with Castleman's disease. Lymph nodes from 14 HIV-seronegative Castleman's disease patients were compared to hyperplastic lymph nodes from 25 HIV-seronegative patients as well as Kaposi's sarcoma lesions from 48 patients for KSHV infection and vIL-6, human IL-6, and Epstein-Barr virus EBER expression. While all Kaposi's sarcoma tissues examined were polymerase chain reaction-positive and all control lymph nodes were polymerase chain reaction-negative for KSHV, none had detectable vIL-6 expression. Six of 14 (43%) Castleman's tissues were positive for KSHV by polymerase chain reaction and all 6 had evidence of vIL-6 expression by immunohistochemistry. vIL-6-positive Castleman's disease patients generally had the multicentric plasma cell variant form of the disease and had a rapidly fatal clinical course frequently associated with autoimmune hemolytic anemia and gammopathy. In contrast, 7 (88%) of the 8 vIL-6-negative Castleman's disease patients had localized disease and have remained disease-free after therapy. KSHV vIL-6 expression appears to be limited to hematopoietic cells and is not present in Kaposi's sarcoma spindle cells. These data suggest that Castleman's disease is a syndrome of multiple etiologies involving aberrant IL-6 activity from either endogenous or viral sources. Images Figure 1. A Figure 2. A PMID:9403701
Parravinci, C.; Corbellino, M.; Paulli, M.; Magrini, U.; Lazzarino, M.; Moore, P. S.; Chang, Y.
Parkinson's disease is a common movement disorder caused by a deficiency of dopamine in the brain. The disease is chronic and progressive. While there are many treatments for symptomatic relief, there is no cure. This article addresses the etiology, clinical manifestations, standard and experimental therapeutics and role of the nurse in the comprehensive care of the patient and family. PMID:2529323
Vernon, G M
Cardiovascular disease (CVD), particularly CHD (coronary heart disease) and stroke, remain the leading causes of death of women in America and most developed countries. In recent years the rate of CVD has declined in men but not in women. This is contributed to by an under-recognition of women’s C...
The proliferation of information regarding Alzheimer's disease in current years has had a tremendous impact on the literature being generated on this topic. Until fairly recently, Alzheimer's disease was believed to be incurable, and its progress inexorable. In recent years research has come up with encouraging results which give hope that new treatments and even a cure is possible in
Prion diseases comprise a set of rare fatal neurological diseases found in humans and other mammals. A prion is a protein capable of converting a normal cellular protein (PrPC) into a prion and thereby propagating an infection. A prion and PrPC differ solely in their conformation. There are differen...
Genetic and environmental determinants inducing Graves' disease are still poorly defined, especially those leading to the appearance of TSH receptor antibodies, which are both the hallmark of the disease and the keystone of its diagnosis. The treatment of Graves' disease is based on the use of antithyroid drugs and no therapeutic protocol has proven superior to the other. Surgical or radiometabolic treatments, largely restricted to relapses and to patients with comorbidities could be considered earlier provided we had reliable predictive markers for relapse. The treatment of Graves' orbitopathy relies first on a rigorous analysis of severity and activity of the disease. Intravenous steroids appear as a reference treatment in active forms. Evaluation of new therapeutics is in process. Graves' disease during pregnancy requires a multidisciplinary approach and an expert ultrasound evaluation of the fetus. Because of a suspected teratogenicity of carbimazole and methimazole, propylthiouracyl is the preferred drug used during early pregnancy. PMID:25090772
Illouz, Frédéric; Rodien, Patrice
Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract and is an important cause of morbidity in children and adolescents. In India Crohn's disease (CD) was considered a rare disease, however, during the last 10 years CD in adults is being reported from several centers especially in Southern India. CD is characterized by transmural granulomatous inflammation involving any part of the gastrointestinal tract in a discontinuous manner. The peak incidence of Crohn's disease occurs during the adolescent and young adult years. The clinical presentation and complications are varied and several extraintestinal manifestations have been recognized. The understanding of the pathophysiology has opened new avenues in the management. The recognition of this problem in children and adolescents by pediatricians is necessary for proper diagnosis and management. PMID:16936369
Sathiyasekaran, Malathi; Shivbalan, So
Blood samples from 29 healthy individuals (control), 16 chronic alcohol abusers without clinical symptoms of liver disease, 22 patients with alcoholic steatosis and 31 patients with alcoholic cirrhosis were obtained. The antiviral activity, only partially neutralized by polyclonal and monoclonal anti-HuIFN-alpha and monoclonal anti-HuIFN-gamma antibodies, was detected in sera of 38% healthy controls and of 64-77% alcoholic abusers without or with ALD. To measure the activity of the IFN system, leukocyte cultures of chronic alcohol abusers and control individuals were set up using a whole blood technique. Common IFN inducers: NDV, PHA and ConA were used. Blood leukocytes of patients with alcoholic steatosis and cirrhosis responded to NDV, PHA and ConA with significantly lower IFN levels than controls, whereas IFN response of alcoholics without liver diseases was lower only after stimulation with ConA. Regarding the lymphoproliferative test performed with PHA, a remarkably diminished lymphocyte response of patients with cirrhosis was observed as compared to control. Our data indicate that long term ethanol intake impairs the ability of leukocytes and their subpopulation to produce IFNs. The correlation between ALD progression and the defect in IFN production suggests that suppressive action of ethanol, liver injury and immune reactions involved in liver damage may be responsible for impairment of the IFN system in heavy drinkers. PMID:7487359
Daniluk, J; Kandefer-Szersze?, M
The three yr results of a multicenter trial in de novo pediatric KT treated with a proliferative signal inhibitor and low dose CNI are presented. Thirty-seven children (9.1 ± 5 yr old) received basiliximab, cyclosporine A (CyA C2:1400 ng/mL), (MMF C0:1.5-3 ?g/mL), and prednisone. Three wk later everolimus was started (C0:5-10 ng/mL), CyA was reduced (C2:600 ng/mL after 90 days 300 ng/mL), and MMF discontinued. During the three-yr period patient and graft survivals were 96%. One patient died for causes unrelated to the immunosuppression. Cumulative acute rejection rate including protocol and indication biopsies was 21.9%. None of the patients had signs of chronic humoral rejection. Incidence of dnDSA was 5%, 11%, and 22% at one, two, and three yr post-transplant, respectively. Mean glomerular filtration rate measured at one yr and three yr post-transplant was 105.5 ± 31 and 110.7 ± 27 mL/min/1.73 m(2), respectively. A growth velocity of 7.7 ± 6.7 cm/yr was achieved with positive catch-up growth. No malignancy or post-transplant lymphoproliferative diseases were diagnosed. In conclusion, the treatment based on basiliximab induction, everolimus, low-dose cyclosporine, and low-dose prednisone leads to good long-term efficacy in de novo pediatric KT recipients. PMID:24802342
Ferraresso, Mariano; Belingheri, Mirco; Ginevri, Fabrizio; Murer, Luisa; Dello Strologo, Luca; Cardillo, Massimo; Parodi, Angelica; Ghirardo, Giulia; Guzzo, Isabella; Innocente, Annalisa; Ghio, Luciana
Peyronie's disease is caused by collagen deposits in the tunica albuginea of the corpus cavernosum following microtrauma. Symptoms may include a combination of penile curvature, a palpable plaque, painful erections and erectile dysfunction. Peyronie's disease can have a major impact on the quality of life. In the course of the disease two phases can be discerned. In the first, active phase there is penile curvature with painful erections. The second, stable phase is characterised by painless curvature of the penis. Treatment in the active phase is conservative and supportive. Surgical treatment is useful only in the stable phase and may consist of penile plication surgery or penile graft surgery. PMID:25004781
Ruiter, Annebeth E C; Meuleman, Eric J H
Fabry disease is an uncommon, X-linked lysosomal storage disorder, caused by partial or complete deficiency of the enzyme a-galactosidase A. The defect leads to accumulation of uncleaved globotriaosylceramide on the vascular endothelium and visceral tissues, being the skin, heart, kidneys and central nervous system the most affected organs. We performed review of the literature related to the disease and emphasized that early recognition of angiokeratomas and hypohidrosis are key diagnostic signs of this serious disease. We also addressed the need of multidisciplinary assessment of these patients. PMID:19851669
Boggio, Paula; Luna, Paula Carolina; Abad, María Eugenia; Larralde, Margarita
The pericardium provides an enclosed lubricated space for the beating heart and functions to fix the heart in the chest cavity relative to adjacent organs. Pericardial pathophysiology is often manifested in a spectrum of distinct cardiac and systemic disease states. The pericardial response to injury typically involves a spectrum of inflammation with both acute and chronic features and/or fluid accumulation. Recent advances in imaging methods have refined the diagnosis and therapy of pericardial disease. This article presents the anatomy and physiology of pericardial disease and the clinical approach for diagnosis and treatment. PMID:22289657
Dudzinski, David M; Mak, Gary S; Hung, Judy W
Hirschsprung disease is a relatively common condition managed by pediatric surgeons. Significant advances have been made in understanding its etiologies in the last decade, especially with the explosion of molecular genetic techniques and early diagnosis. The surgical management has progressed from a two- or three-stage procedure to a primary operation. More recently, definitive surgery for Hirschsprung disease through minimally invasive techniques has gained popularity. In neonates, the advancement of treatment strategies for Hirschsprung disease continues with reduced patient morbidity and improved outcomes. PMID:19019295
Haricharan, Ramanath N; Georgeson, Keith E
... Graves' disease can cause the following symptoms: Nervousness Insomnia Emotional swings Sweating Hand tremor Palpitations Unexplained weight ... medication such as propanolol (Inderal). For anxiety and insomnia, your doctor may prescribe diazepam (Valium), lorazepam (Ativan) ...
Kawasaki disease is an acute febrile, systemic vasculitic syndrome of an unknown etiology that primarily occurs in children younger than five years of age. The principal presentations of Kawasaki disease include fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy. Coronary artery aneurysms or ectasia develops in 15% to 25% of untreated children with the disease, which may later lead to myocardial infarction, sudden death, or ischemic heart disease. Treatment with intravenous gamma globulin (IVIG) is effective, but the mode of action is still unclear. The development of a diagnostic test, a more specific therapy, and ultimately the prevention of this potentially fatal illness in children are all dependent upon the continued advances in determining the etiopathogenesis of this fascinating disorder. PMID:17191303
Fungal diseases of lentils are the most important biological constraint to productivity. Ascochyta lentis (ascochyta blight) and Fusarium oxysporum f. sp. lentis (fusarium wilt) are the major fungal pathogens that can cause severe losses in most lentil growing regions of the world.\\u000a Fungal diseases such as botrytis grey mould (Botrytis fabae and B. cinerea), rust (Uromyces viciae-fabae), stemphylium blight (Stemphylium
Paul Taylor; Kurt Lindbeck; Weidong Chen; Rebecca Ford
with Neurodegenerative Diseases The protein deposits found in Alzheimer disease, Huntington disease and prion diseaseNeurodegenerative diseases ranging from Alzheimer disease and polyglutamine diseases, we focus on three neuro- degenerative diseases, Alzheimer disease, Huntington disease and prion
Vulvar diseases might cause problems in the differential diagnosis, because the clinical presentation of inflammatory, infectious and neoplastic disorders may be quite similar. Itching and pain as well as dysuria and dyspareunia are the most common symptoms of vulvar diseases. Inflammatory dermatoses like atopic and contact dermatitis, lichen planus, lichen sclerosus and atrophic vulvitis account for the majority of cases in specialized clinics. Furthermore, neoplastic conditions such as vulvar carcinoma, vulvar intraepithelial neoplasia (VIN) and vulvar Paget's disease have to be considered. Another frequent group are infections. Candida spp., herpes simplex viruses and human papilloma viruses are common pathogens. Additionally, vulvodynia is a typical problem that is sometimes difficult to treat. Because of the wide spectrum of clinical symptoms, cooperation with gynaecologists and psychosomatic specialists should be considered in difficult cases. The typical clinical presentations, their specific signs and symptoms, and pitfalls in the dermatological consultation are discussed. PMID:25475624
Peckruhn, M; Elsner, P
On the basis of strong evidence, gastrointestinal symptoms and failure to thrive are classic presentations of celiac disease, but atypical, nongastrointestinal symptoms are also extremely common, particularly in the older child and adolescent. (3)(4)(8). On the basis of some research evidence and consensus, guidelines recommend celiac testing in symptomatic children with typical and atypical symptoms and consideration of testing in those with associated conditions and first-degree relatives of those with celiac disease. (3)(9). On the basis of strong research evidence, measurement of tTG IgA and total serum IgA level has been reported to be the most cost-effective and accurate means of serologic testing for celiac disease and is the test of choice unless the child is younger than 2 years or IgA deficient. (9). On the basis of strong research evidence, children with elevated titers of celiac antibodies or strong clinical suspicion for celiac disease should be referred to a gastroenterologist for upper endoscopy and biopsy. Until this procedure is performed, the child should continue on a diet with ingestion of gluten. (3)(9). On the basis of strong research evidence, all those with a confirmed diagnosis of celiac disease should follow a strict gluten-free diet for life, with avoidance of all foods that contain wheat, barley, and rye ingredients. (3)(4). Referral to a health care professional with specialized knowledge of celiac disease and the gluten-free diet is critical because of the numerous ways, often hidden, in which gluten may be present in the diet and environment. PMID:25274968
Ediger, Tracy R; Hill, Ivor D
Behçet's disease is a systemic vasculitis of unknown aetiology characteristically affecting venules. Onset is typically in young adults with recurrent oral and genital ulceration, uveitis, skin manifestations, arthritis, neurological involvement, and a tendency to thrombosis. It has a worldwide distribution but is prevalent in Japan, the Middle East, and some Mediterranean countries. International diagnostic criteria have been proposed, however diagnosis can be problematical, particularly if the typical ulcers are not obvious at presentation. Treatment is challenging, must be tailored to the pattern of organ involvement for each patient and often requires combination therapies.???Keywords: Behçet's disease; oral ulcers; uveitis; immunosuppressants PMID:11009577
Kontogiannis, V; Powell, R
Pilonidal disease presents many therapeutic challenges to surgeons throughout the world. Its varied clinical presentations necessitate a wide range of treatments, thus underscoring the need to tailor the treatment to the patient and the severity of disease. Recent studies confirm the efficacy of smaller, more conservative operations for appropriate indications. When flap closures are performed, every attempt should be directed to placing sutures off (lateral) to the midline gluteal cleft. Meticulous attention to the details of immediate and long-term postoperative care is paramount. PMID:22379405
Khanna, Amit; Rombeau, John L.
While immunosuppressive regimens improve the overall survival of renal transplant recipients, they also contribute to the long-term complications of post-transplant malignancies. Chronic immune suppression in renal transplant recipients (RTR) increases the risk of viral-associated cancers. In male RTR, human papillomavirus (HPV) is implicated in the development of penile, anal, oropharyngeal, and non-melanoma skin carcinomas. Despite the significance of this virus in RTR, there is an overall deficiency in the understanding of the natural history of HPV infection in male RTR. In the next 20?years, it is believed that cancers will be the leading cause of death in kidney transplant recipients. HPV-associated carcinomas are of particular interest since they are sexually transmitted and in theory may be preventable diseases. This commentary highlights some of the progress made in understanding how HPV is transmitted amongst couples in the general population. It also summarizes the current knowledge of HPV infection in male RTR and describes the deficiencies in published medical literature. PMID:23369244
Genzer, Oksana; El-Sayegh, Suzanne E; Kleiner, Morton J; Castellanos, Mario R
Multiparameter flow cytometry (MFC) can identify leukemia-associated immunophenotypes in more than 90% of cases of acute leukemia with detection limits of 10(-3)-10(-4). In order to better understand the potential utility of MFC to measure minimal residual disease (MRD) in the setting of myeloablative hematopoietic cell transplantation (HCT), we studied cohorts of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in complete remission (CR) both pre- and post-HCT. Among 253 patients with AML, the 3-year estimates of overall survival were 73% (CR1) and 73% (CR2) for those who were MRD(neg) and 32% (CR1) and 44% (CR2) for those who were MRD(pos), with relapse rates being more than doubled in those who were MRD(pos) pre-HCT (21% vs 58% for CR1 patients and 19% vs 68% for CR2 patients). The presence of MRD anytime during the first 100 days post-HCT predicted a 6-fold higher risk of subsequent relapse. In 157 patients with ALL, the 3-year overall survivals were 68% for the MRD(neg) cohort vs 40% for those who were MRD(pos) pre-HCT, with probabilities of relapse of 16% in those who were MRD(neg) vs 33% in the MRD(pos) group. As in AML, the presence of MRD in the post-transplant setting indicated that the risk of subsequent relapse was high, but not inevitable. PMID:24309531
Appelbaum, Frederick R
With the threat of a warmer, wetter world and a larger global population, scientists are researching how climate change may impact the spread of infectious diseases,ťsuch as cholera and dengue fever, and how outbreaks may be prevented.ť "Changing Planet" is produced in partnership with the National Science Foundation.
... just above your kidneys. They produce hormones that affect how your body responds to stress. In people who have Addison’s disease, the adrenal glands do not produce enough corticosteroid hormones, such as cortisol and ... can occur at any age and affects men and women equally. It is also called ...
Morbihan disease, which consists of solid facial edema, is a rare complication of rosacea, a common cutaneous disorder in middle-aged individuals. The characteristic features of Morbihan disease are its chronic course, typical clinical picture, lack of specific laboratory and histopathologic findings, and refractoriness to therapeutic measures. Since its initial description in 1957, only a small number of cases have been reported in the dermatologic literature. We report a 54-year-old man who developed a two-year duration of erythema and edema that affects the upper and mid face, with accentuation in the periorbital region. Patch tests excluded an allergic contact dermatitis and histopathologic investigation showed small, nodular clusters of epithelioid cells in the dermis that were consistent with sarcoidal granulomata. A diagnosis of Morbihan disease was made owing to the combination of clinical and histopathologic findings. Therapeutic options for the disease remain unsatisfactory and treatments reported in the literature include systemic glucocorticoids, oral tetracyclines, thalidomide, isotretinoin, ketotifen, and clofazimine. Our patient failed a six-to-seven months course of minocycline prior to presentation and has since experienced improvement on gradually-increasing doses of isotretinoin. PMID:23286817
Hu, Stephanie W; Robinson, Maria; Meehan, Shane A; Cohen, David E
... by the GAA into glucose, a sugar that fuels muscles. In Pompe disease, mutations in the GAA gene reduce or completely eliminate this essential enzyme. Excessive amounts of lysosomal glycogen accumulate everywhere in the body, but the cells of the heart and skeletal muscles are the ...
... Northern California. It has also been reported in China, Europe, Japan, Australia, and the parts of the ... Lyme disease can be treated and cured with one of several oral antibiotics for 3–4 weeks. The skin rash ... diagnosis or treatment provided by a qualified health care provider.
Definition of the disease Behçet disease (BD) is a chronic, relapsing, multisystemic disorder characterized by mucocutaneous, ocular, vascular and central nervous system manifestations. Epidemiology BD seems to cluster along the ancient Silk Road, which extends from eastern Asia to the Mediterranean basin. European cases are often described, not exclusively in the migrant population. Clinical description The clinical spectrum includes oral and genital ulcerations, uveitis, vascular, neurological, articular, renal and gastrointestinal manifestations. Etiology The etiopathogenesis of the disease remains unknown, although genetic predisposition, environmental factors and immunological abnormalities have been implicated. Diagnostic methods Diagnosis is only based on clinical criteria. Differrential diagnosis It depends on the clinical presentation of BD, but sarcoidosis, multiple sclerosis, Crohn’s disease, Takayasu’s arteritis, polychondritis or antiphospholipid syndrome need to be considered. Management Treatment is symptomatic using steroids and immunomodulatory therapy. It is efficient depending on the rapidity of initiation, the compliance, and the duration of therapy. Prognosis The prognosis is severe due to the ocular, neurological and arterial involvement. PMID:22497990
Winkler's disease otherwise known as chondrodermatitis nodularis chronica helices (CNHC) is characterized by a painful persistent erythematous nodule, mostly located at the rim of helix of pinna. Occurs mostly in men over 40 years of age. Standard therapy is by local excision or carbon dioxide laser vaporization. Recurrence is frequent. PMID:23120207
Jacob K, Joe; Satheesh, S; Menon, P; Saju, K G
Winkler's disease otherwise known as chondrodermatitis nodularis chronica helices (CNHC) is characterized by a painful persistent\\u000a erythematous nodule, mostly located at the rim of helix of pinna. Occurs mostly in men over 40 years of age. Standard therapy\\u000a is by local excision or carbon dioxide laser vaporization. Recurrence is frequent.
Joe Jacob. K; S. Satheesh; P. Menon; K. G. Saju
In this retrospective study, we evaluated the impact of pre- and posttransplant minimal residual disease (MRD) detected by multiparametric flow cytometry (MFC) on outcome in 160 patients with ALL who underwent myeloablative allogeneic hematopoietic cell transplantation (HCT). MRD was defined as detection of abnormal B or T cells by MFC with no evidence of leukemia by morphology (<5% blasts in marrow) and no evidence of extramedullary disease. Among 153 patients who had pre-HCT flow data within 50 days before transplant, MRD pre-HCT increased the risk of relapse (hazard ratio (HR) = 3.64; 95% confidence interval (CI), 1.87–7.09; P = .0001) and mortality (HR = 2.39; 95% CI, 1.46–3.90, P = .0005). Three-year estimates of relapse were 17% and 38% and estimated 3-year OS was 68% and 40% for patients without and with MRD pre-HCT, respectively. 144 patients had at least one flow value post-HCT, and the risk of relapse among those with MRD was higher than that among those without MRD (HR = 7.47; 95% CI, 3.30–16.92, P < .0001). The risk of mortality was also increased (HR = 3.00; 95% CI, 1.44–6.28, P = .004). These data suggest that pre- or post-HCT MRD, as detected by MFC, is associated with an increased risk of relapse and death after myeloablative HCT for ALL. PMID:24778882
Bar, Merav; Wood, Brent L.; Radich, Jerald P.; Doney, Kristine C.; Woolfrey, Ann E.; Appelbaum, Frederick R.; Gooley, Ted A.
In this retrospective study, we evaluated the impact of pre- and posttransplant minimal residual disease (MRD) detected by multiparametric flow cytometry (MFC) on outcome in 160 patients with ALL who underwent myeloablative allogeneic hematopoietic cell transplantation (HCT). MRD was defined as detection of abnormal B or T cells by MFC with no evidence of leukemia by morphology (<5% blasts in marrow) and no evidence of extramedullary disease. Among 153 patients who had pre-HCT flow data within 50 days before transplant, MRD pre-HCT increased the risk of relapse (hazard ratio (HR) = 3.64; 95% confidence interval (CI), 1.87-7.09; P = .0001) and mortality (HR = 2.39; 95% CI, 1.46-3.90, P = .0005). Three-year estimates of relapse were 17% and 38% and estimated 3-year OS was 68% and 40% for patients without and with MRD pre-HCT, respectively. 144 patients had at least one flow value post-HCT, and the risk of relapse among those with MRD was higher than that among those without MRD (HR = 7.47; 95% CI, 3.30-16.92, P < .0001). The risk of mortality was also increased (HR = 3.00; 95% CI, 1.44-6.28, P = .004). These data suggest that pre- or post-HCT MRD, as detected by MFC, is associated with an increased risk of relapse and death after myeloablative HCT for ALL. PMID:24778882
Bar, Merav; Wood, Brent L; Radich, Jerald P; Doney, Kristine C; Woolfrey, Ann E; Delaney, Colleen; Appelbaum, Frederick R; Gooley, Ted A
... ENews Home > Lung Disease > Pulmonary Vascular Disease Understanding Pulmonary Vascular Disease Pulmonary vascular disease is a category of disorders. ... in a person's pulmonary arteries gets dangerously high. Pulmonary Veno-occlusive Disease This is an extremely rare form of high ...
Hairy cell leukemia (HCL) is a highly treatable, but generally incurable B-cell lymphoproliferative disorder with a long natural history. The purine analogs cladribine and pentostatin are the treatments of choice and both induce complete remission (CR) by peripheral blood counts and morphologic examination of the marrow in the large majority of patients. However, some patients, otherwise in apparent CR, have evidence of minimal residual disease (MRD) as detected by a number of different techniques, including immunohistochemistry, immunophenotypying by flow cytometry, and polymerase chain reaction (PCR). Immunohistochemistry is readily available, but precise criteria which constitute MRD are not uniform. Immunophenotyping can identify a characteristic immunophenotype, but leukemia cells may be difficult to obtain from a fibrotic bone marrow. Patient-specific PCR, while highly specific, is not readily available. Furthermore, the introduction of newer effective therapies such as the monoclonal antibody rituximab and immunoconjugate BL22 following a purine analog or concurrently with a purine analog may eradicate MRD. However, the optimal method for detecting MRD is not known. Furthermore, whether the eradication of MRD improves overall survival has not been established. PMID:21463116
Tallman, Martin S
Tumor necrosis factor ? (TNF-?) antibody agents are an effective therapy for the treatment of inflammatory bowel disease (IBD); however, because of the potential for immune suppression with these drugs, TNF-? antibody agents can increase the risk of malignancy. We report here the case of an 11-year-old boy who presented with bowel obstruction. He also had a history of periodic fever, aphthous stomatitis, and cervical adenitis (PFAPA). Intestinal inflammation continued and impaired his quality of life; he was diagnosed with IBD of an undetermined type (IBD-U). Symptoms improved with infliximab, but he developed elevated transaminase levels with hepatosplenomegaly 1 year after scheduled infusions. Skin biopsy revealed an atypical lymphoid infiltrate consistent with an Epstein-Barr virus (EBV)-positive natural killer (NK)/T-cell lymphoma with associated hemophagocytic lymphohistiocytosis. Bone marrow biopsy revealed a similar EBV-positive lymphoid infiltrate consistent with an NK/T-cell lymphoma. EBV-positive tissue was present in gastrointestinal biopsies. Flow-cytometric analysis revealed an atypical, clonal NK-cell population, and biopsy specimens from several tissue sites tested positive for CD3, CD56, and CD30. The patient died soon after the diagnosis was made. This patient developed an EBV-driven malignancy while receiving infliximab. All patients with IBD who receive infliximab should be monitored for malignancy, especially young patients. This case underscores the need for future studies to better understand the biology of lymphoproliferative disorders. PMID:20837584
Deneau, Mark; Wallentine, Jeremy; Guthery, Stephen; O'Gorman, Molly; Bohnsack, John; Fluchel, Mark; Bezzant, John; Pohl, John F
Summary Controlled expansion and contraction of lymphocytes both during and after an adaptive immune response is imperative to sustaining a healthy immune system. Both extrinsic and intrinsic pathways of lymphocyte apoptosis are programmed to eliminate cells at the proper time to ensure immune homeostasis. Genetic disorders of apoptosis described in mice and humans have established Fas and Bim as critical pro-apoptotic molecules responsible for T-cell death in response to T-cell receptor restimulation and cytokine withdrawal, respectively. Emerging evidence prompts revision of this classic paradigm, especially for our understanding of restimulation-induced cell death (RICD) and its physiological purpose. Recent work indicates that RICD employs both Fas and Bim for T-cell deletion, dispelling the notion that these molecules are assigned to mutually exclusive apoptotic pathways. Furthermore, new mouse model data combined with our discovery of defective RICD in X-linked lymphoproliferative disease (XLP) patient T cells suggest RICD is essential for precluding excess T-cell accumulation and associated immunopathology during the course of certain infections. Here we review how these advances offer a refreshing new perspective on the phenomenon of T-cell apoptosis induced through antigen restimulation, including its relevance to immune homeostasis and potential for therapeutic interventions. PMID:20636809
Snow, Andrew L.; Pandiyan, Pushpa; Zheng, Lixin; Krummey, Scott M.; Lenardo, Michael J.
Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal ?-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual ?-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal ?-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked ?-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human ?-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones. PMID:21092187
The Legg-Calve-Perthes disease is an idiopathic avascular necrosis of the hip during early childhood. It is characterized by different stages with the main risk of persisting hip deformation, dysfunction of the joint movement, and the potential for early osteoarthritis. For the evaluation of prognosis and therapy planning patients age and extent of the necrotic area of the epiphysis are important factors. For an early diagnosis and sufficient therapy all radiological efforts have to be performed. MR imaging is an ideal method for the assessment of osteonecrotic changes of the Morbus Perthes. Compared to plain radiography by MR imaging pathologic alterations can be detected earlier and with higher specificity. However, conventional radiograms have to be still used as basic imaging modality. Nowadays x-rays and MR imaging should be the main methods for the evaluation of children suffering from Perthes disease. PMID:12149903
Kramer, J; Hofmann, S; Scheurecker, A; Tschauner, C
Presenting a multidisciplinary approach to the diagnosis and treatment of thyroid disease, this volume provides a comprehensive picture of current thyroid medicine and surgery. The book integrates the perspectives of the many disciplines that deal with the clinical manifestations of thyroid disorders. Adding to the clinical usefulness of the book is the state-of-the-art coverage of many recent developments in thyroidology, including the use of highly sensitive two-site TSH immunoradionetric measurements to diagnose thyroid activity; thyroglobulin assays in thyroid cancer and other diseases; new diagnostic applications of MRI and CT; treatment with radionuclides and chemotherapy; new developments in thyroid immunology, pathology, and management of hyperthyroidism; suppressive treatment with thyroid hormone; and management of Graves' ophthalmopathy. The book also covers all aspects of thyroid surgery, including surgical treatment of hyperthyroidism; papillary, follicular, and other carcinomas; thyroidectomy; and prevention and management of complications.
When the adenosine triphosphate (ATP)-binding cassette (ABC) transporter gene, ABCA4 (originally named ABCR), was cloned and characterized in 1997 as the causal gene for autosomal recessive Stargardt disease (arSTGD or STGD1) (1) it seemed as if just another missing link was added to the extensive table of genetic determinants of rare monogenic retinal\\u000a dystrophies. Now, 9 yr later, the ABCA4
Menkes disease (MD) is a lethal multisystemic disorder of copper metabolism. Progressive neurodegeneration and connective tissue disturbances, together with the peculiar ‘kinky’ hair are the main manifestations. MD is inherited as an X-linked recessive trait, and as expected the vast majority of patients are males. MD occurs due to mutations in the ATP7A gene and the vast majority of ATP7A
Zeynep Tümer; Lisbeth B Mřller
Wilson's disease (WD), an inborn error of copper (Cu) metabolism, is now one of the leading liver diseases in children in India. The clinical presentation can be extremely varied viz.,--all forms of acute and chronic liver disease, minimal to severe neurological disease, psychiatric problems, bony deformities, hemolytic anemia and endocrine manifestations. A high index of suspicion is necessary along with a judicious battery of investigations for diagnosis. Hepatic copper estimation is the most reliable test but is not easily available in India. Liver biopsy may not be possible because of bleeding problems and histological features are often not diagnostic of WD. In the absence of hepatic Cu, a low ceruloplasmin, high 24 hour urinary copper and presence of KF rings aid in making the diagnosis. The mainstay of initial therapy is Cu-chelators like D-Penicillamine, and Trientine for reduction in body copper to sub-toxic levels. Subsequent maintenance therapy is necessarily lifelong with D-Penicillamine, Trientine or Zinc. Children on therapy must be monitored regularly for response, side-effects, compliance and rehabilitation. Response to therapy may be unpredictable, but acute and early presentations like fulminant hepatic failures have a poor outcome. All siblings must be screened for WD as early diagnosis and treatment result in a good outcome. The identification of the WD gene on chromosome 13 has led to the possible use of molecular genetics (haplotype and mutational analyses) in the diagnosis of WD. Parent groups/associations must take active part in holistic management of WD. PMID:12420912
Pandit, Anand; Bavdekar, Ashish; Bhave, Sheila
Modern treatment protocols lead to complete remission (CR) in a considerable proportion of patients with lymphoproliferative disorders. However, many of these patients ultimately relapse, implying that achievement of a clinical CR is compatible with significant amounts of residual malignant cells. Cytogenetic, molecular and immunological techniques that are more sensitive than morphology are increasingly used to assess and quantify minimal residual
Monika Brüggemann; Christiane Pott; Matthias Ritgen; Michael Kneba
After two workers at the nuclear weapons plant at Oak Ridge National Laboratory in Tennessee were diagnosed earlier this year with chronic beryllium disease (CBD), a rare and sometimes fatal scarring of the lungs, the Department of Energy ordered up a 4-year probe. Now, part of that probe has begun - tests conducted by the Oak Ridge Associated Universities' Center for Epidemiological Research measuring beryllium sensitivity in 3,000 people who've been exposed to the metal's dust since Manhattan Project managers opened the Y-12 plant at Oak Ridge in 1943. Currently, 119 Y-12 employees process beryllium, which has a number of industrial uses, including rocket heat shields and nuclear weapon and electrical components. The disease often takes 20 to 25 years to develop, and the stricken employees haven't worked with beryllium for years. There is no cure for CBD, estimated to strike 2% of people exposed to the metal. Anti-inflammatory steroids alleviate such symptoms as a dry cough, weight loss, and fatigue. Like other lung-fibrosis diseases that are linked to lung cancer, some people suspect CBD might cause some lung cancer. While difficult to diagnose, about 900 cases of CBD have been reported since a Beryllium Case Registry was established in 1952. The Department of Energy (DOE) estimates that about 10,000 DOE employees and 800,000 people in private industry have worked with beryllium.
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
Having determined whether a patient has central or peripheral vestibular disease, clinicians must then determine what diseases are likely to result in such a presentation. This article describes the more common diseases causing vestibular disease in dogs and cats. Having formulated a list of potential causes of vestibular disease, clinicians should proceed through a systematic investigation to diagnose the underlying condition. A companion article describes the anatomy, physiology, and clinical signs associated with vestibular disease. PMID:22847321
A diagnosis of demyelination carries important therapeutic and prognostic implications. In most cases the diagnosis is made clinically, and involvement of the histopathologist is largely confined to postmortem confirmation and clinicopathological correlation. However, every now and then, accurate diagnosis of the presence or cause of demyelination before death hinges on the histopathological assessment. Recognition of demyelination depends on an awareness of this as a diagnostic possibility, and on the use of appropriate tinctorial and immunohistochemical stains to identify myelin, axons and inflammatory cells. In biopsy specimens, the critical distinction is usually from ischaemic or neoplastic disease, and the types of demyelinating disease most likely to be encountered are multiple sclerosis, acute?disseminated encephalomyelitis, progressive multifocal leucoencephalopathy and extrapontine myelinolysis. Interpretation of the pathology has to be made in the context of the clinical, radiological and biochemical findings. Freezing of a small amount of fresh tissue allows for later virological studies, and electron microscopy is occasionally helpful for demonstration of viral particles. PMID:17071802
Risk factors for the development of a new (secondary) malignancy after marrow transplantation are still incompletely defined. In the present study, we analyzed results in 700 patients with severe aplastic anemia treated with allogeneic marrow transplantation at the Fred Hutchinson Cancer Research Center in Seattle, WA, or at the Hôpital St Louis in Paris, France. Twenty-three patients developed a malignancy 1.4 to 221 months (median, 91 months) after transplantation for a Kaplan-Meier estimate of 14% (95% confidence interval, 4% to 24%) at 20 years. Five cases were lymphoid malignancies (two acute lymphoblastic leukemias and three lymphoproliferative disorders) occurring 1.4 to 14.6 months (median, 3 months) posttransplant, and 18 were solid tumors (17 squamous cell and one mucoepidermoid carcinoma) presenting 30 to 221 months (median, 99 months) posttransplant. Thus, the hazard for lymphoid malignancies declined rapidly posttransplant, while the hazard for solid tumors increased progressively with time posttransplant. Risk factors for solid tumors identified in univariable analysis included the underlying diagnosis of Fanconi anemia (P = .0002), azathioprine therapy for chronic graft-versus-host disease (GVHD) (P < .0001), irradiation (total body or thoracoabdominal) as part of the conditioning regimen (P = .0002), chronic GVHD (P = .0099), acute GVHD (P = .0135), and male sex (P = .0499). In multivariable, stepwise proportional hazards models, azathioprine therapy (P < .0001) and the diagnosis of Fanconi anemia (P < .0001) were significant factors for all patients. Irradiation was a significant factor (P = .004) only if the time-dependent variable azathioprine was not included in the analysis. If only non-Fanconi patients were considered, azathioprine (P = .0043), age (P = .025), and irradiation (P = .042) were significant factors. Results in patients with Fanconi anemia and malignancies other than solid tumors were not subjected to an analysis because of the small number of events. It is of note, however, that no case of myeloproliferative disorder was observed. In summary, the highest risk of developing a solid tumor was associated with the diagnosis of Fanconi anemia. Better prevention of GVHD or omission of azathioprine as GVHD therapy (or both) may reduce the risk of late tumor development. Similarly, nonirradiation conditioning regimens may reduce the tumor risk, at least in patients without Fanconi anemia. Interactions between potential risk factors are complex, and further observation and additional analyses will be of interest. PMID:8547667
Deeg, H J; Socié, G; Schoch, G; Henry-Amar, M; Witherspoon, R P; Devergie, A; Sullivan, K M; Gluckman, E; Storb, R
... for patients and health care professionals to help increase awareness of bowel control problems. Celiac Disease Awareness Campaign ... for patients and health care professionals to help increase awareness of celiac disease. Kidney Disease Kidney Diseases Information ...
... Select a Language: Fact Sheet 652 HIV and Cardiovascular Disease HIV AND CARDIOVASCULAR DISEASE WHY SHOULD PEOPLE WITH HIV CARE ABOUT CVD? ... OF CVD? WHAT ABOUT CHANGING MEDICATIONS? HIV AND CARDIOVASCULAR DISEASE Cardiovascular disease (CVD) includes a group of problems ...
Keywords Alzheimer's Disease Antimicrobial Peptides Proteomics Posttranslational Modifications collaborations. Current international collaborations focus on Alzheimer's disease (Tau and A), molecular mechanisms of cell aging (glycation, oxidation) and related diseases (diabetes, Alzheimer's disease) as well
Focal-segmental glomerulosclerosis (FSGS) is the most common glomerular cause of renal failure in children and after transplantation is associated with a significantly increased risk of renal allograft loss . Recurrence of FSGS following transplantation occurs in 15–50% of the cases [2–10]. The median time to recurrence is 14 days after transplantation , suggesting a role for a systemic abnormality or
Asher D. Schachter; Terry B. Strom
In this trial, patients age 70 or younger with multiple myeloma will be randomly assigned to treatment with one of three regimens after receiving high-dose melphalan chemotherapy and autologous stem cell transplantation.
CONTENTS INTRODUCTION .......... . .. . ........ . SEEDLI NG DISEASES ... . ... . .. . ........ . FOLIAGE DISEASES ................... .. SHEATH AND STEM DISEASES .......... . DISEASES ATT ACKI NG THE KERNEL ..... . PHYSIOLOGICAL DiSORDERS... or middle porti of the leaves. Symptoms are most conspicuouso the flag leaf just before heading. Diseased plan have less vigor and height and produce small panicles. On severely diseased plants the flag Ie and sheath become twisted and hold the panic...
Alzheimer's disease is the largest unmet medical need in neurology. Current drugs improve symptoms, but do not have profound disease-modifying effects. However, in recent years, several approaches aimed at inhibiting disease progression have advanced to clinical trials. Among these, strategies targeting the production and clearance of the amyloid-? peptide — a cardinal feature of Alzheimer's disease that is thought to
This report describes the clinical courses of two acute myeloid leukemia patients. Both had MLL translocations, the first a t(10;11)(p11.2;q23) with MLL-AF10 and the second a t(11;19)(q23;p13.1) with MLL-ELL fusion. They achieved a clinical remission under conventional chemotherapy but relapsed shortly after end of therapy. Both had a history of invasive mycoses (one had possible pulmonary mycosis, one systemic candidiasis). Because no HLA-identical donor was available, a haploidentical transplantation was performed in both cases. Using a specially designed PCR method for the assessment of minimal residual disease (MRD), based on the quantitative detection of the individual chromosomal breakpoint in the MLL gene, both patients achieved complete and persistent molecular remission after transplantation. The immune reconstitution after transplantation is described in terms of total CD3+/CD4+, CD3+/CD8+, CD19+, and CD16+/CD56+ cell numbers over time. The KIR and HLA genotypes of donors and recipients are reported and the possibility of a KIR-mediated alloreactivity is discussed. This report illustrates that haploidentical transplantation may offer a chance of cure without chronic graft-versus-host disease in situations where no suitable HLA-identical donor is available even in a high-risk setting and shows the value of MRD monitoring in the pre- and posttransplant setting. PMID:23211007
Myelodysplastic and Myeloproliferative Disorders; Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Chronic Myelogenous Leukemia; Multiple Myeloma; Plasma Cell Dyscrasia; Lymphoproliferative Disorders; Hematologic Diseases
Chediak-Higashi Syndrome; Graft Versus Host Disease; X-Linked Lymphoproliferative Syndrome; Familial Erythrophagocytic Lymphohistiocytosis; Hemophagocytic Lymphohistiocytosis; Virus-Associated Hemophagocytic Syndrome
Osler's disease, also known as hereditary hemorrhagic telangiectasia (HHT) and Osler-Weber-Rendu syndrome, is an autosomal dominant disorder leading to abnormal blood vessel formation in the skin, mucous membranes and often in organs, such as the lungs, liver and brain (arteriovenous malformations AVM). Various types are known. Patients may present with epistaxis. Teleangiectasia can be identified by visual inspection during physical examination of the skin or oral cavity or by endoscopy. Diagnosis is made after clinical examination and genetic testing based on the Curacao criteria. Modern imaging modalities, such as computed tomography (CT) or magnetic resonance imaging (MRI) have become more important as they can depict the AVMs. Pulmonary AVMs can be depicted in CT imaging even without the use of a contrast agent while other locations including the central nervous system (CNS) usually require administration of contrast agents. Knowledge of possible clinical manifestations in various organs, possible complications and typical radiological presentation is mandatory to enable adequate therapy of these patients. Interventional procedures are becoming increasingly more important in the treatment of HHT patients. PMID:24276214
Ahlhelm, F; Lieb, J; Schneider, G; Müller, U; Ulmer, S
Fabry disease (FD) is an X-linked disorder caused by deficiency of the enzyme alpha-galactosidase A, required for the degradation of globotriaosylceramide. Accumulation of substrate occurs in multiple cell types resulting in a multi-system disorder, affecting both males and females. Clinical features include neuropathic pain and angiokeratoma, with subsequent development of proteinuria, renal failure, left ventricular hypertrophy, arrhythmias and stroke. Beyond palliative therapies for organ involvement and pain control, enzyme replacement therapy directed at the underlying metabolic defect became available in 2001-2003. Knowledge of the pathophysiology and clinical features of FD is vital for assessing the rationale and evidence of efficacy of therapies for FD and their limitations. Whilst ERT improves many of the symptoms of FD, its effect on the natural history of the disorder has yet to be fully demonstrated. Improved understanding of the appropriate use of adjunctive therapies and the development of new treatment strategies, including pharmacologic chaperone therapy and gene therapy, coupled with long term clinical outcome data on the effects of ERT are all key components of optimising treatment for FD. PMID:25345090
Thomas, Atison S; Hughes, Derralynn A
Most patients diagnosed with primary chronic cold agglutinin disease (CAD) have a clonal lymphoproliferative bone marrow disorder. Treatment with rituximab is the only well-documented effective therapy, leading to 45%-60% partial responses (PR). Complete responses (CR) are rare, and median response duration is only 11 months. In a prospective multicenter trial, 29 patients received rituximab 375 mg/m(2) on days 1, 29, 57 and 85; and fludarabine orally, 40 mg/m(2) on days 1-5, 29-34, 57-61 and 85-89. Twenty-two patients (76%) responded, 6 (21%) achieving CR and 16 (55%) PR. Among 10 patients nonresponsive to rituximab monotherapy, 1 achieved CR and 6 PR. Median increase in hemoglobin level was 3.1 g/dL among the responders and 4.0 g/dL in those who achieved CR. Lower quartile of response duration was not reached after 33 months. Estimated median response duration was more than 66 months. Grade 3-4 hematologic toxicity occurred in 12 patients (41%). In conclusion, fludarabine and rituximab combination therapy is very efficient in patients with CAD. Toxicity may be a concern, and benefits should be carefully weighed against risks in very old and comorbid patients. It remains to be established whether the combination should be first-line or an efficient second-line therapy in CAD patients requiring treatment. PMID:20634373
Berentsen, Sigbjřrn; Randen, Ulla; Vĺgan, Anne Marita; Hjorth-Hansen, Henrik; Vik, Anders; Dalgaard, Jakob; Jacobsen, Eva-Marie; Thoresen, Aud S; Beiske, Klaus; Tjřnnfjord, Geir E
Alzheimer Disease (AD) is an outcome as well as source of many diseases. Alzheimer is linked with many other diseases like Diabetes type 2, cholesterolemia, hypertension and many more. But how each of these diseases affecting other is still unknown to scientific community. Signaling Pathways of one disease is interlinked with other disease. But to what extent healthy brain is affected when any signaling in human body is disturbed is the question that matters. There is a need of Pathway analysis, Protein-Protein interaction (PPI) and the conserved interactome study in AD and linked diseases. It will be helpful in finding the potent drug or vaccine target in conscious manner. In the present research the Protein-Protein interaction of all the proteins involved in Alzheimer Disease is analyzed using ViSANT and osprey tools and pathway analysis further reveals the significant genes/proteins linking AD with other diseases. PMID:24753659
Rao, Balaji S.; Gupta, Krishna Kant; Karanam, Pujitha; Peruri, Anusha
Abstract Immunosuppressive agents are used for treatment of a variety of autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosis (SLE), and psoriasis, as well as for prevention of tissue rejection after organ transplantation. Recrudescence of herpesvirus infections, and increased risk of carcinogenesis from herpesvirus-associated tumors are related with immunosuppressive therapy in humans. Post-transplant lymphoproliferative disorder (PTLD), a condition characterized by development of Epstein Barr Virus (EBV)-associated B-lymphocyte lymphoma, and Kaposi's Sarcoma (KS), a dermal tumor associated with Kaposi Sarcoma-associated virus (KSHV), may develop in solid organ transplant patients. KS also occurs in immunosuppressed Acquired Immunodeficiency (AIDS) patients. Kaposi Sarcoma-associated virus (KSHV) is a herpes virus genetically related to EBV. Murine gammaherpes-virus-68 (MHV-68) is proposed as a mouse model of gammaherpesvirus infection and recrudescence and may potentially have relevance for herpesvirus-associated neoplasia. The pathogenesis of MHV-68 infection in mice mimics EBV/KSHV infection in humans with acute lytic viral replication followed by dissemination and establishment of persistent latency. MHV-68-infected mice may develop lymphoproliferative disease that is accelerated by disruption of the immune system. This manuscript first presents an overview of gammaherpesvirus pathogenesis and immunology as well as factors involved in viral recrudescence. A description of different types of immunodeficiency then follows, with particular focus on viral association with lymphomagenesis after immunosuppression. Finally, this review discusses different gammaherpesvirus animal models and describes a proposed MHV-68 model to further examine the interplay of immunomodulatory agents and gammaherpesvirus-associated neoplasia. PMID:24512328
Aligo, Jason; Walker, Mindi; Bugelski, Peter; Weinstock, Daniel
Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Childhood Renal Cell Carcinoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Clear Cell Renal Cell Carcinoma; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; de Novo Myelodysplastic Syndromes; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Juvenile Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; 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 Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell 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 Renal Cell Cancer; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Anemia; Refractory Anemia With Ringed Sideroblasts; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Splenic Marginal Zone Lymphoma; Stage I Adult Burkitt Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Mixed Cell Lymphoma; Stage I Adult Immunoblastic Large Cell Lymphoma; Stage I Adult Lymphoblastic Lymphoma; Stage I Adult T-cell Leukemia/Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymp
Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; 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; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; 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 Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurre
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
Cohen, Jeffrey I
Treating Alzheimer's disease (AD) is the biggest unmet medical need in neurology. Current drugs improve symptoms, but do not have profound disease-modifying effects. Three main classes of disease-modification approaches can be defined: one that is broadly neurotrophic or neuroprotective, one that targets specific aspects of AD pathology, and one that is based on epidemiological observation. This review discusses all three
... some rheumatic diseases (SLE, APS, Sjögren’s and, particularly, scleroderma), also warrants mention. Because this severe disease frequently ... period—pregnancy isconsidered inadvisable. Other diseases such as scleroderma (in the absence of pulmonary hypertension or lung ...
... A. Jacobs, M.D., Emeritus Professor, Division of Infectious Diseases, University of California - San Francisco [ Video ] Lyme Disease ... on line Find a Local Physician Knowledgeable About Infectious Diseases The best private organization-based site that can ...
... Referral Center Alzheimer's Disease Education and Referral Center Alzheimer's Disease Education and Referral Center Home About Alzheimer’s ... National Alzheimer's Project Act (NAPA) About ADEAR Understanding Alzheimer's Disease: What You Need to Know Introduction Many ...
... being researched? What are clinical trials? How is Alzheimer's disease treated? Alzheimer's disease is complex, and it is unlikely that any ... better to one drug than another. See also: Alzheimer's Disease Medications Fact Sheet Are there treatments available for ...
... with Alzheimer's disease? What is dementia? What is Alzheimer's disease? Alzheimer’s disease is an irreversible, progressive brain disease ... devastating disease. What happens to the brain in Alzheimer's disease? Although we still don’t know how the ...
Antithymocyte globulin (ATG) induction therapy is associated with an increased long-term risk of infection- and cancer-related death. To analyze long-term effects of ATG induction on lymphocyte function, we prospectively assessed CD4 helper function, B-cell/monocyte and cytokine responses in 84 renal transplant recipients (ATG, n = 44) up to 1 year post-transplant. A PWM-driven allogeneic coculture system was used to assess helper function of CD4+ T cells and T-cell-dependent B-cell responses. SAC I was used for T-cell-independent stimulation of B-cell cultures. In vitro cytokine secretion and serum soluble CD30 (sCD30) were determined by enzyme-linked immunosorbent assay (ELISA). ATG induced a persistent decrease of peripheral blood lymphocyte counts compared with non-ATG treatment because of a predominant decrease of CD4+ T cells (4 months, 1 year; P < 0.0005) which was associated with a decreased CD28 expression (1 year, P = 0.02) and CD4 cell interleukin 2 (IL-2) response (4 months, P < 0.0005). However, Th2 responses (CD4 help, CD4 cell IL-4 and IL-10 responses, sCD30), which proved to be predictive of graft outcome, were not affected, and neither was the secretion of the lymphoma growth factors IL-6 and IL-10 by B cells and monocytes. Our data show that ATG induction therapy in immunological high-risk patients induces a profound long-term decrease in cell counts and Th1 but not Th2 responses of CD4+ T cells which may explain long-term effects on infection and post-transplant lymphoproliferative disease (PTLD) incidence because of inadequate T-cell control. PMID:15691277
Weimer, Rolf; Staak, Anne; Süsal, Caner; Streller, Sabine; Yildiz, Sevgi; Pelzl, Steffen; Renner, Fabrice; Dietrich, Hartmut; Daniel, Volker; Rainer, Lucy; Kamali-Ernst, Shirin; Ernst, Wolfgang; Padberg, Winfried; Opelz, Gerhard
PURPOSE: This study relates our experience with local surgical management of perianal Crohn's disease. METHOD: Of 1,735 patients with Crohn's disease seen between 1980 and 1990, records of 66 patients (3.8 percent) with symptomatic perianal Crohn's disease treated by local operations were retrospectively reviewed to study outcome of local surgical intervention. RESULTS: All patients had intestinal disease that was limited
Yash P. Sangwan; David J. Schoetz; John J. Murray; Patricia L. Roberts; John A. Coller
Kidney Disease of Diabetes National Kidney and Urologic Diseases Information Clearinghouse is the final stage of chronic kidney disease (CKD). Diabetes is the most common cause of kidney failure, accounting for nearly 44 percent of new cases.1 Even when diabetes is controlled, the disease can lead to CKD
Baker, Chris I.
Diseases of the aorta are imaged using different modalities according to the cause and clinical situation. Current imaging strategies for the clinically most pertinent aortic diseases are analysed. These disease entities may be differentiated into congenital, acquired and inflammatory diseases. Traumatic and non-traumatic aortic aneurysms and dissections are emphasised in context with endovascular treatment options and subsequent follow-up. PMID:17479238
Reimer, P; Vosshenrich, R; Landwehr, P; Storck, M
. PNAS, 104: 8685 (2007). #12;Mendelian diseases E6V6 Sickle Cell Disease: Autosomal recessive disorder 4. Curr Opin Pediatr, 13: 22 (2001). Leads to sickle cell anemia Manifestation of disease vastly differentPSB 2009 Molecular Bioinformatics for Diseases Tutorial Atul Butte, Maricel Kann, Yves Lussier
Danon disease (‘lysosomal glycogen storage disease with normal acid maltase’) is characterized by a cardiomyopathy, myopathy and variable mental retardation. Mutations in the coding sequence of the lysosomal-associated membrane protein 2 (LAMP-2) were shown to cause a LAMP-2 deficiency in patients with Danon disease. LAMP-2 deficient mice manifest a similar vacuolar cardioskeletal myopathy. In addition to the patient reports LAMP-2
Paul Saftig; Kurt von Figura; Yshitaka Tanaka; Renate Lüllmann-Rauch
The pediatric kidney transplant recipient differs from the adult recipient in many ways, including immune responsiveness, drug metabolism and clearance, perfusion of transplanted organs, and risk for posttransplant lymphoproliferative disease. Pediatric patients also have special quality of life issues such as cosmetic side effects of medications, stunted growth and sexual maturation, and separation from their peers. Congenital urological anomalies and glomerulosclerosis are the most common causes of pediatric end-stage renal disease. In the pediatric patients, consideration for preemptive transplantation should be first and arteriovenous fistula placement second. Pediatric patients should receive priority for kidneys from deceased donors to shorten the wait time for transplant. Fevers or changes in blood pressure may identify allograft dysfunction weeks before changes in creatinine occur. Thus, monitoring serum creatinine level is a poor indicator of allograft dysfunction in this setting. There is great concern about nonadherence to immunosuppressive therapy as children reach the stage of adolescence. This report highlights these and other important differences in the evaluation and management of the pediatric kidney transplant recipients compared with the adult and provides practical guidance to the practitioners involved in caring for such patients. PMID:24241086
Organ transplantation is an increasingly used medical procedure for treating otherwise fatal end stage organ diseases with 107,000 transplants performed worldwide in 2010. Newly developed anti-rejection drugs greatly helped to prolong long-term survival of both the individual and the transplanted organ, and they facilitate the diffusion of organ transplantation. Presently, 5-year patient survival rates are around 90% after kidney transplant and 70% after liver transplant. However, the prolonged chronic use of immunosuppressive drugs is well known to increase the risks of opportunistic diseases, particularly infections and virus-related malignancies. Although transplant recipients experience a nearly 2-fold elevated risk for all types of de-novo cancers, persistent infections with oncogenic viruses - such as Kaposi sarcoma herpes virus, high-risk human papillomaviruses, and Epstein-Barr virus - are associated with up to 100-fold increased cancer risks. This review, focusing on kidney and liver transplants, highlights updated evidences linking iatrogenic immunosuppression, persistent infections with oncogenic viruses and cancer risk. The implicit capacity of oncogenic viruses to immortalise infected cells by disrupting the cell-cycle control can lead, in a setting of induced lowered immune surveillance, to tumorigenesis and this ability is thought to closely correlate with cumulative exposure to immunosuppressive drugs. Mechanisms underlying the relationship between viral infections, immunosuppressive drugs and the risk of skin cancers, post-transplant lymphoproliferative disorders, Kaposi sarcoma, cervical and other ano-genital cancers are reviewed in details. PMID:23278452
Piselli, P; Busnach, G; Fratino, L; Citterio, F; Ettorre, G M; De Paoli, P; Serraino, D
Imaging in chest disease may be performed:•to investigate symptoms (e.g. high temperature, cough)•to confirm or exclude suspected diagnoses (e.g. pulmonary embolic disease, cancer)•in the further investigation of known diseases (e.g. diffuse lung disease)•to monitor disease status (e.g. consolidation in pneumonia, pleural effusion in empyema, mediastinal lymphadenopathy in lung cancer).A combination of different imaging modalities may be used to aid diagnosis
Fergus V Gleeson
Castleman’s disease is a group of rare lymphoproliferative disorders. The plasmablastic multicentric Castleman’s disease is frequently discovered in HIV-infected individuals in association with Kaposi sarcoma (HHV-8). Thirty-five year old male presented to our care with the main compliant of severe back pain for one week. His past medical problems include acquired immune deficiency syndrome diagnosed 12 years prior and Kaposi sarcoma, currently on highly active antiretroviral therapy (HAART). Radiographic imaging revealed hepatomegaly and diffuse lymphadenopathy. The HIV viral load was <20 polymerase chain reaction copies/mL, absolute CD4 count was 453 cells/mcL (490-1740 cells/mcL) and CD8 count was 4142 cells/mcL (180-1170 cells/ mcL). Excisional biopsy of the left supraclavicular lymph node was performed with pathological findings of HHV8+ Kaposi sarcoma in the background of multicentric Castleman’s disease (plasmacytic variant). No evidence of transformation into large B-cell or plasmablastic lymphoma was noted. He was discharged on HAART and follow up to receive chemotherapy with cyclophosphamide, adriamycin, vincristine plus prednisone was started and rituximab plus prophylaxis for pneumocystis carinii. Multicentric Castleman’s disease has become more relevant in recent years due to its association with HIV and HHV-8 (Kaposi sarcoma) and its potential to progress into plasmablastic B-cell lymphoma. The progression of MCD to B-cell lymphoma is a concern, especially in patients with HIV infection because it precludes the worst outcome and a high mortality, despite treatment. The most intriguing part of this case is that MCD occurred in a HIV-positive on HAART. This case signals a warning that a high suspicion for MCD can be justified even in those HIV-positive patients on HAART because the possibly of progression to plasmablastic B-cell lymphoma. PMID:25276327
Ortega, Lauro; Cooper, Chad J.; Otoukesh, Salman; Mojtahedzadeh, Mona; Didia, Claudia S.; Torabi, Alireza; Nahleh, Zeina
Cardiovascular Diseases Periodontal Disease and Cardiovascular Conditions Heart Disease and Dental Treatment Myocardial Infarction (Heart Attack) High Blood ... it is a current list. Periodontal Disease and Cardiovascular Conditions Periodontal disease can affect your overall health. Over time, it ...
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Cardiovascular disease is the most common cause of mortality in rich countries and today it has the same meaning for health care as the epidemics of past centuries had for medicine in earlier times: 50% of the population in these countries die of cardiovascular disease. The amount of cardiovascular disease is also increasing in the developing countries together with economic growth. By 2015 one in three deaths will globally be due to cardiovascular diseases. Coronary heart disease is a chronic disease that starts in childhood, even if the symptoms first occur in the middle age. The risks for coronary heart disease are well-known: lipid disorders, especially high serum LDL-cholesterol concentration, high blood pressure, tobacco smoking, obesity, diabetes, male gender and physical inactivity. Obesity is both an independent risk factor for cardiovascular disease but is also closely connected with several other risk factors. This review focuses on the connection between overweight or obesity and cardiovascular disease. PMID:25387321
Multicentric Castleman disease (MCD) is a lymphoproliferative disorder caused by human herpesvirus 8 (HHV8) infection HIV associated MCD (HIV-MCD) presents with various clinical symptoms. Many HIV-negative MCD patients are often treated with anti-human interleukin-6 (IL6) receptor monoclonal antibodies (tocilizumab), and successful results have been reported. IL-6 plays an important role in the development of both HIV-positive and HIV-negative MCD; however, the efficacy of tocilizumab in HIV-MCD patients is unknown. We herein report the clinical and biologic courses of two HIV-MCD patients treated with tocilizumab. In both cases, a significant and rapid clinical improvement was observed after the first infusion. However, the treatment efficacy was not maintained for a long period, and relapse occurred at 15 and 22 weeks, respectively. Both patients received rituximab and subsequently achieved complete clinical remission. Our report, in addition to data presented in the literature, suggests that tocilizumab could be an initial treatment option in patients with HIV-MCD. PMID:24438824
Prion diseases, also called transmissible spongiform encephalopathies (TSEs), lead to neurological dysfunction in animals and are fatal. Infectious prion proteins are causative agents of many mammalian TSEs, including scrapie (in sheep), chronic wasting disease (in deer and elk), bovine spongiform encephalopathy (BSE; in cattle), and Creutzfeldt-Jakob disease (CJD; in humans). BSE, better known as mad cow disease, is among the many recently discovered zoonotic diseases. BSE cases were first reported in the United Kingdom in 1986. Variant CJD (vCJD) is a disease that was first detected in 1996, which affects humans and is linked to the BSE epidemic in cattle. vCJD is presumed to be caused by consumption of contaminated meat and other food products derived from affected cattle. The BSE epidemic peaked in 1992 and decreased thereafter; this decline is continuing sharply owing to intensive surveillance and screening programs in the Western world. However, there are still new outbreaks and/or progression of prion diseases, including atypical BSE, and iatrogenic CJD and vCJD via organ transplantation and blood transfusion. This paper summarizes studies on prions, particularly on prion molecular mechanisms, BSE, vCJD, and diagnostic procedures. Risk perception and communication policies of the European Union for the prevention of prion diseases are also addressed to provide recommendations for appropriate government policies in Korea. PMID:24159531
Lee, Jeongmin; Kim, Su Yeon; Hwang, Kyu Jam; Ju, Young Ran; Woo, Hee-Jong
... sudden cardiac death in patients with coronary heart disease. Cigarette smoking also acts with other risk factors to ... but their risk isn't as great as cigarette smokers'. Exposure to other people's smoke increases the risk of heart disease even for nonsmokers. Learn about smoking and cardiovascular ...
Prion diseases, also called transmissible spongiform encephalopathies (TSEs), lead to neurological dysfunction in animals and are fatal. Infectious prion proteins are causative agents of many mammalian TSEs, including scrapie (in sheep), chronic wasting disease (in deer and elk), bovine spongiform encephalopathy (BSE; in cattle), and Creutzfeldt–Jakob disease (CJD; in humans). BSE, better known as mad cow disease, is among the many recently discovered zoonotic diseases. BSE cases were first reported in the United Kingdom in 1986. Variant CJD (vCJD) is a disease that was first detected in 1996, which affects humans and is linked to the BSE epidemic in cattle. vCJD is presumed to be caused by consumption of contaminated meat and other food products derived from affected cattle. The BSE epidemic peaked in 1992 and decreased thereafter; this decline is continuing sharply owing to intensive surveillance and screening programs in the Western world. However, there are still new outbreaks and/or progression of prion diseases, including atypical BSE, and iatrogenic CJD and vCJD via organ transplantation and blood transfusion. This paper summarizes studies on prions, particularly on prion molecular mechanisms, BSE, vCJD, and diagnostic procedures. Risk perception and communication policies of the European Union for the prevention of prion diseases are also addressed to provide recommendations for appropriate government policies in Korea. PMID:24159531
Lee, Jeongmin; Kim, Su Yeon; Hwang, Kyu Jam; Ju, Young Ran; Woo, Hee-Jong
Metabolic bone disease is a common complication of chronic kidney disease (CKD) and is part of a broad spectrum of disorders of mineral metabolism that occur in this clinical setting and result in both skeletal and extraskeletal consequences. Detailed research in that past 4 decades has uncovered many of the mechanisms that are involved in the initiation and maintenance of
Kevin J. Martin; Esther A. Gonzalez
Tacrolimus and Mycophenolate Mofetil in Preventing Graft-Versus-Host Disease in Patients Who Have Undergone Total-Body Irradiation With or Without Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant for Hematologic Cancer
Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; 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 Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Prolymphocytic Leukemia; 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 Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell 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; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Small Intestine Lym