Singavi, Arun K; Harrington, Alexandra M; Fenske, Timothy S
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
Cavadas, P C; Thione, A; Blanes, M; Mayordomo-Aranda, E
Posttransplant lymphoproliferative disorder (PTLD) is a heterogeneous group of clinical and pathological entities characterized by malignant lymphoid cell proliferation occurring after solid organ transplantation, with frequent extranodal involvement. Central nervous system (CNS) involvement occurs in 7-15% of the cases and it is a significant negative prognostic factor. A case of primary CNS (PCNS) PTLD in the first bilateral lower limb transplant recipient is presented. PMID:25968917
Evens, A M; Choquet, S; Kroll-Desrosiers, A R; Jagadeesh, D; Smith, S M; Morschhauser, F; Leblond, V; Roy, R; Barton, B; Gordon, L I; Gandhi, M K; Dierickx, D; Schiff, D; Habermann, T M; Trappe, R
We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32-5.17, p = 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29-13.46, p = 0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56-29.57, p = 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity. PMID:23721553
Mittal, Ruchi; Thumann, Gabrielle; Souteyrand, George; Kuerten, David; Coupland, Sarah E
Toxoplasmosis is a relatively rare complication in renal transplant patients and can pose diagnostic challenges, especially when it manifests as an ocular inflammation. Authors hereby report an unusual case of a 57-year-old male who developed retinochoroidal toxoplasmosis after 15 years of renal transplant, the diagnoses of which were challenging as the patient was also a known case of cerebral post-transplant lymphoproliferative disease (PTLD) of Hodgkin's type, which misled the ophthalmologists towards a clinical diagnosis of ocular PTLD. Histopathology examination of the enucleated eye revealed numerous toxoplasmosis cysts within the retina and choroid. No ocular PTLD was observed. PMID:26239296
Kim, Manbok; Rahman, Masmudur M; Cogle, Christopher R; McFadden, Grant
Epstein-Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. PMID:25843801
Marques, Heloisa Helena de Sousa; Shikanai-Yasuda, Maria Aparecida; dAzevedo, Luiz Sérgio Fonseca de; Caiaffa-Filho, Hélio Helh; Pierrotti, Lígia Camera; Aquino, Maria Zilda de; Lopes, Marta Heloisa; Maluf, Natalya Zaidan; Campos, Silvia Vidal; Costa, Silvia Figueiredo
Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disease (PTLD) is one of the most serious complications associated with solid organ and hematopoietic stem cell transplantation. PTLD is most frequently seen with primary EBV infection post-transplant, a common scenario for pediatric solid organ recipients. Risk factors for infection or reactivation of EBV following solid organ transplant are stronger immunosuppressive therapy regimens, and being seronegative for receptor. For hematopoietic stem cell transplantation, the risk factors relate to the type of transplant, human leukocyte antigen disparity, the use of stronger immunosuppressants, T-cell depletion, and severe graft-versus-host disease. Mortality is high, and most frequent in patients who develop PTLD in the first six months post-transplant. The primary goal of this article is to provide an overview of the clinical manifestations, diagnosis, accepted therapies, and management of EBV infection in transplant recipients, and to suggest that the adoption of monitoring protocols could contribute to a reduction in related complications. PMID:25467252
Claviez, A; Tiemann, M; Wagner, H J; Dreger, P; Suttorp, M
In contrast to solid organ transplantation (Tx), the incidence of post-transplant lymphoproliferative disease (PTLD) after hematopoietic stem cell Tx (HSCT) is generally low. This risk, however, is significantly elevated in patients receiving human leukocyte antigen (HLA) mis-matched or T-cell-depleted grafts, or after treatment for severe graft-versus-host disease (GvHD). An 18-yr-old patient with positive Epstein-Barr virus (EBV) serology received a fully matched, unmanipulated bone marrow graft from an unrelated EBV-positive donor for treatment of acute myeloid leukemia (AML) in second complete remission. GvHD prophylaxis was performed with cyclosporin A (CsA) and a short course of methotrexate. Four months after Tx, the patient developed ulcerative tonsillitis that was unresponsive to antibiotic treatment. Diarrhea appearing simultaneously was interpreted as gastrointestinal GvHD and steroids were added to CsA. A few days later the patient was admitted to hospital because of generalized seizure and pneumonia. Despite reduction of immunosuppression, intensification of anti-viral treatment, and subsequent mechanical ventilation, the patient died of acute respiratory distress 6 days later. Autopsy demonstrated disseminated EBV-induced, multi-nodular lymphoma infiltration of the entire colon but no signs of GvHD. Moreover, both lungs, paratracheal lymph nodes, kidneys, thyroid gland, and liver were infiltrated with large B-cell non-Hodgkin's lymphomas. This case underlines the rapid and aggressive course of EBV-induced disseminated PTLD after HSCT, initially mimicking intestinal GvHD because of massive colonic lymphoma infiltration. Tissue biopsies should be performed early for establishing correct diagnosis, thus enabling specific therapy, e.g. infusion of donor leukocytes with cytotoxic T-lymphocytes. PMID:11272609
Honda, Masaya; Koga, Michiaki; Kanda, Takashi
The post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous disease entity of lymphoid and plasmacytic proliferations that can occur after solid organ and bone marrow/stem cell transplantation. PTLD sometimes involves the central nervous system (CNS), but primary occurrence in central nervous system (PCNS-PTLD) is rare. The Epstein-Barr virus (EBV) plays a causative role, and up to 90% of the tumors are associated with this virus. Diagnosing PCNS-PTLD is often challenging based solely on computed tomography, magnetic resonance imaging, and physical findings; therefore, direct biopsy of the lesion is usually necessary to make a definitive diagnosis. The optimal therapy for PCNS-PTLD remains unknown. Dose reduction or discontinuation of immunosuppressive agents is effective for approximately half of PTLD patients, but not for most patients with PCNS-PTLD. It has been noted that CNS involvement is a poor prognostic factor, but early diagnosis and initiation of chemotherapy or radiotherapy seem critical for maximizing the likelihood of a favorable outcome. PMID:25082316
Wilberger, Adam C; Prayson, Richard A
We report a 61-year-old man with intracranial multiple myeloma (MM) presenting as a posttransplant lymphoproliferative disorder (PTLD) following a kidney transplant. Two months after his transplant, the man developed acute rejection with Epstein-Barr virus (EBV) viremia, requiring aggressive immunosuppression. Twenty months following transplantation, the patient presented with multiple neurologic deficits. Imaging revealed numerous lytic lesions in the skull, most conspicuously a 4.1cm right frontal skull mass with prominent intracranial extension. Histologic sections of the frontal bone lesion showed sheets of atypical plasma cells that were positive for CD138 and kappa immunoglobulin light chains. Chromogenic in situ hybridization for EBV-encoded small RNA was also positive. Plasma cell neoplasms, either as MM or a plasmacytoma, are one of the least common forms of PTLD, and their rarity limits the possibility of major studies to detail their behavior. Most often seen after renal transplantation, the majority are EBV-driven, similarly to other PTLD. While studies have demonstrated several risk factors, behavior and optimal management of PTLD plasma cell neoplasms are unknown. Plasma cell neoplasms affect the nervous system in a variety of ways but rarely via intracranial disease. MM usually presents initially with several classic signs and symptoms, but our patient's presentation was typical of a localized brain tumor with generalized and focal gross neurologic defects. PMID:26375326
Spence-Shishido, Allyson; Streicher, Jenna L; George, Roshan P; Parker, Sareeta R; Lawley, Leslie P
Posttransplant lymphoproliferative disorder (PTLD) is a known complication of solid organ transplantation. The majority are B cell in origin and related to Epstein-Barr virus infection. T-cell PTLD is much less common; most are Epstein-Barr virus negative and have a worse prognosis. Primary cutaneous T-cell lymphoma (CTCL) as a presentation of PTLD is rare. CTCL has a less favorable prognosis in transplant patients compared with that in immune-competent patients. Herein, we report a case of a 13-year-old boy who developed folliculotropic mycosis fungoides, a rare subtype of CTCL, subsequent to renal transplantation. To our knowledge, this is the first report of this type of PTLD in a pediatric patient. PMID:26283779
P. S. Randhawa; A. Zeevi; C. Alvares; S. Gollin; R. Agostini; E. Yunis; S. Saidman; L. Contis; A. J. Demetris; M. A. Nalesnik
Summary A B-cell line was established from the liver of an 11-yr-old boy with Epstein-Barr virus (EBV)-associated post-transplant\\u000a lymphoproliferative disease (PTLD). The cells were morphologically heterogenous, CD10 (CALLA) negative, and expressed several\\u000a B-cell antigens, including CD23, in a manner reminiscent of lymphoblastoid cell lines (LCLs) reported in the literature. However,\\u000a the cells also showed expression of the CD77 antigen, carried a
Piccin, Andrea; Morello, Enrico; Svaldi, Mirija; Haferlach, Torsten; Facchetti, Fabio; Negri, Giovanni; Vecchiato, Cinzia; Fisogni, Simona; Pusceddu, Irene; Cortelazzo, Sergio
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
Gonzalez-Cuyar, Luis F; Tavora, Fabio; Burke, Allen P; Gocke, Christopher D; Zimrin, Ann; Sauk, John J; Zhao, Xiafeng F
Background Post-transplant lymphoproliferative disorder (PTLD) is a spectrum of hematological diseases arising in context of immunosuppression after organ transplantation. PTLD can involve any organ; however, it is extremely rare in oral cavity. Methods Using morphologic and immunophenotypic approaches we have studied a case of monomorphic PTLD of the tongue that developed in a patient following unilateral kidney and pancreas transplantation on immunosuppressive therapy. Additionally, cases of PTLD in the oral cavity were reviewed in the English literature. Results The neoplasm showed large cell morphology and B-cell phenotype. In situ hybridization for Epstein-Barr virus was positive. Complete remission was obtained after decreasing immunosuppressive therapy. The patient remained in remission at 790 days' follow up. Conclusion This rare case increased our awareness of PTLD in the oral cavity of patients following solid organ transplantation and immunosuppressive therapy. PMID:18093326
Current preventive strategies and management of Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplantation in Europe. Results of the ESGICH Questionnaire-based Cross-sectional Survey.
San-Juan, R; Manuel, O; Hirsch, H H; Fernández-Ruiz, M; López-Medrano, F; Comoli, P; Caillard, S; Grossi, P; Aguado, J M
There is limited clinical evidence on the utility of the monitoring of Epstein-Barr virus (EBV) DNAemia in the pre-emptive management of post-transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients. We investigated current preventive measures against EBV-related PTLD through a web-based questionnaire sent to 669 SOT programmes in 35 European countries. This study was performed on behalf of the ESGICH study group from the European Society of Clinical Microbiology and Infectious Diseases. A total of 71 SOT programmes from 15 European countries participated in the study. EBV serostatus of the recipient is routinely obtained in 69/71 centres (97%) and 64 (90%) have access to EBV DNAemia assays. EBV monitoring is routinely used in 85.9% of the programmes and 77.4% reported performing pre-emptive treatment for patients with significant EBV DNAemia levels. Pre-emptive treatment for EBV DNAemia included reduction of immunosuppression in 50.9%, switch to mammalian target of rapamycin inhibitors in 30.9%, and use of rituximab in 14.5% of programmes. Imaging by whole-body 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) is used in 60.9% of centres to rule out PTLD and complemented computer tomography is used in 50%. In 10.9% of centres, FDG-PET is included in the first-line diagnostic workup in patients with high-risk EBV DNAemia. Despite the lack of definitive evidence, EBV load measurements are frequently used in Europe to guide diagnostic workup and pre-emptive reduction of immunosuppression. We need prospective and controlled studies to define the impact of EBV monitoring in reducing the risk of PTLD in SOT recipients. PMID:25686696
Joo, Sun Hyung; Acun, Zeki; Stefanovic, Alexandra; Blieden, Clifford R; Ikpatt, Offiong F; Moon, Jang
Intestinal obstruction after liver transplant is a rare complication, with diverse clinical manifestations. Intestinal adhesion is the most common cause. However, internal hernia, abdominal wall hernia, and neoplasm are also reported. Intussusception is another rare cause of intestinal obstruction, which has been reported primarily in pediatric patients. Herein, we report a case of intestinal obstruction from intussusception in an adult liver transplant patient associated with post-transplant lymphoproliferative disorder. PMID:22324047
Kruel, Cleber R.; Shiller, S. Michelle; Anthony, Tiffany L.; Goldstein, Robert M.; Kim, Peter T. W.; Levy, Marlon F.; McKenna, Gregory J.; Onaca, Nicholas; Testa, Giuliano; Klintmalm, Goran B.
Posttransplant lymphoproliferative disorder (PTLD) is a well-known complication associated with the transplant recipient. We chronicle a case of PTLD in a failed graft presenting as a small bowel obstruction in a pancreas-only transplant patient. While typical symptoms may be elusive in the complex immunosuppressed patient, graft pain along with persistent graft pancreatitis and a positive Epstein-Barr viremia should raise suspicion for an underlying PTLD. PMID:25484508
Ghigna, Maria-Rosa; Reineke, Tanja; Rincé, Patricia; Schüffler, Peter; El Mchichi, Bouchra; Fabre, Monique; Jacquemin, Emmanuel; Durrbach, Antoine; Samuel, Didier; Joab, Irène; Guettier, Catherine; Lucioni, Marco; Paulli, Marco; Tinguely, Marianne; Raphael, Martine
Posttransplant lymphoproliferative disorders (PTLD) represent a spectrum of lymphoid diseases complicating the clinical course of transplant recipients. Most PTLD are Epstein-Barr virus (EBV) associated with viral latency type III. Several in vitro studies have revealed an interaction between EBV latency proteins and molecules of the apoptosis pathway. Data on human PTLD regarding an association between Bcl-2 family proteins and EBV are scarce. We analyzed 60 primary PTLD for expression of 8 anti- (Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic proteins (Bak and Bax), the so-called BH3-only proteins (Bad, Bid, Bim, and Puma), as well as the apoptosis effector cleaved PARP by immunohistochemistry. Bim and cleaved PARP were both significantly (p = 0.001 and p = 5.251e-6) downregulated in EBV-positive compared to EBV-negative PTLD [Bim: 6/40 (15%), cleaved PARP: 10/43 (23%), vs. Bim: 13/16 (81%), cleaved PARP: 12/17 (71%)]. Additionally, we observed a tendency toward increased Bcl-2 protein expression (p = 0.24) in EBV-positive PTLD. Hence, we provide evidence of a distinct regulation of Bcl-2 family proteins in EBV-positive versus negative PTLD. The low-expression pattern of the proapoptotic proteins Bim and cleaved PARP together with the high-expression pattern of the antiapoptotic protein Bcl-2 by trend in EBV-positive tumor cells suggests disruption of the apoptotic pathway by EBV in PTLD, promoting survival signals in the host cells. PMID:22868923
Patrick, A; Wee, A; Hedderman, A; Wilson, D; Weiss, J; Govani, M
Primary central nervous system (CNS) posttransplant lymphoproliferative disorder (PTLD) is a well-recognized but rare complication of solid organ transplantation. Most of these disorders are B-cell in origin and generally carry poor prognosis. Rituximab, an anti-CD20 monoclonal antibody, has been used effectively in patients with systemic PTLD. However, its role in primary CNS PTLD is doubtful because it does not cross blood-brain barrier efficiently (<5%). Also, mechanisms, by which rituximab operates are not optimally effective in CNS. Here, we describe a renal transplant patient with monomorphic, multifocal, CD20-positive, primary B-cell CNS PTLD, who was treated with high-dose intravenous rituximab given in dose-escalation protocol, which has been used effectively for the patients with chronic lymphocytic leukemia. At 1-year follow-up, magnetic resonance imaging (MRI) showed complete resolution. High-dose rituximab may have a role in highly selected patients with primary CNS PTLD. PMID:20872273
Hart, Melissa; Thakral, Beenu; Yohe, Sophia; Balfour, Henry H; Singh, Charanjeet; Spears, Michael; McKenna, Robert W
Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBV MCU) is a B-cell lymphoproliferative disorder occurring in elderly or iatrogenic immunocompromised patients. It has not been reported in solid organ transplant recipients. We observed 7 patients with EBV MCU in a cohort of 70 transplant recipients with EBV posttransplant lymphoproliferative disorder (PTLD). Transplants included: 5 renal, 1 heart, and 1 lung. Median patient age was 61; 5 were male. EBV MCU was observed in oral mucosa in 4 and gastrointestinal tract in 3. Duration of immunosuppressive therapy before EBV MCU was 0.6 to 13 years. Ulcers were undermined by inflammatory cells and polymorphic or monomorphic large cell lymphoproliferation. Reed-Sternberg-like cells were present in 5/7. Large B cells were CD20, CD30, and EBV-encoded RNA positive in all cases. Diagnosis in 3 recent patients was EBV MCU; 4 patients diagnosed before familiarity with EBV MCU were classified as monomorphic large cell (n=3) and polymorphic (n=1) PTLD. None of the patients had EBV DNA in their blood (<1000 copies/mL) at diagnosis or follow-up versus 35/44 transplant patients with systemic PTLD (P<0.001). All lesions resolved with reduced immunosuppression (7/7), change in immunosuppression (2/7), and rituximab (3/7). Five patients are living: 4 healthy, 1 awaiting second renal transplant. Two patients died 3 and 5 years after resolution of EBV MCU. No patient recurred with EBV MCU or other PTLDs. EBV MCU mimics more aggressive categories of PTLD but lacks EBV DNA in blood, which may be a useful distinguishing feature. Lesions are likely to resolve with conservative management. Awareness of EBV MCU in the posttransplant setting is necessary for appropriate diagnosis and treatment. PMID:25007145
Lager, D J; Burgart, L J; Slagel, D D
Sequential formalin-fixed, paraffin-embedded tissue biopsies from 10 patients with a posttransplant lymphoproliferative disorder (PTLD) were evaluated retrospectively for the presence of Epstein-Barr virus (EBV) DNA using the polymerase chain reaction (PCR). The patients included seven renal and two liver allograft recipients and one renal and cardiac allograft recipient. Sequential biopsies were available on every patient and pre-transplant biopsies in six patients. The EBV primers used amplify a 245-bp fragment of the EBV IR3 sequence and were run in parallel with human beta-globin gene primers. Nine patients (90%) had EBV detected during their posttransplant course: three at the time of diagnosis of the PTLD, and six from 15 to 121 days prior to diagnosis. Sites of presentation of the PTLD included liver (four), brain (two), native kidney (one), renal allograft (one), lymph node (one), and lung (one). Three patients died 61, 56, and 30 days posttransplantation, fourth at 198 days, and a fifth patient at 2 yr. All had clinical or histologic evidence of residual PTLD. In contrast, EBV DNA was detected in tissue from two of 29 "healthy" renal allograft recipients examined 2 to 16 mo posttransplantation. None of these patients has clinical evidence of a PTLD. We conclude that allograft biopsies provide a substrate for early detection of EBV by PCR, particularly when an atypical lymphoid infiltrate is encountered by light microscopy. PMID:8381232
Petrara, Maria Raffaella; Giunco, Silvia; Serraino, Diego; Dolcetti, Riccardo; De Rossi, Anita
Post-transplant lymphoproliferative disorders (PTLDs) represent the most severe complication of both solid organ and hematopoietic stem cell transplantation. The Epstein-Barr Virus (EBV) is the main driver of PTLD, particularly those occurring early after transplantation. EBV-driven malignancies are associated with selective expression of latent viral proteins, but uncontrolled lytic replication may favor early phases of cell transformation. Besides immunodepression, persistent immune activation and chronic inflammation play an important role in both virus reactivation and expansion of EBV-infected B cells. EBV-induced immortalization requires the expression of telomerase. TERT, the rate-limiting component of the telomerase complex, is central in the switch from the lytic to the latent viral program, and TERT inhibition induces the EBV lytic cycle and cell death. Immunotherapy and combination of EBV lytic cycle inducers with antiviral drugs are promising strategies to improve the treatment of PTLD patients. This review is aimed at providing an update on the intriguing association between EBV and PTLD, mainly focusing on cases arising after kidney and liver transplantation, which account for the vast majority of transplants. PMID:26279520
Matar, Abraham J; Patil, Aarti R; Al-Musa, Ahmad; Hanekamp, Isabel; Sachs, David H; Huang, Christene A; Duran-Struuck, Raimon
Post-transplant lymphoproliferative disease (PTLD) is a major complication of clinical organ and cell transplantation. Conditioning and immunosuppressive regimens that significantly impair T cell immunity, including depleting antibodies and calcineurin inhibitors, increase the risk of PTLD after transplantation. Swine PTLD has been shown to closely resemble human PTLD in morphology, histology, and viral-driven reactivation of B cells. Previously, we reported high incidences of PTLD after hematopoietic cell transplantation (HCT) in miniature swine recipients conditioned with thymic irradiation (TI) in addition to T cell depletion and cyclosporine A monotherapy after transplantation. Replacement of TI with 100 cGy of total body irradiation resulted in similar numbers of B cells early post-transplantation, greater numbers of T cells at day 0, and markedly decreased incidence of PTLD, suggesting that a threshold number of T cells may be necessary to prevent subsequent B cell proliferation and development of overt PTLD. Results from this large cohort of animals provide insight into the important effect of irradiation and T cell immunity on the incidence of PTLD after HCT and reinforce the pig model as a valuable tool for the study of PTLD and HCT. PMID:26210443
Panagiotidis, Emmanouil; Quigley, Ann-Marie; Pencharz, Deborah; Ardeshna, Kirit; Syed, Rizwan; Sajjan, Rakesh; Bomanji, Jamshed
The aim of the present study was to investigate the role of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in the diagnosis of post-transplant lymphoproliferative disorder (PTLD), a serious complication of solid organ and bone marrow transplant. Between January 2004 and January 2012, 40 patients (22 males; median age 52 ± 17.4 years, range 11-77 years) underwent (18)F-FDG PET/CT scans in our department for diagnostic evaluation of PTLD. Twenty-three (57.5%) patients had negative (18)F-FDG PET/CT and 17 (42.5%) had a positive examination. In five patients PET/CT revealed extranodal disease (adrenal, pleural, spleen, liver, lung, esophagus and bone involvement). On the basis of our results, (18)F-FDG PET/CT had a sensitivity of 88.2% (95% confidence interval [CI] 0.62-0.98), a specificity of 91.3% (CI 0.70-0.98), a positive predictive value of 88.2% (CI 0.62-0.98) and a negative predictive value of 91.3% (CI 0.70-0.98). The diagnostic performance of CT in patient-based analysis was: a sensitivity of 87.5% (CI 0.60-0.97), a specificity of 88.8% (CI 0.64-0.98), a positive predictive value of 87.5% (CI 0.60-0.97) and a negative predictive value of 88.8% (CI 0.64-0.98). PET/CT in five cases revealed more findings than CT, upstaging the disease, and revealed three extranodal findings, not visualized in conventional imaging. (18)F-FDG PET/CT plays a significant role in the setting of PTLD diagnosis, demonstrating its high accuracy in detecting PTLD. PMID:23772644
Tepeo?lu, Merih; At?lgan, Alev Ok; Ozdemir, B Handan; Haberal, Mehmet
Inflammatory myofibroblastic tumor is a rare benign lesion found mostly in children and young adults. It originates from the lung, abdominopelvic region, and retroperitoneum. The tumor is composed of myofibroblasts and inflammatory cell infiltration in the tissue. The cause and pathogenesis of this tumor are not completely understood. Epstein-Barr virus has been held responsible in some reported cases of inflammatory myofibroblastic tumors. Another tumor (which is known to be related to the Epstein-Barr virus) is posttransplant lymphoproliferative disorder. We report the case of a 2-year-old boy who underwent a liver transplant at the age of 9 months (the donor was his mother) because of biliary atresia. At 11 months after transplant, we detected posttransplant lymphoproliferative disorder and inflammatory myofibroblastic tumor concurrently. This entity is presented to highlight possible Epstein-Barr virus involvement in inflammatory myofibroblastic tumor of lung. PMID:25184247
Epstein-Barr virus (EBV) is a ubiquitous human gamma-herpes virus that establishes a life-long asymptomatic infection in immunocompetent hosts by colonizing memory B lymphocytes and hijacking cellular signaling pathways that regulate antigen-dependent B-cell activation and differentiation. In patients with solid organ or hematopoietic stem cell transplantation, the defect in EBV-specific immune responses may allow the outgrowth of EBV-carrying B lymphocytes that may give rise to a spectrum of different clinico-pathologic entities encompassed by the term post-transplantation lymphoproliferative disorders (PTLD). EBV-driven immortalization of B-cells is mediated by the cooperative activity of viral proteins that derange critical cellular pathways controlling growth and/or survival of B lymphocytes. Full transformation of infected B-cells is achieved by the contribution of poorly defined additional co-factors, including microenvironmental stimuli, genetic and epigenetic alterations. The quantification of circulating EBV DNA and EBV-specific T cells are valuable tools in the clinical monitoring of EBV-associated PTLD. The recent advances in elucidation of the mechanisms underlying EBV-induced growth transformation will be instrumental in guiding the design of novel approaches for the treatment of these often life-threatening lymphoproliferative disorders. PMID:18035317
Khedmat, Hossein; Ghamar-Chehreh, Mohammad Ebrahim; Amini, Mohsen; Agah, Shahram; Taheri, Saeed
Gastric localization of post-transplant lymphoproliferative disorders (PTLDs) is very rare. In this study, we aimed to accumulate existing data in the current literature to reveal the clinical, histopathological and prognostic specificities associated with gastric PTLDs and to find the best treatment strategies in this patient population. A comprehensive search was conducted for the available data in the current literature using Pubmed and Google scholar search engines for reports on gastric PTLD in renal transplant recipients. Data of different studies were standardized and entered into a database and analyzed. No statistically significant difference was found between gastric and non-gastric PTLD. Gastric PTLD was relatively more prevalent in female patients (P = 0.08) and showed a trend toward better outcome (P = 0.1) and less metastasis (P = 0.07). Surgical intervention and rituximab therapy were associated with a more favorable outcome (17% mortality). Our study showed that organ transplant recipients having gastric PTLD develop metastasis less frequently and tend to have a relatively more favorable outcome. Prospective studies with larger patient populations are needed to confirm or modify our results. PMID:24626003
Yoon, Ga Young; Kim, Mi Young; Huh, Joo Rryung; Jo, Kyung-Wook; Shim, Tae Sun
To investigate the chest computed tomography (CT) and F-18 fluoro-2-deoxy-D-glucose positron emission tomographic (FDG-PET) findings of posttransplant lymphoproliferative disorder (PTLD) in the thorax.From November 2004 to February 2013, the cases of 12 adult patients (3 female and 9 male, age range 34-68, and median age 46 years) with proven PTLD were retrospectively reviewed. The transplanted organs included the kidney (5/12), liver (4/12), heart (1/12), combined kidney and pancreas (1/12), and hematopoietic stem cell (1/12). We investigated the relationship of the Epstein-Barr virus (EBV) to the patients' long-term follow-up, and evaluated the characteristics of the lesions on the chest CT and FDG-PET. The lesions were classified into 2 patterns: that of lymph node and lung involvement.The interval between the transplantation and the onset of PTLD was 2 to 128 months (median, 49). Positive EBV-encoded RNA in the pathologic specimens was found in 10 patients (83.3%). Eight patients were positive for EBV PCR in their blood, and 3 patients showed seroconversion without antiviral therapy. The responses to treatment were complete in 7 cases (58.3%), partial remission in 4 cases (33.3%), and undetermined in 1 case (8.3%). The more common chest CT patterns showed lymph node involvement (10/12) rather than lung involvement (3/12). The median maximum-standardized uptake value on the FDG-PET scans was 7.7 (range, 2.7-25.5).In patients with PTLD involving the thorax, lymphadenopathy was the more common manifestation on the chest CT rather than lung involvement. The lesions showed hypermetabolism on FDG-PET. PMID:26252295
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 ...
Mahapatra, Sidharth; Chin, Clifford C; Iagaru, Andrei; Heerema-McKenney, Amy; Twist, Clare J
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
Khedmat, Hossein; Karbasi-Afshar, Reza; Agah, Shahram; Ghamar-Chehreh, Mohammad Ebrahim; Amini, Mohsen
Epstein-Barr virus (EBV) encodes two non-polyadenylated RNAs termed EBV-encoded RNAs (EBERs). In this study, we tried to find series in which data of EBER and onset time of post-transplant lymphoproliferative disorder (PTLD) for patients have been documented to conduct a meta-analysis. A comprehensive search of the literature was performed by Pubmed and Google scholar to find reports indicating test results for EBER and PTLD onset in transplant patients. PTLD was considered "early onset" when it develops within the first post-transplant year. Finally, 265 patients from 15 studies have been included in the meta-analysis. The overall meta-analysis also showed a significant relation between EBER test positivity and early-onset PTLD development [relative risk (RR): 1.36; 95% CI: 1.16-1.59; P <0.001]. The i2 index was 49.8%. Our study suggests that PTLD lesions with positive EBER test are more likely to develop within the early post-transplant period. Since early-onset PTLD is supposed to have better prognosis, having a positive EBER test might not be a bad news. However, for having a precise conclusion, prospective studies are needed to be conducted. PMID:25758868
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...
Krasuska-S?awi?ska, Ewa; Minko-Chojnowska, Izabela; Paw?owska, Joanna; Dembowska-Bagi?ska, Bo?enna; Pronicki, Maciej; Olczak-Kowalczyk, Dorota
BACKGROUND Post-transplant lymphoproliferative disorder (PTLD) is a potential complication of solid organ or bone marrow transplants. The main PTLD risk factors are: the Epstein-Barr virus (EBV), transplant type, and use of immunosuppressants. It mainly consists of an uncontrolled growth of lymphocytes in transplant recipients under chronic immunosuppressive therapy. About 85% of PTLDs are EBV-containing B-cell proliferations; 14% are T-cell proliferations, of which only 40% contain EBV; and the remaining 1% is NK-cell or plasmocyte proliferations. PTLD may present various clinical manifestations, from non-specific mononucleosis-like syndrome to graft or other organ damage resulting from pathologic lymphocyte infiltration. PTLD may manifest in the oral cavity. CASE REPORT The objective of this study was to present the case of a 13-year-old female living-donor liver transplant recipient, resulting from biliary cirrhosis caused by congenital biliary atresia, with exophytic fibrous lesions on buccal mucosa and tongue. Exophytic and hyperplastic lesion of oral mucosa were removed and histopathological examination revealed polymorphic PTLD. The patient underwent 6 cycles of CHOP chemotherapy and all the oral lesions regressed completely. CONCLUSIONS All oral pathological lesions in organ transplant recipients need to be surgically removed and histopathologically examined because they present an increased risk of neoplastic transformations such as PTLD. PMID:26285106
Toscano, G; Fabozzo, A; Fedrigo, M; Gambino, A; Angelini, A; Gerosa, G
Post-transplant lymphoproliferative disorders (PTLDs) are considered a fatal consequence of immunosuppression. We report a case of a 52-year-old patient, who underwent a cardiac transplantation and presented undefined recurrent episodes of pleuropericardial effusions without lymphoadenomegaly at chest radiographs and computed tomography. Histopathological analysis of the bioptic pericardium showed a specific chronic inflammation. Monitoring endomyocardial biopsies (EMBs) showed only 1 episodes of greater than grade 2R acute cellular rejection requiring immunosuppressive treatment, mild vasculitis in 2 subsequently EMBs while constantly negative for antibody-mediated rejection or infection. Only a post-mortem examination demonstrated the presence of an aggressive acute non-Epstein-Barr virus (EBV)-related proliferative disorder with unusual primitive localization into the pericardium and with coronary epicardial and intramyocardial necrotizing vasculitis and superimposed occlusive and subocclusive thrombosis. Recurrence of unexplained early pleuropericardial effusion and mild intramyocardial vasculitis should raise the suspicion of PTLD requiring reduction of immunosuppression, even in the setting of negative intramyocardial cellular infiltrate and tissue EBV-negative molecular assessment. PMID:26361701
Linnerbauer, Stefanie; Behrends, Uta; Adhikary, Dinesh; Witter, Klaus; Bornkamm, Georg W.; Mautner, Josef
Polyclonal Epstein-Barr virus (EBV)-infected B cell line (lymphoblastoid cell lines; LCL)-stimulated T-cell preparations have been successfully used to treat EBV-positive post-transplant lymphoproliferative disorders (PTLD) in transplant recipients, but function and specificity of the CD4+ component are still poorly defined. Here, we assessed the tumor-protective potential of different CD4+ T-cell specificities in a PTLD-SCID mouse model. Injection of different virus-specific CD4+ T-cell clones showed that single specificities were capable of prolonging mouse survival and that the degree of tumor protection directly correlated with recognition of target cells in vitro. Surprisingly, some CD4+ T-cell clones promoted tumor development, suggesting that besides antigen recognition, still elusive functional differences exist among virus-specific T cells. Of several EBV-specific CD4+ T-cell clones tested, those directed against virion antigens proved most tumor-protective. However, enriching these specificities in LCL-stimulated preparations conferred no additional survival benefit. Instead, CD4+ T cells specific for unknown, probably self-antigens were identified as principal antitumoral effectors in LCL-stimulated T-cell lines. These results indicate that virion and still unidentified cellular antigens are crucial targets of the CD4+ T-cell response in this preclinical PTLD-model and that enriching the corresponding T-cell specificities in therapeutic preparations may enhance their clinical efficacy. Moreover, the expression in several EBV-negative B-cell lymphoma cell lines implies that these putative autoantigen(s) might also qualify as targets for T-cell-based immunotherapy of virus-negative B cell malignancies. PMID:24853673
Arkwright, P D; Makin, G; Will, A M; Ayres, M; Gokhale, D A; Fergusson, W D; Taylor, G M
X linked lymphoproliferative disease (XLP; Duncan's disease) is a rare disorder affecting boys and characterised by a defective immune response to Epstein-Barr virus caused by a mutation in a gene located at chromosome Xq25. Three siblings with XLP in a single UK family are reported and the variation in phenotypic expression of the disease in these siblings described. One of the siblings with life threatening fulminant infectious mononucleosis was successfully treated by chemotherapy, followed by bone marrow transplantation using an unaffected brother as the donor. A healthy baby boy recently born into the family was identified as carrying the defective maternal X chromosome using molecular genetic linkage analysis. This family illustrates the extent of present understanding of this often fatal condition. PMID:9771253
EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era.
Fox, C P; Burns, D; Parker, A N; Peggs, K S; Harvey, C M; Natarajan, S; Marks, D I; Jackson, B; Chakupurakal, G; Dennis, M; Lim, Z; Cook, G; Carpenter, B; Pettitt, A R; Mathew, S; Connelly-Smith, L; Yin, J A L; Viskaduraki, M; Chakraverty, R; Orchard, K; Shaw, B E; Byrne, J L; Brookes, C; Craddock, C F; Chaganti, S
EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based allo-SCT is a relatively uncommon and challenging clinical problem but has not received detailed study in a large cohort. Quantitative-PCR (qPCR) monitoring for EBV reactivation post allo-SCT is now commonplace but its diagnostic and predictive value remains unclear. Sixty-nine patients with PTLD following Alemtuzumab-based allo-SCT were studied. Marked clinicopathological heterogeneity was evident; lymphadenopathy was frequently absent, whereas advanced extranodal disease was common. The median viral load at clinical presentation was 49?300 copies/mL (50-65?200?000 copies/mL) and, notably, 23% and 45% of cases, respectively, had ?10?000 and ?40?000 copies/mL. The overall response rate to rituximab as first-line therapy was 70%. For rituximab failures, chemotherapy was ineffectual but DLIs were successful. A four-parameter prognostic index predicted response to therapy (OR 0.30 (0.12-0.74); P=0.009] and PTLD mortality (hazard ratio (HR) 1.81 (1.12-2.93) P=0.02) on multivariate analysis. This is the largest detailed series of EBV-associated PTLD after allo-SCT. At clinical presentation, EBV-qPCR values are frequently below customary thresholds for pre-emptive therapy, challenging current paradigms for monitoring and intervention. A four-point score identifies a proportion of patients at risk of rituximab-refractory disease for whom alternative therapy is needed. PMID:24212561
Maia, D M; Garwacki, C P
X-linked lymphoproliferative disease (XLP) is a rare familial disorder resulting in selective immunodeficiency to the Epstein-Barr virus (EBV), characterized by uncontrolled proliferation of EBV-infected lymphocytes. Phenotypes of this disease are variable and include fulminant infectious mononucleosis, hypogammaglobulinemia, and malignant lymphoma. In this article, we describe a case of a previously healthy 4-year-old boy with serologic evidence of acute EBV infection who died of fulminant hepatic failure. Histopathological examination of tissue obtained postmortem showed hemophagocytosis and prominent polymorphous infiltrates associated with necrosis in the liver, spleen, and lymph nodes. Semiquantitative polymerase chain reaction (PCR) utilizing primers complementary to the EBV gene LMP2a performed on samples of liver tissue demonstrated approximately 0.6 copies of the EBV gene per cell. Immunohistochemistry demonstrated light chain restriction and PCR studies of the immunoglobulin V-D-J region revealed two strong bands, consistent with a clonal B cell proliferation. Extended family history revealed that the boy's family was followed by the XLP Registry, which was established in 1978 to follow kindreds with XLP. The genetic abnormality associated with XLP has been localized to the Xq25, allowing RFLP analysis to identify female carriers and affected boys. PMID:9841710
Rougemont, Anne-Laure; Fournet, Jean-Christophe; Martin, Steven R; de Saint-Basile, Geneviève; Latour, Sylvain; Primeau, Marie-Noël; Rubbia-Brandt, Laura; Haddad, Elie; Le Deist, Françoise
Gastric lesions in primary constitutive immune deficiencies include multifocal atrophic gastritis, erosive pangastritis, and a pattern of gastric lesions reminiscent of graft-versus-host disease. We describe the genetic anomalies in 2 monozygotic twins with an X-linked lymphoproliferative disease (XLP; MIM 308240), a rare familial setting of high susceptibility to Epstein-Barr virus (EBV). Since early childhood, both twin brothers exhibited a severe chronic active atrophic pangastritis. A germline screening of the SH2D1A (MIM 300490) and BIRC4 (MIM 300079) genes was performed, and also a high-resolution whole-genome SNP profiling (Infinium Sentrix Human-1 Genotyping BeadChip, Illumina). A 3 Megabase deletion in the Xq25 region, encompassing the SH2D1A gene, was defined by SNP array genotyping. Histologic analysis of yearly or twice yearly gastric biopsies in both children showed a Helicobacter pylori-negative, Epstein-Barr virus-negative chronic active atrophic pangastritis, with superficial ulcer formation, foveolar hyperplasia, glandular dilatation and ultimately pseudopyloric and intestinal metaplasia. No such chronic active inflammatory gastric lesions have been reported to date in XLP. The similarities between XLP and common variable immunodeficiency (MIM 240500) underscore the need for early recognition and close monitoring of these gastric lesions, with special regard to their neoplastic potential. No infectious cause was determined. We favor a dysimmune mechanism in the development of this chronic atrophic gastritis, presenting a striking similarity to the recently described atrophic autoimmune pangastritis. PMID:18223336
... most humans. In some people it causes infectious mononucleosis (commonly known as "mono"). Normally, after initial infection, ... susceptibility to EBV infection severe susceptibility to infectious mononucleosis X-linked lymphoproliferative syndrome For more information about ...
Booth, Claire; Gilmour, Kimberly C.; Veys, Paul; Gennery, Andrew R.; Slatter, Mary A.; Chapel, Helen; Heath, Paul T.; Steward, Colin G.; Smith, Owen; O'Meara, Anna; Kerrigan, Hilary; Mahlaoui, Nizar; Cavazzana-Calvo, Marina; Fischer, Alain; Moshous, Despina; Blanche, Stephane; Pachlopnick-Schmid, Jana; Latour, Sylvain; de Saint-Basile, Genevieve; Albert, Michael; Notheis, Gundula; Rieber, Nikolaus; Strahm, Brigitte; Ritterbusch, Henrike; Lankester, Arjan; Hartwig, Nico G.; Meyts, Isabelle; Plebani, Alessandro; Soresina, Annarosa; Finocchi, Andrea; Pignata, Claudio; Cirillo, Emilia; Bonanomi, Sonia; Peters, Christina; Kalwak, Krzysztof; Pasic, Srdjan; Sedlacek, Petr; Jazbec, Janez; Kanegane, Hirokazu; Nichols, Kim E.; Hanson, I. Celine; Kapoor, Neena; Haddad, Elie; Cowan, Morton; Choo, Sharon; Smart, Joanne; Arkwright, Peter D.
X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression. PMID:20926771
Lemaire, Anne-Sophie; Daussay, Dorothée; Bouchindhomme, Brigitte; Grardel, Nathalie; Botte, Astrid; Copin, Marie-Christine
Systemic EBV+ T-cell lymphoproliferative disease of childhood is a recent entity described in the 2008 World Health Organisation tumours of haematopoietic system and lymphoid tissues as a clonal T-cell EBV+ systemic proliferation. It occurs after acute or chronic active EBV infection. We report the case of a caucasian, immunocompetent 12-year-old girl, with no particular history, who presented with hemophagocytic lymphohistiocytosis in the aftermath of an infectious mononucleosis. Main symptoms were multiple organ failure, hepatosplenomegaly and pancytopenia. Histopathology of peripheral lymph node and bone marrow revealed a T-cell, CD8+, EBV+ lymphoproliferation. An elevated viral load was detected in blood by PCR. The patient died within 3 weeks. Since most of the cases have been reported in Asia and South America, few cases still have been described in Europe. Unlike B-cell lymphoproliferation in immunocompromised individuals, T-cell EBV+ lymphoproliferation occurs in immunocompetent patients and seems to be the consequence of a proliferative disorder of EBV-infected T-cells, attributed to a cytotoxic T-cell response deficiency. These T-cell proliferations are more frequently immunoreactive for CD8 than CD4. A key feature of the diagnosis might be EBV viral load. PMID:25132446
Ria, Roberto; Reale, Antonia; Moschetta, Michele; Dammacco, Franco; Vacca, Angelo
Background Chemotherapy-induced neutropenia is a major cause of morbidity and mortality. It frequently causes dose reductions or treatment delay, which can be prevented or treated by the administration of granulocyte-colony-stimulating factor (G-CSF). However, a better knowledge of the incidence, day of onset after therapy, and duration of neutropenia is essential to optimize the use of G-CSF. Design and methods Six hundred and ninety-four patients from a single institution, affected by lympho-proliferative diseases, were retrospectively reviewed for the occurrence of grade 4 neutropenia and febrile neutropenia (FN). Duration of neutropenia and time of neutrophil nadir were also retrieved. The diagnoses included non-Hodgkin's lymphoma, Hodgkin's lymphoma, and multiple myeloma. Chemotherapy regimens were obviously different according to the diagnosis, disease stage, and first or subsequent lines of therapy. Results No patient received G-CSF as primary prophylaxis. Median nadir did not significantly differ among patients treated with first or successive lines of therapy. The incidence of grade 4 neutropenia and FN ranged from 0 to 94%, depending on the chemotherapy regimen. Patients receiving a first-line chemotherapy regimen had a significantly lower incidence of febrile grade 4 neutropenia compared to patients treated with a second or subsequent line of therapy. The duration of grade 4 neutropenia was significantly longer in patients given second or subsequent lines. Conclusion The results of this study could be useful to define the nadir onset in the hematologic setting in order to correctly tailor timing and duration of G-CSF prophylaxis and to assess the lowest fully effective dose. PMID:23321273
Dunphy, Cherie H; Galambos, Csaba; Polski, Jacek M; Evans, H Lance; Gardner, Laura J; Grosso, Leonard E; Montone, Kathleen T
Posttransplant lymphoproliferative disorders (PTLDs) represent a morphologic, immunophenotypic, and genotypic spectrum of disease. Most recently, Knowles et al divided PTLDs into 3 distinct categories: (1) plasmacytic hyperplasia, (2) polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma, and (3) immunoblastic lymphoma and multiple myeloma. Although one form of PTLD may progress to another form, only 1 previous case has been reported in which multiple myeloma developed 14 months after an original diagnosis of plasmacytic hyperplasia. The type of solid organ transplant was not specified in that case. We report a post--cardiac transplant plasmacytic hyperplasia developing 7 years posttransplant. Six years subsequent to the plasmacytic hyperplasia, the patient developed a posttransplant plasmacytic malignancy, supported by morphology, flow cytometric immunophenotyping, and genotypic studies. Since we have no data to support disseminated bony disease or an abnormal serum protein, we have not used the term "multiple myeloma" for this case. PMID:11860313
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 ...
Nabhani, Schafiq; Ginzel, Sebastian; Miskin, Hagit; Revel-Vilk, Shoshana; Harlev, Dan; Fleckenstein, Bernhard; Hönscheid, Andrea; Oommen, Prasad T; Kuhlen, Michaela; Thiele, Ralf; Laws, Hans-Jürgen; Borkhardt, Arndt; Stepensky, Polina; Fischer, Ute
Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20-30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon ? production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease. PMID:26113417
Thacore, H R; Cunningham, R K; Nakeeb, S; Zaleski, M B
Healthy, adult C57BL/6Kh mice of both sexes were transfused with blood or blood products from syngeneic donors with retrovirus (LP-BM5)-induced lymphoproliferative disease. The disease produced in the recipients 8 weeks after transfusion was characterized by splenomegaly, disseminated lymphadenopathy, leukopenia with neutrophilia, abrogation of the primary immune response to SRBC, decreased in vitro proliferation of spleen cells co-stimulated with phorbol ester and IL-2 or ionomycin and abrogation of synergistic effect of the co stimulators. Quantitative analysis of the blood or blood products used for transfusion show that a single transfusion of 0.2 ml of PBS containing 0.2 mu 1 of whole blood or 2 microliters of plasma or 400 Ficoll-isolated peripheral blood mononuclear cells was sufficient for the inducing the disease. The results suggest that the retroviruses were present in preparations of peripheral blood mononuclear cells and plasma of mice with the disease. However, the latter was 10-fold less efficient in inducing the disease. Transfusion of 1.8 x 10(6) isolated erythrocytes failed to induce the disease suggesting a marginal role, if any, in transmission of the disease via transfusion of these cells. Thus, a simple, reliable and reproducible method for propagation of the murine lymphoproliferative disease in the laboratory has been elaborated. These results also point to some important differences with regard to blood transfusion between human and murine AIDS. PMID:8926622
Vlahakos, Demetrios V; Marathias, Katerina P; Agroyannis, Basil; Madias, Nicolaos E
Posttransplant erythrocytosis (PTE) is defined as a persistently elevated hematocrit to a level greater than 51% after renal transplantation. It occurs in 10% to 15% of graft recipients and usually develops 8 to 24 months after engraftment. Spontaneous remission of established PTE is observed in one fourth of the patients within 2 years from onset, whereas in the remaining three fourths it persists for several years, only to remit after loss of renal function from rejection. Predisposing factors include male gender, retention of native kidneys, smoking, transplant renal artery stenosis, adequate erythropoiesis prior to transplantation, and rejection-free course with well-functioning renal graft. Just as in other forms of erythrocytosis, a substantial number (approximately 60%) of patients with PTE experience malaise, headache, plethora, lethargy, and dizziness. Thromboembolic events occur in 10% to 30% of the cases; 1% to 2% eventually die of associated complications. Posttransplant erythrocytosis results from the combined trophic effect of multiple and interrelated erythropoietic factors. Among them, endogenous erythropoietin appears to play the central role. Persistent erythropoietin secretion from the diseased and chronically ischemic native kidneys does not conform to the normal feedback regulation, thereby establishing a form of "tertiary hypererythropoietinemia." However, erythropoietin levels in most PTE patients still remain within the "normal range," indicating that erythrocytosis finally ensues by the contributory action of additional growth factors on erythroid progenitors, such as angiotensin II, androgens, and insulin-like growth factor 1 (IGF-1). Inactivation of the renin-angiotensin system (RAS) by an angiotensin-converting enzyme (ACE) inhibitor, or an angiotensin II type 1 AT1 receptor blocker represents the most effective, safe, and well-tolerated therapeutic modality. PMID:12631334
GOMPELS, M M; HODGES, E; LOCK, R J; ANGUS, B; WHITE, H; LARKIN, A; CHAPEL, H M; SPICKETT, G P; MISBAH, S A; SMITH, J L
We have undertaken a retrospective study of antibody deficient patients, with and without lymphoma, and assessed the ability of specific polymerase chain reaction (PCR) primers to determine if the detection of clonal lymphocyte populations correlates with clinical and immunohistochemical diagnosis of lymphoma. We identified 158 cases with antibody deficiency presenting during the past 20 years. Paraffin-embedded biopsy specimens or slides were available for analysis in a cohort of 34 patients. Of these patients, 29 had common variable immunodeficiency, one X-linked agammaglobulinaemia, one X-linked immunoglobulin deficiency of uncertain cause and three isolated IgG subclass deficiency. We have confirmed that lymphoma in antibody deficiency is predominantly B cell in origin. Clonal lymphocyte populations were demonstrated in biopsies irrespective of histology (16/19 with lymphoma and 11/15 without). Isolated evidence of clonality in biopsy material is therefore an insufficient diagnostic criterion to determine malignancy. Furthermore, our data suggest that clonal expansions are rarely the result of Epstein–Barr virus-driven disease. PMID:14616793
Allison, Andrew B; Kevin Keel, M; Philips, Jamie E; Cartoceti, Andrew N; Munk, Brandon A; Nemeth, Nicole M; Welsh, Trista I; Thomas, Jesse M; Crum, James M; Lichtenwalner, Anne B; Fadly, Aly M; Zavala, Guillermo; Holmes, Edward C; Brown, Justin D
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
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
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
Katewa, Arna; Pettersen, Ann K.; Osvath, Sarah R.; Farrell, Geoff C.; Stewart, Graeme J.; Bendall, Linda J.; Alexander, Stephen I.
To delineate the relative roles of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand in lymphocyte biology and lymphoproliferative disease, we generated mice defective in both molecules. B6.GT mice develop severe polyclonal lymphoproliferative disease because of accumulating CD3+CD4?CD8?B220+ T cells, CD4+ and CD8+ T cells, and follicular B cells, and mice die prematurely from extreme lymphocytosis, thrombocytopenia, and hemorrhage. Accumulating lymphocytes resembled antigen-experienced lymphocytes, consistent with the maximal resistance of B6.GT CD4+ and CD8+ T cell to activation-induced cell death. More specifically, we show that TRAIL contributes to Fas ligand-mediated activation-induced cell death and controls lymphocyte apoptosis in the presence of interferon-? once antigen stimulation is removed. Furthermore, dysregulated lymphocyte homeostasis results in the production of anti-DNA and rheumatoid factor autoantibodies, as well as antiplatelet IgM and IgG causing thrombocytopenia. Thus, B6.GT mice reveal new roles for TRAIL in lymphocyte homeostasis and autoimmune lymphoproliferative syndromes and are a model of spontaneous idiopathic thrombocytopenia purpura secondary to lymphoproliferative disease. PMID:20185587
Montero, Rosa M.; Olsburgh, Jonathon
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
Jinta, Minako; Imadome, Ken-Ichi; Komatsu, Honami; Yoshimori, Mayumi; Kurata, Morito; Fujiwara, Shigeyoshi; Miura, Osamu; Arai, Ayako
We investigated the effects of L-asparaginase (L-asp) on Epstein-Barr virus (EBV)-positive T/NK lymphoproliferative diseases (EBV-T/ NK-LPDs). Seven doses of L-asp (6,000 U/m2) were administered intravenously, with one dose administered on every alternate day. Five consecutive patients were enrolled. Three patients completed the treatment. The clinical symptoms resolved in 1 patient who started the administration 8 months after the onset, being the earliest among the 5 patients. Her EBV-DNA level in whole blood markedly decreased to 0.08 times of that before treatment, and the level in plasma became undetectable. In the other 2 patients whose administration was started 3 and 3.5 years after the onset, however, a remarkable improvement was not detected. Treatment was discontinued in 2 patients because of disease progression or idiopathic dystonia. The mRNA levels of asparagine synthetase in EBV-infected cells were examined. The level from the patient who responded to L-asp treatment was low, but it did not correlate with the effects in the other patients. Liver dysfunction (grades 2 and 3) was observed in 2 patients and neutropenia (grade 3) was noted in 1 patient. In conclusion, the effect of L-asp as monotherapy in EBV-T/NK-LPDs is limited, and early treatment initiation might be effective. PMID:26111530
J. C. Sfiiz; A. Rodriguez; M. Gonzalez; F. Alonso; F. Sobrino
The in vitro viral lymphoproliferative response of pigs vaccinated against foot-and-mouth disease virus (FMDV) has been characterized. Peripheral blood mononuclear cells from immunized animals up to 1 year post-immunization (p.i.) showed a time-depen- dent FMDV-specific response, as assayed by virus- specific cellular blastogenesis. The optimum viral concentration decreased with time (around 20 weeks p.i.), and the response was faster and
Taikai Toubo; Naohiro Suga; Shouichi Ohga; Akihiko Nomura; Yasuhiro Onoe; Hidetoshi Takada; Toshiro Hara
We report a case of successful umbilical cord blood transplantation (CBT) for Epstein-Barr virus (EBV)-associated lymphoproliferative\\u000a disease (LPD) in a 6-year-old girl. The patient had hemophagocytic syndrome with excessive circulating levels of EBV DNA that\\u000a was refractory to immunochemotherapy. Multiple hepatosplenic lesions favored the diagnosis of EBV-associated LPD, although\\u000a the aggressive course precluded the histopathologic diagnosis. Unrelated CB cells mismatched
Wang, Pin-Yi; Currier, Mark A; Hansford, Loen; Kaplan, David; Chiocca, E. Antonio; Uchida, Hiroaki; Goins, William F.; Cohen, Justus B.; Glorioso, Joseph C.; van Kuppevelt, Toin H.; Mo, Xiaokui; Cripe, Timothy P
Epstein-Barr virus (EBV)-associated B cell lymphoproliferative disease (LPD) after hematopoietic stem cell or solid organ transplantation remains a life-threatening complication. Expression of the virus-encoded gene product, EBER, has been shown to prevent apoptosis via blockade of PKR activation. Because PKR is a major cellular defense against Herpes simplex virus, and oncolytic HSV-1 (oHSV) mutants have shown promising anti-tumor efficacy in preclinical models, we sought to determine whether EBV-LPD cells are susceptible to infection by oHSVs. We tested three primary EBV-infected lymphocyte cell cultures from neuroblastoma (NB) patients as models of naturally acquired EBV-LPD. NB12 was most susceptible, NB122R was intermediate, and NB88R2 was essentially resistant. Despite EBER expression, PKR was activated by oHSV infection. Susceptibility to oHSV correlated with the expression of the HSV receptor, nectin-1. The resistance of NB88R2 was reversed by exogenous nectin-1 expression, whereas down-regulation of nectin-1 on NB12 decreased viral entry. Xenografts derived from the EBV-LPDs exhibited only mild (NB12) or no (NB88R2) response to oHSV injection, compared with a neuroblastoma cell line that showed a significant response. We conclude that EBV-LPDs are relatively resistant to oHSV virotherapy, in some cases due to low virus receptor expression but also due to intact anti-viral PKR signaling. PMID:23254370
Patel, J. R.; Shilleto, R. W.
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
Zhu, Jia; Zhang, Yu; Zhen, Zi-Jun; Chen, Yan; Wang, Juan; Cai, Rui-Qing; Sun, Xiao-Fei
Lymphoma is seen in up to 30% of patients with X-linked lymphoproliferative disease (XLP), but cerebral vasculitis related with XLP after cure of Burkitt lymphoma is rarely reported. We describe a case of a 5-year-old boy with XLP who developed cerebral vasculitis two years after cure of Burkitt lymphoma. He had Burkitt lymphoma at the age of 3 years and received chemotherapy (non-Hodgkin's lymphoma-Berlin-Frankfurt-Milan-90 protocol plus rituximab), which induced complete remission over the following two years. At the age of 5 years, the patient first developed headache, vomiting, and then intellectual and motorial retrogression. His condition was not improved after anti-infection, dehydration, or dexamethasone therapy. No tumor cells were found in his cerebrospinal fluid. Magnetic resonance imaging showed multiple non-homogeneous, hypodense masses along the bilateral cortex. Pathology after biopsy revealed hyperplasia of neurogliocytes and vessels, accompanied by lymphocyte infiltration but no tumor cell infiltration. Despite aggressive treatment, his cognition and motor functions deteriorated in response to progressive cerebral changes. The patient is presently in a vegetative state. We present this case to inform clinicians of association between lymphoma and immunodeficiency and explore an optimal treatment for lymphoma patients with compromised immune system. PMID:23816555
Pochon, Cécile; Oger, Emmanuel; Michel, Gérard; Dalle, Jean-Hugues; Salmon, Alexandra; Nelken, Brigitte; Bertrand, Yves; Cavé, Hélène; Cayuela, Jean-Michel; Grardel, Nathalie; Macintyre, Elizabeth; Margueritte, Geneviève; Méchinaud, Françoise; Rohrlich, Pierre; Paillard, Catherine; Demeocq, François; Schneider, Pascale; Plantaz, Dominique; Poirée, Marilyne; Eliaou, Jean-François; Semana, Gilbert; Drunat, Séverine; Jonveaux, Philippe; Bordigoni, Pierre; Gandemer, Virginie
Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease (MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days -30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions (DLI) were programmed for patients with a pre- or post-transplant MRD status ?10(-3) . Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival (OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment (P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention. PMID:25522886
Randen, Ulla; Trøen, Gunhild; Tierens, Anne; Steen, Chloé; Warsame, Abdirashid; Beiske, Klaus; Tjønnfjord, Geir E; Berentsen, Sigbjørn; Delabie, Jan
Primary chronic cold agglutinin disease is a rare hemolytic disease mediated by monoclonal IGHV4-34-encoded cold agglutinins with a predominant specificity for the blood group antigen I. Bone marrow from 54 patients was studied to type the underlying lymphoproliferative disorder better. Bone marrow biopsies showed circumscribed intra-parenchymatous nodules with small monotonous monoclonal B cells in 40/54 patients (median infiltration: 10% of marrow cells) with a CD20(+), IgMs(+), IgDs(+), CD27(+), CD5(-/+), CD11c(-), CD23(-), CD38(-) immunophenotype. Neither plasmacytoid cytological features nor expression of plasma cell differentiation-associated transcription factors MUM1, XBP1 and BLIMP1 were noted in these B cells. However, a limited number of mature monoclonal IgM(+), IgD(-) plasma cells were present outside the lymphoid nodules and were diffusely scattered throughout the marrow. Of interest, the MYD88 L265P mutation, typical of lymphoplasmacytic lymphoma, was not detected (17/17 cases). Somatically mutated monoclonal IGHV4-34 gene rearrangement was demonstrated in eight patients with frozen samples (mean sequence homology 95.4%). However, mutations of BCL6 intron 1 were not demonstrated, except in one patient, suggesting that the lymphoma cells had not matured in the germinal center. In conclusion, cold agglutinin-associated lymphoproliferative disease displays homogeneous histological and immunophenotypic features. The absence of plasmacytoid cells, the presence of plasma cells predominantly outside the nodular lymphoid infiltrates, IGHV4-34 restriction and absence of MYD88 L265P mutation strongly suggest that cold agglutinin-associated lymphoproliferative disease is a distinct entity that is different from lymphoplasmacytic lymphoma. PMID:24143001
Turkan Patiroglu; Alper Ozcan; Musa Karakukcu; Mehmet Akif Ozdemir; Gamze Poyrazoglu; Mehmet Canpolat; Ekrem Unal
Introduction Pseudotumor cerebri (PTC) is a syndrome characterized with increased intracranial pressure, normal cerebrospinal fluid content\\u000a (CSF), and a normal brain on imaging studies. In this case report, PTC has been linked to mycophenolate mofetil (MMF) that\\u000a has been used for autoimmune lymphoproliferative syndrome (ALPS).\\u000a \\u000a \\u000a \\u000a \\u000a Case report A 5-year-old boy, who was using MMF for 4 months because of the ALPS, suffered from
Jie Yang; Qian Tao; Ian W. Flinn; Paul G. Murray; Linda E. Post; Hong Ma; Steven Piantadosi; Michael A. Caligiuri; Richard F. Ambinder
Post-transplantation lymphoproliferative disease (PTLD) is associated with Epstein- Barr virus (EBV). Quantitative and qualita- tive differences in EBV in peripheral blood mononuclear cells (PBMCs) of PTLD pa- tients and healthy controls were charac- terized. A quantitative competitive poly- merase chain reaction (QC-PCR) tech- nique confirmed previous reports that EBV load in PBMCs is increased in pa- tients with PTLD in
Zheng, Xiaodan; Xie, Jianlan; Zhou, Xiaoge
Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disease (LPD) is not uncommon in China, but gastrointestinal involvement is very rare. We report on an immunocompetent patient with EBV-associated T-cell LPD of the colon. The 26-year-old man was initially misdiagnosed with ulcerative colitis (UC). A colon biopsy revealed the presence of small to medium-sized lymphoid cells infiltrating the intestinal wall. The neoplastic cells expressed CD3, CD5, and granzyme B, not CD56. EBV-encoded small ribonucleic acid was detected in the tumor cells of the colon as well as the lymph node, and the T-cell receptor gene rearrangement result displayed ? gene monoclonal rearrangement. The patient died 2 moths after the diagnosis. The clinical course of EBV-associated T-cell LPD is aggressive and the prognosis is poor, the wrong diagnosis may delay treatment. Therefore, we should be very careful to prevent misdiagnosis. When patients have multiple intestinal ulcers that are not typical of UC and the clinical course is unusual, although morphology looks like inflammatory change, pathologist should consider the possibility of EBV-associated LPD. The treatment strategy and prognosis of these two diseases are different.
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
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)
Nagy, Noemi; Matskova, Liudmila; Hellman, Ulf; Klein, George; Klein, Eva
Deletion or mutation of the SH2D1A gene located at Xq25 is responsible for the development of the X-linked lymphoproliferative disease, XLP. Primary infection of the affected individuals with EBV leads to fulminant and often fatal infectious mononucleosis, FIM. Moreover, they run a 200 fold elevated risk for lymphoma development. Due to the critical role of the immune response for the outcome of EBV infection and the detection of EBV genomes in several malignancies, XLP studies have been mainly focused on the immunological aspects. The involvement of SAP in the apoptotic machinery provides a further aspect in the complex syndrome of XLP. Functional impairment of SAP leads to defective apoptotic responses. Activation induced apoptosis plays a pivotal role in the termination of the lymphocyte proliferation in IM. This mechanism is inefficient in XLP patients. In addition, in the absence of SAP, lymphoma development may be promoted by the illegitimate survival of lymphocytes with damaged DNA that would be normally eliminated by apoptosis. PMID:19738428
Latkowski, Jo-Ann; Henderson, Tanya; Schlessinger, Karni; Ding, Yi; Shen, Jie; Tadokoro, Carlos E.; Lafaille, Juan J.
Notch signaling is essential for the development of T cell progenitors through the interaction of NOTCH1 receptor on their surface with the ligand, Delta-like 4 (DLL4), which is expressed by the thymic epithelial cells. Notch signaling is quickly shut down once the cells pass ?-selection, and CD4/CD8 double positive (DP) cells are unresponsive to Notch. Over the past two decades a number of papers reported that over-activation of Notch signaling causes T cell acute lymphoblastic leukemia (T-ALL), a cancer that prominently features circulating monoclonal CD4/CD8 double positive T cells in different mouse models. However, the possible outcomes of Notch over-activation at different stages of T cell development are unknown, and the fine timing of Notch signaling that results in T-ALL is poorly understood. Here we report, by using a murine model that ectopically expresses DLL4 on developing T cells, that the T-ALL onset is highly dependent on a sustained Notch activity throughout the DP stage, which induces additional mutations to further boost the signaling. In contrast, a shorter period of Notch activation that terminates at the DP stage causes a polyclonal, non-transmissible lymphoproliferative disorder that is also lethal. These observations resolved the discrepancy of previous papers on DLL4 driven hematological diseases in mice, and show the critical importance of the timing and duration of Notch activity. PMID:24386421
Gero, Daniel; Queiros da Mota, Vanessa; Boubaker, Ariane; Berthod, Gregoire; de Leval, Laurence; Demartines, Nicolas; Matter, Maurice
Sentinel lymph node dissection (SLND) identifies melanoma patients with metastatic disease who would benefit from radical lymph node dissection (RLND). Rarely, patients with melanoma have an underlying lymphoproliferative disease, and melanoma metastases might develop as collision tumours in the sentinel lymph node (SLN). The aim of this study was to measure the incidence and examine the effect of collision tumours on the accuracy of SLND and on the validity of staging in this setting. Between 1998 and 2012, 750 consecutive SLNDs were performed in melanoma patients using the triple technique (lymphoscintigraphy, gamma probe and blue dye). The validity of SLND in collision tumours was analysed. False negativity was reflected by the disease-free survival. The literature was reviewed on collision tumours in melanoma. Collision tumours of melanoma and chronic lymphocytic leukaemia (CLL) were found in two SLN and in one RLND (0.4%). Subsequent RLNDs of SLND-positive cases were negative for melanoma. The patient with negative SLND developed relapse after 28 months with an inguinal lymph node metastasis of melanoma; RLND showed collision tumours. The literature review identified 12 cases of collision tumours. CLL was associated with increased melanoma incidence and reduced overall survival. This is, to our knowledge, the first assessment of the clinical value of SLND when collision tumours of melanoma and CLL are found. In this small series of three patients with both malignancies present in the same lymph node basin, lymphocytic infiltration of the CLL did not alter radioisotope uptake into the SLN. No false-negative result was observed. Our data suggest the validity of SLND in collision tumours, but given the rarity of the problem, further studies are necessary to confirm this reliability. PMID:24922190
Cacoub, P; Bourlière, M; Hausfater, P; Charlotte, F; Khiri, H; Toci, S; Piette, J C; Poynard, T; Halfon, P
Chronic hepatitis C virus (HCV) infection is frequently associated with type II mixed cryoglobulinaemia (MC), a benign lymphoproliferative disease (LPD). More recently, HCV has been implicated as a possible aetiologic factor of B-cell non-Hodgkin lymphoma (B-NHL). CD81, a B-cell surface receptor, has been proposed as a receptor for HCV binding and entry in circulating B cells. The stimulation of CD81 complex enables B cells to respond to lower concentrations of antigen and finally induces B-cell proliferation. We studied the phenotypic expression of CD81, CD19 and CD5 on circulating B cells in HCV patients LPD-positive or LPD-negative. Sixty-two patients were anti-HCV antibody positive. Among HCV positive patients, 44 were HCV RNA positive with an histologically proven chronic active hepatitis of whom 10 had a B-NHL, 14 an MC and 24 no extrahepatic manifestation. Eighteen patients were HCV RNA negative with evidence of resolved infection. A control group included 40 healthy subjects. Peripheral blood mononuclear cells (PBMC) were stained for surface expression of CD81, CD19 and CD5 using monoclonal antibodies, and were analyzed by flow cytometry. The percentage of PBMC expressing CD81, CD19 and CD5 receptors were compared between the groups by univariate analysis. Logistic regression model variables were then evaluated to correlate the presence of an LPD with HCV infection characteristics (i.e. age, gender, genotype, duration of infection, HCV RNA positivity, liver histological lesions), or phenotypic expression of CD81, CD19 and CD5 receptors on PBMC. HCV antibody-positive compared with HCV-negative subjects had a higher expression of CD19 receptor (23 +/- 13 vs 13 +/- 1%, P = 0.003). Among HCV RNA positive-patients, LPD+ compared with LPD- patients had a lower expression of CD81 (58 +/- 28 vs 82 +/- 18%, P = 0.001) and CD5 receptor (66 +/- 16 vs 74 +/- 13%, P = 0.04). In multivariate analysis, the expression of CD81 receptor was a negative (OR = 0.15, 95% CI = 0.04-0.64, P = 0.01) and CD19 receptor a positive (OR = 4.81, 95% CI =1.29-17.88, P = 0.02) predictive factor for an LPD. We found two negative predictive factors for HCV RNA positivity, i.e. age (OR = 0.23, 95% CI. = 0.08-0.62, P = 0.003) and the expression of CD81 receptor (OR = 0.34, 95% CI = 0.13-0.89, P = 0.02). In patients with a chronic active HCV infection, the presence of a lymphoproliferative disease, either MC or B-NHL, is associated with lower expression of CD81 and higher expression of CD19 receptor on peripheral B cells. PMID:12558906
Nagy, Noémi; Mattsson, Karin; Maeda, Akihiko; Liu, Anquan; Székely, László; Klein, Eva
The unique manifestation of the inherited immunodeficiency, X-linked lymphoproliferative disease (XLP), is the impaired control of EBV infection. The gene, which carries mutations or is deleted in the patients, has been identified (Xq25). The encoded protein (SAP, 128 aa) contains a single SH2 domain and binds to signaling lymphocytic activation molecule (SLAM) and to other related surface molecules that are expressed on activated T, B and NK cells. SAP modifies signal transduction through its association with these molecules. Initially it was assumed that SAP acts passively by interfering and blocking active interactions involving other SH2 carrying molecules. We demonstrated that SAP protein is expressed in activated T and NK, but not in activated B cells. This finding is in line with the fact that in vitro performance of effector cells derived from XLP patients is impaired. However, it is still not known why the severe symptoms (fatal mononucleosis or malignant lymphoproliferation in the survivors of the primary infection) are elicited by EBV. We studied SAP expression in several Burkitt lymphoma (BL) derived lines. In contrast to normal B cells, certain lines expressed SAP. These were all type I cells in the Burkitt line nomenclature: they expressed only one of the EBV encoded proteins (EBNA-1) and their phenotype corresponded to resting B cells. Lymphoblastoid cell lines and type III BLs, whose phenotype resembled activated B cells and expressed all nine EBV encoded proteins, were devoid of SAP. The relationship between cell activation and SAP expression is reciprocal in T and B cells i.e. BL lines, activated T and NK cells express SAP, while BL blasts do not express SAP. This opposite relationship may be exploited for studies about the function of SAP. PMID:12008045
Wester, Hans Jürgen; Keller, Ulrich; Schottelius, Margret; Beer, Ambros; Philipp-Abbrederis, Kathrin; Hoffmann, Frauke; Šime?ek, Jakub; Gerngross, Carlos; Lassmann, Michael; Herrmann, Ken; Pellegata, Natalia; Rudelius, Martina; Kessler, Horst; Schwaiger, Markus
Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [68Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [68Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [68Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [68Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/CXCL12 ligand interaction in the pathogenesis and treatment of cancer, cardiovascular diseases and autoimmune and inflammatory disorders. PMID:25825601
Chopra, Sameer S; Leshchiner, Ignaty; Duzkale, Hatice; McLaughlin, Heather; Giovanni, Monica; Zhang, Chengsheng; Stitziel, Nathan; Fingeroth, Joyce; Joyce, Robin M; Lebo, Matthew; Rehm, Heidi; Vuzman, Dana; Maas, Richard; Sunyaev, Shamil R; Murray, Michael; Cassa, Christopher A
Glycosaminoglycans (GAGs) such as chondroitin are ubiquitous disaccharide carbohydrate chains that contribute to the formation and function of proteoglycans at the cell membrane and in the extracellular matrix. Although GAG-modifying enzymes are required for diverse cellular functions, the role of these proteins in human development and disease is less well understood. Here, we describe two sisters out of seven siblings affected by congenital limb malformation and malignant lymphoproliferative disease. Using Whole-Genome Sequencing (WGS), we identified in the proband deletion of a 55 kb region within chromosome 12q23 that encompasses part of CHST11 (encoding chondroitin-4-sulfotransferase 1) and an embedded microRNA (MIR3922). The deletion was homozygous in the proband but not in each of three unaffected siblings. Genotyping data from the 1000 Genomes Project suggest that deletions inclusive of both CHST11 and MIR3922 are rare events. Given that CHST11 deficiency causes severe chondrodysplasia in mice that is similar to human limb malformation, these results underscore the importance of chondroitin modification in normal skeletal development. Our findings also potentially reveal an unexpected role for CHST11 and/or MIR3922 as tumor suppressors whose disruption may contribute to malignant lymphoproliferative disease.
A Case of Alport Syndrome with Posttransplant Antiglomerular Basement Membrane Disease despite Negative Antiglomerular Basement Membrane Antibodies by EIA Treated with Plasmapheresis and Intravenous Immunoglobulin
Armstead, Sumiko I.; Hellmark, Thomas; Wieslander, Jorgen; Zhou, Xin J.; Rajora, Nilum
Posttransplant antiglomerular basement membrane (anti-GBM) disease occurs in approximately 5% of Alport patients and usually ends in irreversible graft failure. Recent research has focused on characterizing the structure of the anti-GBM alloepitope. Here we present a case of a 22-year-old male with end-stage renal disease secondary to Alport syndrome, with a previously failed renal allograft, who received a second deceased-donor kidney transplant. Six days after transplantation, he developed acute kidney injury. The serum anti-GBM IgG was negative by enzyme immunoassay (EIA). On biopsy, he had crescentic glomerulonephritis with linear GBM fixation of IgG. With further analysis by western blotting, we were able to detect antibodies to an unidentified protein from the basement membrane. This patient was treated with plasmapheresis twice per week and monthly intravenous immunoglobulin (IVIG) for a total of five months. At the end of treatment, these unknown antibodies were no longer detected. His renal function improved, and he has not required dialysis. We conclude that anti-GBM disease in patients with Alport Syndrome may be caused by circulating antibodies to other components of the basement membrane that are undetectable by routine anti-GBM EIA and may respond to treatment with plasmapheresis and IVIG. PMID:24363950
Sumegi, Janos; Seemayer, Thomas A; Huang, Dali; Davis, Jack R; Morra, Massimo; Gross, Thomas G; Yin, Luo; Romco, Giovanni; Klein, Eva; Terhorst, Cox; Lanyi, Arpad
X-linked lymphoproliferative disease (Duncan's Disease) was first encountered by David T. Purtilo in 1969. The first communication describing the disease was published in 1975. In 1989 the disease locus was mapped to Xq25. Ten years later the gene (SH2D1A, SAP, DSHP), which is absent or mutated in XLP patients was identified. Since that the protein crystal structure of this small, SH2-domain containing protein has been solved, target molecules of the protein have been identified, physiological and pathological protein/protein interactions have been characterized, and the mouse model of the gene mutation has been developed. That said, a complete understanding of the function of the normal SH2D1A protein in immunoregulation and of the altered immune responses in XLP patients is not yet at hand. Therein lies the legacy of Purtilo's discovery for, as with other primary immunodeficiencies, these "experiments of nature" offer a window on the beauty of the immune system. In due course, the manner by which this gene orchestrates an elegant response (akin to a Mozart divertimento) to EBV infection shall be defined. PMID:12152986
Fuchs, Ephraim J.; Luznik, Leo; Lanzkron, Sophie M.; Gamper, Christopher J.; Jones, Richard J.; Brodsky, Robert A.
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
Wirth, Timo; Westendorf, Astrid M; Bloemker, Dominique; Wildmann, Johannes; Engler, Harald; Mollerus, Sina; Wadwa, Munisch; Schäfer, Martin K-H; Schedlowski, Manfred; del Rey, Adriana
The sympathetic nervous system (SNS) plays a crucial role in the course and development of autoimmune disease in Fas-deficient lpr/lpr mice. As regulatory T cells (Tregs) are considered important modulators of autoimmune processes, we analyzed the interaction between the SNS and Tregs in this murine model of lymphoproliferative disease. We found that the percentage of Tregs among CD4(+) T cells is increased in the spleen, lymph nodes, and thymus of lpr/lpr mice as compared to age-matched C57Bl/6J (B6) mice. Furthermore, noradrenaline (NA), the main sympathetic neurotransmitter, induced apoptosis in B6- and lpr/lpr-derived Tregs. NA also reduced the frequency of Foxp3(+) cells and Foxp3 mRNA expression via ?2-adrenoceptor (?2-AR)-mediated mechanisms in a concentration and time-dependent manner. Destruction of peripheral sympathetic nerves by 6-hydroxydopamine significantly increased the percentage of Tregs in B6 control mice to an extent comparable to aged-matched lpr/lpr mice. The concentration of splenic NA negatively correlated with the frequency of CD4(+)Foxp3(+) Tregs. Additionally, 60days after sympathectomy, a partial recovery of NA concentrations led to Treg percentages comparable to those of intact, vehicle-treated controls. Immunohistochemical analysis of the spleen revealed localization of single Foxp3(+) Tregs in proximity to NA-producing nerve fibers, providing an interface between Tregs and the SNS. Taken together, our data suggest a relation between the degree of splenic sympathetic innervation and the size of the Treg compartment. While there are few examples of endogenous substances capable of affecting Tregs, our results provide a possible explanation of how the magnitude of the Treg compartment in the spleen can be regulated by the SNS. PMID:24440144
Marsh, Rebecca A; Bleesing, Jack J; Chandrakasan, Shanmuganathan; Jordan, Michael B; Davies, Stella M; Filipovich, Alexandra H
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
Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases.
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
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
Radford, Kristen J; Vari, Frank; Hart, Derek N J
Lymphoproliferative disorders, including follicular lymphoma (FL), multiple myeloma (MM) and chronic lymphatic leukaemia (CLL), are slowly progressive malignancies which remain incurable despite advances in therapy. Harnessing the immune system to recognise and destroy tumours is a promising new approach to treating these diseases. Dendritic cells (DC) are unique antigen-presenting cells that play a central role in the initiation and direction of immune responses. DC loaded ex vivo with tumour-associated antigens and administered as a vaccine have already shown promise in early clinical trials for a number of lymphoproliferative disorders, but the need for improvement is widely agreed. Recent advances in the understanding of basic DC biology and lessons from early clinical trials have provided exciting new insights into the generation of anti-tumour immune responses and the design of vaccine strategies. In this review we provide an overview of our current understanding of DC biology and their function in patients with lymphoproliferative disorders. We discuss the current status of clinical trials and new approaches to exploit the antigen presenting capacity of DC to design vaccines of the future. PMID:16373232
Rosenblum, M D; Drobyski, W R; Keever-Taylor, C; Chang, C-C
We report the case of a t(14:18)(+) follicular lymphoma (FL) patient in long-term clinical remission after undergoing an allogeneic bone marrow transplantation (allo-BMT) from a human leukocyte antigen (HLA)-identical sibling donor who was the normal healthy carrier of a t(14:18)(+) B cell clone. Using real-time quantitative PCR (RQ-PCR) and gel electrophoresis, we document the temporal disappearance of the patient's t(14:18)(+) clone early post-transplant with the concomitant emergence and long-term persistence of the donor's t(14:18)(+) clone in the patient's peripheral blood. This report indicates that the use of PCR-based techniques to measure minimal residual disease in FL patients post-alloBMT should incorporate pretransplant screening of the donor for t(14;18). Furthermore, it suggests that healthy individuals with t(14:18) need not be excluded as donors for FL patients treated with allo-BMT. PMID:12748676
Skare, J.C.; Milunsky, A.; Byron, K.S.; Sullivan, J.L.
The X-linked lymphoproliferative syndrome is triggered by Epstein-Barr virus infection and results in fatal mononucleosis, immunodeficiency, and lymphoproliferative disorders. This study shows that the mutation responsible for X-linked lymphoproliferative syndrome is genetically linked to a restriction fragment length polymorphism detected with the DXS42 probe (from Xq24-q27). The most likely recombination frequency between the loci is 4%, and the associated logarithm of the odds is 5.26. Haplotype analysis using flanking restriction fragment length polymorphism markers indicates that the locus for X-linked lymphoproliferative syndrome is distal to probe DXS42 but proximal to probe DXS99 (from Xq26-q27). It is now possible to predict which members of a family with X-linked lymphoproliferative syndrome are carrier females and to diagnose the syndrome prenatally.
Tanzina Haque; Gwen M. Wilkie; Marie M. Jones; Craig D. Higgins; Gillian Urquhart; Phoebe Wingate; David Burns; Karen McAulay; Marc Turner; Christopher Bellamy; Peter L. Amlot; Deirdre Kelly; Alastair MacGilchrist; Maher K. Gandhi; Anthony J. Swerdlow; Dorothy H. Crawford
We present the results of a multicenter clinical trial using Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) generated from EBV-seropositive blood donors to treat patients with EBV- positive posttransplantation lymphopro- liferative disease (PTLD) on the basis of the best HLA match and specific in vitro cytotoxicity. Thirty-three PTLD patients who had failed on conventional therapy were enrolled. No adverse effects
... cause symptoms other than a brief infection or mononucleosis. Boys with XLP, however, can have severe reactions ... to viral infection, such as development of severe mononucleosis in response to EBV infection. A blood test ...
Allegra, A; Russo, S; Gerace, D; Calabrò, L; Maisano, V; Innao, V; Musolino, C
Anti-tumor vaccines in lymphoproliferative disorders hold out the prospect of effective tumor therapies with minimal side effects. The addition of immunotherapy to old and new chemotherapy regimens has improved both response rates and disease-free survival, leading in many cases to an extended overall survival. Ideally, an antigen that is used for vaccination would be specifically expressed in the tumor; it must have an important, causal part in the multifactorial process that leads to cancer, and it must be expressed stably even after it is attacked by the immune system. Immunotherapies, which aim to activate the immune system to kill cancer cells, include strategies to increase the frequency or potency of antitumor T cells, to overcome suppressive factors in the tumor microenvironment, and to reduce T-cell suppression systemically. In this review, we focus on the results of clinical trials of vaccination in lymphoma, and discuss potential strategies to enhance the efficacy of immunotherapy in the future. PMID:26298174
Ghobrial, Rafik M.; Gornbein, Jeffery; Steadman, Randy; Danino, Natale; Markmann, James F.; Holt, Curtis; Anselmo, Dean; Amersi, Farin; Chen, Pauline; Farmer, Douglas G.; Han, Steve; Derazo, Francisco; Saab, Sammy; Goldstein, Leonard I.; McDiarmid, Sue V.; Busuttil, Ronald W.
Objective To develop a prognostic model that determines patient survival outcomes after orthotopic liver transplantation (OLT) using readily available pretransplant variables. Summary Background Data The current liver organ allocation system strongly favors organ distribution to critically ill recipients who exhibit poor survival outcomes following OLT. A severely limited organ resource, increasing waiting list deaths, and rising numbers of critically ill recipients mandate an organ allocation system that balances disease severity with survival outcomes. Such goals can be realized only through the development of prognostic models that predict survival following OLT. Methods Variables that may affect patient survival following OLT were analyzed in hepatitis C (HCV) recipients at the authors’ center, since HCV is the most common indication for OLT. The resulting patient survival model was examined and refined in HCV and non-HCV patients in the United Network for Organ Sharing (UNOS) database. Kaplan-Meier methods, univariate comparisons, and multivariate Cox proportional hazard regression were employed for analyses. Results Variables identified by multivariate analysis as independent predictors for patient survival following primary transplantation of adult HCV recipients in the last 10 years at the authors’ center were entered into a prognostic survival model to predict patient survival. Accordingly, mortality was predicted by 0.0293 (recipient age) + 1.085 (log10 recipient creatinine) + 0.289 (donor female gender) + 0.675 urgent UNOS - 1.612 (log10 recipient creatinine times urgent UNOS). The above variables, in addition to donor age, total bilirubin, prothrombin time (PT), retransplantation, and warm and cold ischemia times, were applied to the UNOS database. Of the 46,942 patients transplanted over the last 10 years, 25,772 patients had complete data sets. An eight-factor model that accurately predicted survival was derived. Accordingly, the mortality index posttransplantation = 0.0084 donor age + 0.019 recipient age + 0.816 log creatinine + 0.0044 warm ischemia (in minutes) + 0.659 (if second transplant) + 0.10 log bilirubin + 0.0087 PT + 0.01 cold ischemia (in hours). Thus, this model is applicable to first or second liver transplants. Patient survival rates based on model-predicted risk scores for death and observed posttransplant survival rates were similar. Additionally, the model accurately predicted survival outcomes for HCV and non-HCV patients. Conclusions Posttransplant patient survival can be accurately predicted based on eight straightforward factors. The balanced application of a model for liver transplant survival estimate, in addition to disease severity, as estimated by the model for end-stage liver disease, would markedly improve survival outcomes and maximize patients’ benefits following OLT. PMID:12192318
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
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
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
Yildiz, Cenk Eray; Sinan, Ümit Ya?ar; Yildiz, Ahmet; Çetin, Gürkan; Küçüko?lu, Serdar
Cardiac cystic echinococcosis is a rare parasitic infestation caused by Echinococcus granulosus larvae and it composes 0.5-2% of all human cystic echinococcosis cases. The left ventricle is the most common affected area followed by right ventricle, interventricular septum, left atrium, right atrium, and interatrial septum. The diagnosis is difficult because of nonspecific clinical and radiographic findings. We present a case of isolated apical cardiac cystic echinococcosis mimicking lymphoproliferative disease. PMID:25470654
Park, Chul Soo
Diabetogenic traits in patients undergoing liver transplantation (LT) are exacerbated intraoperatively by exogenous causes, such as surgical stress, steroids, blood transfusions, and catecholamines, which lead to intraoperative hyperglycemia. In contrast to the strict glucose control performed in the intensive care unit, no systematic protocol has been developed for glucose management during LT. Intraoperative blood glucose concentrations typically exceed 200 mg/dL in LT, and extreme hyperglycemia (> 300 mg/dL) is common during the neohepatic phase. Only a few retrospective studies have examined the relationship between intraoperative hyperglycemia and post-transplant complications, with reports of infectious complications or mortality. However, no prospective studies have been conducted regarding the influence of intraoperative hyperglycemia in LT on post-transplant outcome. In addition to absolute blood glucose values, the temporal patterns in blood glucose levels during LT may serve as prognostic features. Persistent neohepatic hyperglycemia (without a decline) throughout LT is a useful indicator of early graft dysfunction. Moreover, intraoperative variability in glucose levels may predict the need for reoperation for hemorrhage after LT. Thus, there is an urgent need for guidelines for glucose control in these patients, as well as prospective studies on the impact of glucose control on various post-transplant complications. This report highlights some of the recent studies related to perioperative blood glucose management focused on LT and liver disease. PMID:26078559
Park, Chul Soo
Diabetogenic traits in patients undergoing liver transplantation (LT) are exacerbated intraoperatively by exogenous causes, such as surgical stress, steroids, blood transfusions, and catecholamines, which lead to intraoperative hyperglycemia. In contrast to the strict glucose control performed in the intensive care unit, no systematic protocol has been developed for glucose management during LT. Intraoperative blood glucose concentrations typically exceed 200 mg/dL in LT, and extreme hyperglycemia (> 300 mg/dL) is common during the neohepatic phase. Only a few retrospective studies have examined the relationship between intraoperative hyperglycemia and post-transplant complications, with reports of infectious complications or mortality. However, no prospective studies have been conducted regarding the influence of intraoperative hyperglycemia in LT on post-transplant outcome. In addition to absolute blood glucose values, the temporal patterns in blood glucose levels during LT may serve as prognostic features. Persistent neohepatic hyperglycemia (without a decline) throughout LT is a useful indicator of early graft dysfunction. Moreover, intraoperative variability in glucose levels may predict the need for reoperation for hemorrhage after LT. Thus, there is an urgent need for guidelines for glucose control in these patients, as well as prospective studies on the impact of glucose control on various post-transplant complications. This report highlights some of the recent studies related to perioperative blood glucose management focused on LT and liver disease. PMID:26078559
Chandramohan, Vaishnavi; Nagarajan, Vinoth Ponnurangam; Sathyamoorthi, Muthamil Selvan; Kumar, Sathish; Shanmugasundaram, Chitrambalam; Periakaruppan, Gokulakrishnan; Scott, Julius Xavier
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
Fredericks, Emily M; Zelikovsky, Nataliya; Aujoulat, Isabelle; Hames, Anna; Wray, Jo
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
...Vietnam. HCL is a chronic B-cell lymphoproliferative disorder...and that both derive from B-cell neoplasms. Based on its biology, the Committee saw no reason...lymphoproliferative disease of B-cell origin from the overarching...
Cader, Rizna Abdul; Mohd, Rozita; Gafor, Halim Abdul; Kong, Norella CT
Post-transplant lymphoproliferative disorder (PTLD) is a recognized complication exclusive to solid organ transplant recipients and carries a high mortality. We retrospectively reviewed records of all renal transplant recipients under follow up at our institution over the last seven years (2005-2011). We reviewed the patient characteristics, immunosuppression regimen and risk factors for the development of PTLD and its outcomes in our transplant cohort. Four out of 63 patients were diagnosed with PTLD. PTLD was incidentally diagnosed on a transplant biopsy that was performed for an unexplained rise in serum creatinine in three patients. The fourth patient presented with left submandibular lymphadenopathy. Majority presented within 18 months of renal transplantation. After the diagnosis of PTLD on graft biopsy, all patients were fully investigated and two patients had systemic involvement. In the patients with systemic involvement, reduction of immunosuppression and anti B cell therapy with Rituximab was used with good success. The patient with submandibular lymphadenopathy received chemotherapy in addition to reduction of immunosuppression. Three PTLD cases were polyclonal and diagnosed early whereas the fourth case was monoclonal. PTLD can sometimes be incidentally diagnosed on an allograft biopsy performed for rejection. The incidence of PTLD in our centre is higher than reports from other centres but our outcome is good if recognised and treated early.
Hong, Sanghee; Le-Rademacher, Jennifer; Artz, Andrew; McCarthy, Philip L.; Logan, Brent R.; Pasquini, Marcelo C.
Hematopoietic cell transplantation (HCT) with non-myeloablative conditioning (NMA) for lymphoproliferative diseases (LD) includes fludarabine with and without low-dose total body irradiation (TBI). Transplant outcomes were compared among patients ?40 years with LD who received a HCT with TBI (N=382) and no-TBI (N=515) NMA from 2001 to 2011. The groups were comparable except for donor, graft, prophylaxis for graft-versus-host disease (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 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). Subset of 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 to other combinations. TBI-based NMA conditioning induces faster full donor chimerism but overall survival outcomes are comparable to no-TBI regimens. Combination of TBI and MMF are associated with higher rates of GVHD without impact on survival outcomes in patients with LD. PMID:25437248
Doerge, M.J.; Hooper, W.C.; Phyliky, R.L.; Witzig, T.E.; Banks, P.M.; Li, C.Y.; Woloschak, G.E.
Experiments were performed to examine expression of proto-oncogenes and other related genes in ten cases of chronic T-cell lymphoproliferative disorders. The helper vs. suppressor nature of the T-cells was determined using monoclonal antibodies. RNA was isolated from peripheral blood mononuclear cells and/or lymph node sections and 5'-end labelled with ..gamma..-/sub 32/P-ATP. RNA preparations were hybridized under stringent conditions to an excess of nitrocellulose-bound specific cloned DNA; autoradiographs were analyzed by microdensitometry. Hybridizations of PHA-activated T-cells to various probes as well as hybridizations of RNA samples to parent plasmid were negative in all experiments. Results revealed increased expression of K-ras, B-lym, transferrin receptor, ..cap alpha..-tubulin and ..cap alpha..-interferon in 5/5 helper T-cell lymphoproliferative disorders, while 5/5 suppressor T-cell disorders demonstrated levels of hybridization to these clones no higher than background. However, studies of T-suppressor disorders demonstrated enhanced levels of ..beta..-interferon-specific RNA in 5/5 patients, an increase not apparent in T-helper chronic lymphoproliferative disorders. There was no correlation of this pattern of gene expression with the aggressive nature of the disease since T-cells from 2/5 suppressor disorders were actively proliferating.
Autoimmune Pancytopenia; Autoimmune Lymphoproliferative Syndrome (ALPS); Evans Syndrome; Idiopathic Thrombocytopenic Purpura; Anemia, Hemolytic, Autoimmune; Autoimmune Neutropenia; Lupus Erythematosus, Systemic; Inflammatory Bowel Disease; Rheumatoid Arthritis
Oliveira, João B; Bidère, Nicolas; Niemela, Julie E; Zheng, Lixin; Sakai, Keiko; Nix, Cynthia P; Danner, Robert L; Barb, Jennifer; Munson, Peter J; Puck, Jennifer M; Dale, Janet; Straus, Stephen E; Fleisher, Thomas A; Lenardo, Michael J
The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization, and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous, and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4(-), CD8(-) alphabeta T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving TNF receptor superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling, which markedly decreases the proapoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyltransferase inhibitors should be examined in human autoimmune and lymphocyte homeostasis disorders. PMID:17517660
Liver transplantation is believed to reverse the clinical and metabolic abnormalities of cirrhosis. Reduced skeletal muscle mass or sarcopenia contributes to increased mortality and adverse consequences of cirrhosis. Failure of reversal of sarcopenia of cirrhosis after liver transplantation is not well recognized. Six temporally, geographically, and methodologically distinct follow-up studies in 304 cirrhotics reported conflicting data on changes in indirect measures of skeletal muscle mass after transplantation. Distinct measures of body composition but not skeletal muscle mass were used and did not focus on the clinical consequences of sarcopenia after transplantation. A number of studies reported an initial rapid postoperative loss of lean mass followed by incomplete recovery with a maximum follow-up of 2 years. Posttransplant sarcopenia may be responsible for metabolic syndrome and impaired quality of life after liver transplantation. Potential reasons for failure to reverse sarcopenia after liver transplantation include use of immunosuppressive agents [mammalian target of rapamycin (mTOR) and calcineurin inhibitors] that impair skeletal muscle growth and protein accretion. Repeated hospitalizations, posttransplant infections, and renal failure also contribute to posttransplant sarcopenia. Finally, recovery from muscle deconditioning is limited by lack of systematic nutritional and physical-activity-based interventions to improve muscle mass. Despite the compelling data on sarcopenia before liver transplantation, the impact of posttransplant sarcopenia on clinical outcomes is not known. There is a compelling need for studies to examine the mechanisms and consequences of sarcopenia post liver transplantation to permit development of therapies to prevent and reverse this disorder. PMID:23912247
Sharma, Pratima; Bari, Khurram
Liver transplantation is the standard of care for patients with decompensated cirrhosis. Liver transplantation recipients have excellent short-term and long-term outcomes including patient and graft survival. Since the adoption of model for end-stage liver disease (MELD)-based allocation policy, the incidence of post-transplant end stage renal disease has risen significantly. Occurrence of Stage 4 chronic kidney disease and end stage renal disease substantially increases the risk of post-transplant deaths. Because majority of late post-transplant mortality is due to nonhepatic post-transplant comorbidities, personalized care directed toward risk factor modification may further improve post-transplant survival. PMID:26311603
Rubenstein, Jon Nicholas; Beatty, Colleen; Kinkade, Zoe; Bryan, Cara; Hogg, Jeffery Paul; Gibson, Laura F; Vos, Jeffrey A
Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT) is a problematic and sometimes controversial diagnosis. While commonly seen in the stomach in the setting of chronic Helicobacter pylori infection, other extranodal sites, such as the lung, may also present with disease. ENMZL is clinically and morphologically heterogeneous; however, regardless of presentation, the etiology lies in the accumulation of lymphoid tissue in non-traditional sites. This phenomenon is typically secondary to an underlying inflammatory stimulus such as chronic infection or autoimmune states. The current case report details the clinical history of a patient with Sjögren syndrome over a four year period who eventually developed ENMZL. The patient initially presented with an atypical, but polyclonal, lymphoproliferative process diagnosed as lymphocytic interstitial pneumonia. Over time, the patient showed evolution to a monoclonal process with associated radiologic progression of disease. This evolution manifested as a dense lymphoid infiltrate with prominent plasmacytic differentiation and the development of a lung mass radiologically. This case contributes to the growing body of knowledge that suggests ENMZL lies along a biological spectrum of lymphoproliferative disorders whereby a benign, reactive process may eventually undergo malignant transformation. This evolution likely represents the acquisition of genetic abnormalities that allow autonomous proliferation in the absence of the initial immune stimulus. In practice, determining when this event occurs and, thus, distinguishing between reactive and neoplastic disorders within this spectrum may be difficult as no single clinicopathologic feature may be present to establish the diagnosis. This case further illustrates the importance of correlating the clinical, radiologic and pathologic data to evaluate patients with atypical pulmonary lymphoproliferative disorders and to allow the optimal management of their disease.
Kingma, D W; Weiss, W B; Jaffe, E S; Kumar, S; Frekko, K; Raffeld, M
LMP-1, an Epstein-Barr viral (EBV) latency protein, is considered a viral oncogene because of its ability to transform rodent fibroblasts in vivo and render them tumorigenic in nude mice. In human B cells, EBV LMP-1 induces DNA synthesis and abrogates apoptosis. LMP-1 is expressed in EBV-transformed lymphoblastoid cell lines, nasopharyngeal carcinoma (NPC), a subset of Hodgkin's disease (HD), and in EBV-associated lymphoproliferative disorders (EBV-LPDs). Recently, focused deletions near the 3' end of the LMP-1 gene (del-LMP-1, amino acids 346-355), in a region functionally related to the half-life to the LMP-1 protein, have been reported frequently in human immunodeficiency virus (HIV)-associated HD (100%) and EBV+ Malaysian and Danish peripheral T-cell lymphomas (100%, 61% respectively), but less frequently in cases of HD not associated with HIV (28%, 33%) and infectious mononucleosis (33%). To further investigate the potential relationship of del-LMP-1 to EBV-LPDs associated with immunosuppression or immunodeficiency, we studied 39 EBV-associated lymphoproliferations (10 benign, 29 malignant) from four distinct clinical settings: posttransplant (4 malignant, 1 reactive); HIV+ (18 malignant, 2 reactive); nonimmunodeficiency malignant lymphoma (ML) (7 cases); and sporadic EBV infection with lymphoid hyperplasia (7 cases). The presence of EBV within lymphoid cells was confirmed by EBV EBER1 RNA in situ hybridization or by polymerase chain reaction (PCR) analysis. EBV strain type and LMP-1 deletion status were determined by PCR. EBV strain types segregated into two distinct distributions: HIV+ (9 A; 11 B) and non-HIV (19 A, 0 B), consistent with previous reports. Overall, del-LMP-1 were found in 1 of 5 (20%) Burkitt lymphomas (BL); 17 of 24 (71%) aggressive non-Hodgkin's lymphoma (agg-NHL), and 2 of 10 (20%) reactive lymphoid proliferations. Of the agg-NHLs, del-LMP-1 were present in 4 of 4 PT-ML (100%); 10 of 15 HIV+ ML (67%); and 3 of 5 nonimmunodeficiency malignant lymphoma (ML, 60%). A total of 2 of 7 (28%) sporadic EBV-associated lymphoid hyperplasias contained a del-LMP-1. All del-LMP-1 were identical by DNA sequence analysis. No correlation was identified between the presence of del-LMP-1 and the EBV strain type observed. The high incidence of del-LMP-1 observed in agg-NHLs (71%), in contrast to the relatively low incidence observed in reactive lymphoid proliferations (28%), suggests that the deleted form may be preferentially selected in lymphomatous processes. All posttransplant agg-NHLs contained a del-LMP-1, and a similar frequency of del-LMP-1 was observed in both HIV-associated ML (66%) and nonimmunodeficiency ML (60%), suggesting that impairment of immune function alone is not a requirement for the expansion of malignant cells infected by EBV stains containing the deleted LMP-1 gene. PMID:8704180
Stallone, Giovanni; Infante, Barbara; Grandaliano, Giuseppe
The central issue in organ transplantation remains suppression of allograft rejection. Thus, the development of immunosuppressive drugs has been the key to successful allograft function. The increased immunosuppressive efficiency obtained in the last two decades in kidney transplantation dramatically reduced the incidence of acute rejection. However, the inevitable trade-off was an increased rate of post-transplant infections and malignancies. Since the incidence of cancer in immunosuppressed transplant recipients becomes greater over time, and the introduction of new immunosuppressive strategies are expected to extend significantly allograft survival, the problem might grow exponentially in the near future. Thus, cancer is becoming a major cause of morbidity and mortality in patients otherwise successfully treated by organ transplantation. There are at least four distinct areas requiring consideration, which have a potentially serious impact on recipient outcome after transplantation: (i) the risk of transmitting a malignancy to the recipient within the donor organ; (ii) the problems of previously diagnosed and treated malignancy in the recipient; (iii) the prevention of de novo post-transplant malignant diseases and (iv) the management of these complex and often life-threatening clinical problems. In this scenario, the direct and indirect oncogenic potential of immunosuppressive therapy should be always carefully considered.
Wheat, William H.; Cool, Carlyne D.; Morimoto, Yoshikazu; Rai, Pradeep R.; Kirkpatrick, Charles H.; Lindenbaum, Barbara A.; Bates, Christopher A.; Ellison, Misoo C.; Serls, Amanda E.; Brown, Kevin K.; Routes, John M.
Patients who have common variable immunodeficiency (CVID) and granulomatous/lymphocytic interstitial lung disease (GLILD) are at high risk for early mortality and B cell lymphomas. Infection with human herpes virus type 8 (HHV8), a B cell lymphotrophic virus, is linked to lymphoproliferative disorders in people who have secondary immunodeficiencies. Therefore, we determined the prevalence of HHV8 infection in CVID patients with GLILD. Genomic DNA isolated from peripheral blood mononuclear cells was screened by nested- and real time-quantitative PCR (QRT-PCR) for the presence of HHV8 genome. It was positive in 6/9 CVID patients with GLILD (CVID-GLILD), 1/21 CVID patients without GLILD (CVID-control), and no patients receiving intravenous gamma globulin (n = 13) or normal blood donors (n = 20). Immunohistochemistry (IHC) demonstrated expression of the latency-associated nuclear antigen-1 (LANA-1) in the biopsies of the lung, liver, and bone marrow of four patients with CVID-GLILD. One CVID-GLILD patient developed a B cell lymphoma during the course of the study. QRT-PCR demonstrated high copy number of HHV8 genome and IHC showed diffuse staining for LANA-1 in the malignant lymph node. HHV8 infection may be an important factor in the pathogenesis of the interstitial lung disease and lymphoproliferative disorders in patients with CVID. PMID:16103407
Tomasian, Anderanik; Sandrasegaran, Kumar; Elsayes, Khaled M; Shanbhogue, Alampady; Shaaban, Akram; Menias, Christine O
The incidence of hematologic malignancies and their extranodal manifestations is continuously increasing. Previously unsuspected hepatic involvement in hematologic malignancies such as Hodgkin disease and non-Hodgkin lymphoma, posttransplant lymphoproliferative disorder, myeloid sarcoma (chloroma), multiple myeloma, Castleman disease, and lymphohistiocytosis may be seen by radiologists. Although the imaging features of more common hepatic diseases such as hepatocellular carcinoma, metastases, and infection may overlap with those of hepatic hematologic malignancies, combining the imaging features with clinical manifestations and laboratory findings can facilitate correct diagnosis. Clinical features that suggest a hematologic neoplasm as the cause of liver lesions include a young patient (<40 years of age), no known history of cancer, abnormal bone marrow biopsy results, fever of unknown origin, and night sweats. Imaging features that suggest hematologic malignancy include hepatosplenomegaly or splenic lesions, vascular encasement by a tumor without occlusion or thrombosis, an infiltrating mass at the hepatic hilum with no biliary obstruction, and widespread adenopathy above and below the diaphragm. Familiarity with the imaging features of hepatic hematologic malignancies permits correct provisional diagnosis and may influence therapeutic management. For example, when biopsy is performed, core biopsy may be needed in addition to fine-needle aspiration so that the tissue architecture of the neoplasm can be discerned. The predominant treatment of hematologic malignancies is chemotherapy or radiation therapy rather than surgery. Online supplemental material is available for this article. PMID:25590389
Hilgenfeldt, E; Firpi, R J
Hepatitis C virus (HCV)-related cirrhosis is the leading cause for liver transplantation (LT) in developed countries. One of the most troubling complications following LT in patients with HCV is that of recurrence. Unfortunately, this occurs in nearly all patients with HCV. Patients suffering recurrence are known to have faster times to fibrosis and consequently higher rates of graft failure. In general, patients whom undergo transplantation for HCV cirrhosis have higher mortalities comparatively. It is for this reason that HCV in post-transplant patients must be strictly monitored for and treated. Until recently, treatment with standard therapy or pegylated interferon and ribavirin was only marginally effective and the use in this population was off-label. With the advent of direct acting antivirals (DAA), hopes for improved sustained virologic response (SVR) exists. This review will attempt to provide an update regarding recent data for HCV treatment in post-transplant patients, and by doing so, hopefully shed light on a previously dim and dreaded illness. PMID:25390286
... with ALPS. These disorders can damage the kidneys (glomerulonephritis), liver (autoimmune hepatitis), eyes (uveitis), nerves (Guillain-Barre ... autoimmune leukoproliferative disorder National Institute of Allergy and Infectious Diseases (NIAID): ALPS Treatment You might also find ...
Ciurea, Stefan O; Zhang, Mei-Jie; Bacigalupo, Andrea A; Bashey, Asad; Appelbaum, Frederick R; Aljitawi, Omar S; Armand, Philippe; Antin, Joseph H; Chen, Junfang; Devine, Steven M; Fowler, Daniel H; Luznik, Leo; Nakamura, Ryotaro; O'Donnell, Paul V; Perales, Miguel-Angel; Pingali, Sai Ravi; Porter, David L; Riches, Marcie R; Ringdén, Olle T H; Rocha, Vanderson; Vij, Ravi; Weisdorf, Daniel J; Champlin, Richard E; Horowitz, Mary M; Fuchs, Ephraim J; Eapen, Mary
We studied adults with acute myeloid leukemia (AML) after haploidentical (n = 192) and 8/8 HLA-matched unrelated donor (n = 1982) transplantation. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate, and posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88 received reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737 received reduced intensity conditioning regimens. In the myeloablative setting, day 30 neutrophil recovery was lower after haploidentical compared with matched unrelated donor transplants (90% vs 97%, P = .02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96% (P = .25). In the myeloablative setting, 3-month acute grade 2-4 (16% vs 33%, P < .0001) and 3-year chronic GVHD (30% vs 53%, P < .0001) were lower after haploidentical compared with matched unrelated donor transplants. Similar differences were observed after reduced intensity conditioning transplants, 19% vs 28% (P = .05) and 34% vs 52% (P = .002). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 45% (95% CI, 36-54) and 50% (95% CI, 47-53) after haploidentical and matched unrelated donor transplants (P = .38). Corresponding rates after reduced intensity conditioning transplants were 46% (95% CI, 35-56) and 44% (95% CI, 0.40-47) (P = .71). Although statistical power is limited, these data suggests that survival for patients with AML after haploidentical transplantation with posttransplant cyclophosphamide is comparable with matched unrelated donor transplantation. PMID:26130705
Horie, N; Kawano, R; Kaneko, T; Shimoyama, T
Methotrexate (MTX) is the primary drug used in the management of rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. MTX is a strong immunosuppressive agent and has been reported to cause iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPDs). Stomatitis caused by MTX-related cytotoxicity may occur, but gingival MTX-related LPDs are rare. In this article we present a case of gingival MTX-related LPD in a 60-year-old male with RA. The local findings of the gingival ulceration and alveolar bone exposure were similar to those of bisphosphonate-related osteonecrosis of the jaw. However, he had never received bisphosphonate therapy. The biopsy specimen of the gingival lesion was diagnosed as diffuse large B-cell lymphoma with Epstein-Barr virus positivity. Immediate withdrawal of MTX resulted in marked remission of the LPD. PMID:25302816
Juvet, Stephen C; Thomson, Christopher W; Kim, Edward Y; Han, Mei; Zhang, Li
Patients with autoimmune lymphoproliferative syndrome (ALPS) and lymphoproliferation (LPR) mice are deficient in Fas, and accumulate large numbers of ??-TCR(+), CD4(-), CD8(-) double negative (DN) T cells. The function of these DN T cells remains largely unknown. The common ? subunit of the activating Fc receptors, FcR?, plays an important role in mediating innate immune responses. We have shown previously that a significant proportion of DN T cells express FcR?, and that this molecule is required for TCR transgenic DN T cells to suppress allogeneic immune responses. Whether FcR? plays a critical role in LPR DN T cell-mediated suppression of immune responses to auto and allo-antigens is not known. Here, we demonstrated that FcR?(+), but not FcR?(-) LPR DN T cells could suppress Fas(+) CD4(+) and CD8(+) T cell proliferation in vitro and attenuated CD4(+) T cell-mediated graft-versus host disease. Although FcR? expression did not allow LPR DN T cells to inhibit the expansion of Fas-deficient cells within the LPR context, adoptive transfer of FcR?(+), but not FcR?(-), DN T cells inhibited lymphoproliferation in generalized lymphoproliferative disease (GLD) mice. Furthermore, FcR? acted in a cell-intrinsic fashion to limit DN T cell accumulation by increasing the rate of apoptosis in proliferated cells. These results indicate that FcR? can confer Fas-dependent regulatory properties on LPR DN T cells, and suggest that FcR? may be a novel marker for functional DN Tregs. PMID:23762329
Araújo, A M; Santos, F; Guimarães, J; Nunes, C S; Casal, M
Renal transplantation from living donors represents a valuable opportunity for patients with end-stage renal disease due to short- and long-term outcomes. Nevertheless, it requires that a detailed set of conditions be considered for donor and recipient selection, with possible implications arising from these criteria in the post-transplant outcome. The present work aims to study demographic and clinical characteristics of donors and kidney recipients that predict post-transplantation outcomes after living donor kidney transplantation. With this aim, all patients who underwent donor nephrectomy and living donor transplantation between January 2012 and December 2013 were selected. Demographics, medical comorbidities, and postoperative outcomes were transcribed from electronic patient records. Linear and logistic regressions were applied for data analysis. The study sample consists of 40 patients who underwent living donor kidney transplantation. The presence of peripheral arterial disease and the etiology of end-stage renal disease were the only pretransplant variables that seem to independently predict hospitalization time. Simultaneously, the occurrence of urorenal and infectious complications had a statistically significant correlation with hospitalization time. Additionally, the incidence of cardiovascular complications was correlated with surgical reinterventions at a significant level. The results suggest that careful selection of the donor and the kidney recipient appears to be a prerequisite for a successful transplantation in vivo. PMID:26036489
Zimmermann, Heiner; Weiland, Theresa; Nourse, Jamie P; Gandhi, Maher K; Reinke, Petra; Neuhaus, Ruth; Karbasiyan, Mohsen; Gärtner, Barbara; Anagnostopoulos, Ioannis; Riess, Hanno; Trappe, Ralf U; Oertel, Stephan
We retrospectively analyzed the p.V158F polymorphism of Fc?-receptor IIIA (FCGR3A, CD16) in patients with PTLD treated with rituximab monotherapy. Previous reports had indicated that the lower affinity F allele affects rituximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and is linked to inferior outcome of rituximab monotherapy in B cell malignancies. 25 patients with PTLD after solid organ transplantation were included in this analysis. They had received 4 weekly doses of rituximab as part of two clinical trials, which had a rituximab monotherapy induction regimen in common. 16/25 patients received further treatment with CHOP-21 after rituximab monotherapy (PTLD-1, NCT01458548). The FCGR3A status was correlated to the response after 4 cycles of rituximab monotherapy. Response to rituximab monotherapy was not affected by F carrier status. This is in contrast to previous findings in B cell malignancies where investigators found a predictive impact of FCGR3A status on outcome to rituximab monotherapy. One explanation for this finding could be that ADCC is impaired in transplant recipients receiving immunosuppression. These results suggest that carrying a FCRG3A F allele does not negatively affect rituximab therapy in immunosuppressed patients. PMID:24741582
Stem Cell Transplantation; Bone Marrow Transplantation; Peripheral Blood Stem Cell Transplantation; Allogeneic Transplantation,; Genetic Diseases; Thalassemia; Pediatrics; Diamond-Blackfan Anemia; Combined Immune Deficiency; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; X-linked Lymphoproliferative Disease; Metabolic Diseases
Elkaim, Elodie; Picard, Christophe; Galambrun, Claire; Barlogis, Vincent; Loundou, Anderson; Curtillet, Catherine; Oudin, Claire; Thuret, Isabelle; Chambost, Hervé; Michel, Gérard
This study aimed to describe kinetics of complete donor chimerism occurrence (cDC, >99·9% donor) after unrelated cord blood transplantation (UCBT), to identify its predictive factors and its impact on post-transplant outcome. Ninety-four children who received single UCBT after a myeloablative conditioning regimen had blood chimerism evaluation at predefined post-transplant dates, using a real-time polymerase chain reaction method with 0·1% sensitivity. Cumulative incidence of cDC at 1 year post-transplantation was 61·8%. Three predictive factors were identified in multivariate analysis: history of malignant disease (P = 0·03), older age (above 2·16 years, the first quartile of age, P = 0·0055) and higher level of cord/recipient human leucocyte antigen mismatch (4/6 vs. 5-6/6, P < 0·001) increased the probability of post-transplant cDC. Although graft cell dose had a strong impact on haematological recovery, it did not apparently influence cDC occurrence. Early cDC (i.e. more than 99·9% donor chimerism on days 15-30 post-transplant) appeared useful to predict engraftment (P = 0·003) as well as acute and chronic graft-versus-host disease (GvHD). Severe acute or chronic GvHD never occurred in patients with DC ?99·9%, suggesting than even minimal residual host haematopoiesis is associated with a very low risk of GvHD after UCBT. PMID:24779895
Chronic Myeloproliferative Disorders; Graft Versus Host Disease; Leukemia; Lymphoma; Lymphoproliferative Disorder; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms
Sundaram Hariharan; Maureen A Mcbride; Wida S Cherikh; Christine B Tolleris; Barbara A Bresnahan; Christopher P Johnson
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
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
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
Ria, Roberto; Reale, Antonia; Melaccio, Assunta; Racanelli, Vito; Dammacco, Franco; Vacca, Angelo
Patients with lymphoproliferative disorders, candidate to autologous stem cell transplantation (ASCT), require mobilization with chemotherapy and granulocyte colony -stimulating factor (G-CSF). This study looked for differences in hematopoietic peripheral stem cells (HPSCs) mobilization in response to the three available G-CSFs, namely lenograstim, filgrastim, and pegfilgrastim. Between 2000 and 2012, 146 patients (66 M and 80 F) who underwent ASCT for multiple myeloma, non-Hodgkin's lymphoma or Hodgkin's lymphoma were studied. All patients received induction therapy and then a mobilization regimen with cyclophosphamide plus lenograstim, or filgrastim, or pegfilgrastim. From days 12 to 14, HPSCs were collected by two to three daily leukaphereses. Our results show that high-dose cyclophosphamide plus lenograstim achieved adequate mobilization and the collection target more quickly and with fewer leukaphereses as compared to filgrastim and pegfilgrastim. No differences between the three regimens were observed regarding toxicity and days to WBC and platelet recovery. Thus, lenograstim may represent the ideal G-CSF for PBSC mobilization in patients with lymphoproliferative diseases. Further studies are needed to confirm these results and better understand the biological bases of these differences. PMID:24722996
De Luna, R; Vuotto, M L; Ielpo, M T; Ambrosio, R; Piantedosi, D; Moscatiello, V; Ciaramella, P; Scalone, A; Gradoni, L; Mancino, D
Dogs are the domestic reservoirs of zoonotic visceral leishmaniasis caused by Leishmania infantum. Early detection of canine infections evolving to clinically patent disease may be important to leishmaniasis control. In this study we firstly investigated the peripheral blood mononuclear cell (PBMC) response to leishmanial antigens and to polyclonal activators concanavalin A, phytohemagglutinin and pokeweed mitogen, of mixed-breed dogs with natural L. infantum infection, either in presymptomatic or in patent disease condition, compared to healthy animals. Leishmania antigens did not induce a clear proliferative response in any of the animals examined. Furthermore, mitogen-induced lymphocyte proliferation was found strongly reduced not only in symptomatic, but also in presymptomatic dogs suggesting that the cell-mediated immunity is suppressed in progressive canine leishmaniasis. To test this finding, naive Beagle dogs were exposed to natural L. infantum infection in a highly endemic area of southern Italy. Two to 10 months after exposure all dogs were found to be infected by Leishmania, and on month 2 of exposure they all showed a significant reduction in PBMC activation by mitogens. Our results indicate that suppression of the lymphoproliferative response is a common occurrence in dogs already at the beginning of an established leishmanial infection. PMID:10507290
Rasche, L; Kapp, M; Einsele, H; Mielke, S
EBV-induced post transplantation lymphoproliferative disorder (EBV-PTLD) is a life-threatening complication after allogeneic hematopoietic cell transplantation. Profound T-cell depletion of the allograft represents a major risk factor for EBV-PTLD. With regard to the increasing use of alternative stem cell sources such as cord blood or purified haploidentical stem cell grafts both associated with impaired immune reconstitution, the frequent occurrence of EBV-PTLD demands particular vigilance on laboratory changes and early symptoms. Here we have summarized today's knowledge about EBV-PTLD in a comprehensive review explaining the underlying mechanisms of EBV-based transformation, EBV-PTLD development, clinical presentation, incidence, diagnosis, screening, therapy and prognosis. In this context, we emphasize on the necessity of regularly applied screening tools and pre-emptive treatment strategies including anti-CD20 Abs particularly in high-risk patients to avoid disease progression to malignant lymphoma. Although EBV-PTLD has always been associated with a high mortality rate, novel immunotherapeutic approaches such as the transfer of EBV-specific T cells nowadays offer improved chances of disease control even at late stages. PMID:23832092
Mora, Bassem N; Huddleston, Charles B
Heart transplantation is an accepted therapeutic modality for end-stage congenital heart disease for both biventricular and univentricular anomalies. Many transplant centers have pushed the limits of transplantation to include patients with high pulmonary vascular resistance, high panel reactive antibodies, positive cross-matches, and ABO-incompatibility. Excellent results have been possible, particularly with the development of improved diagnostic and therapeutic algorithms to prevent and treat rejection, infection, and post-transplant lymphoproliferative disease. Late graft failure and chronic rejection remain vexing problems. The vast majority of patients with biventricular congenital heart disease have undergone prior cardiac surgical procedures. Indications for transplantation in this subgroup are primarily progressive refractory heart failure following prior cardiac surgical reconstructive procedures. Contraindications to transplantation mimic those for other forms of end-stage heart disease. A determination of pulmonary vascular resistance is important in listing patients with biventricular congenital heart disease for heart transplantation. Modifications in the implant technique are necessary and vary depending on underlying recipient anatomy. Risk factors for perioperative outcomes in patients with biventricular congenital heart disease include the need for reoperation, the degree of anatomic reconstruction necessary during the implant procedure, and the degree of antibody sensitization, in addition to a number of other recipient and donor factors. Postoperative outcomes and survival are very good but remain inferior to those with cardiomyopathy in most series. In conclusion, patients with end-stage biventricular congenital heart disease represent a complex group of patients for heart transplantation, and require careful evaluation and management to ensure optimal outcomes. PMID:22548032
Huang, Qin; Chang, Karen L; Gaal, Karl K; Weiss, Lawrence M
Indolent NK-cell lymphoproliferative disorder, also known as chronic natural killer (NK) cell large granular lymphocytosis (leukemia), is a very rare entity in the World Health Organization (WHO) Classification of Tumors of Hematopoietic & Lymphoid Tissues. Unlike aggressive NK-cell leukemia, which is malignant, the WHO does not specify whether indolent NK-cell lymphoproliferative disorder is reactive or neoplastic. Patients with indolent NK-cell lymphoproliferative disorder are usually asymptomatic older adults who have a nonprogressive, very stable clinical course. We report an unusual case of an aggressive extranodal NK-cell lymphoma, non-nasal type, which presented as a subcutaneous tissue mass, which apparently transformed from a preexisting, untreated indolent NK-cell lymphoproliferative disorder in an 65-year-old otherwise healthy white man. The extranodal NK-cell lymphoma and the NK-cell lymphoproliferative disorder in the blood and bone marrow share a distinctive and identical NK-cell immunophenotype and genotype: CD56/CD8/TIA-1-positive and surface CD3-negative, negative for Epstein-Barr virus infection, and no evidence of T-cell and B-cell receptor gene rearrangements. To the best of our knowledge, such aggressive lymphomatous transformation in an indolent NK-cell lymphoproliferative disorder has not been previously reported. PMID:16224224
Introduction Myeloma following kidney transplantation is a rare entity. It can be divided into two groups: relapse of a previous myeloma and de novo myeloma. Some of these myelomas can be complicated by a monoclonal immunoglobulin deposition disease, which is even less common. Less than ten cases of monoclonal immunoglobulin deposition disease after renal graft have been reported in the literature. The treatment of these patients is not well codified. Case presentation We report the case of a 43-year-old white European man who received a renal transplant for a nephropathy of unknown etiology and developed a nephrotic syndrome with kidney failure at 2-years follow-up. We diagnosed a de novo monoclonal immunoglobulin deposition disease associated with a kappa light chain multiple myeloma, which is a very uncommon presentation for this disease. Three risk factors were identified in this patient: Epstein–Barr virus reactivation with cytomegalovirus co-infection; intensified immunosuppressive therapy during two previous rejection episodes; and human leukocyte antigen-B mismatches. Chemotherapy treatment and decrease in the immunosuppressive therapy were followed by remission and slight improvement of renal function. A relapse occurred 8 months later and his renal function worsened rapidly requiring hemodialysis. He died from septic shock 4 years after the diagnosis of monoclonal immunoglobulin deposition disease. Conclusions This rare case of post-transplant lymphoproliferative disorder with an uncommon presentation illustrates the fact that treatment in such a situation is very difficult to manage because of a small number of patients reported and a lack of information on this disease. There are no guidelines, especially concerning the immunosuppressive therapy management. PMID:24942882
Rao, V. Koneti
Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of apoptosis. It is frequently caused by mutations in FAS (TNFRSF6) gene. Unlike most of the self-limiting autoimmune cytopenias sporadically seen in childhood, multi lineage cytopenias due to ALPS are often refractory, as their inherited genetic defect is not going to go away. Historically, more ALPS patients have died due to overwhelming sepsis following splenectomy to manage their chronic cytopenias than due to any other cause, including malignancies. Hence, current recommendations underscore the importance of avoiding splenectomy in ALPS, by long-term use of corticosteroid-sparing immunosuppressive agents like mycophenolate mofetil and sirolimus. Paradigms learnt from managing ALPS patients in recent years is highlighted here and can be extrapolated to manage refractory cytopenias in patients with as yet undetermined genetic bases for their ailments. It is also desirable to develop international registries for children with rare and complex immune problems associated with chronic multilineage cytopenias in order to elucidate their natural history and long-term comorbidities due to the disease and its treatments. PMID:26258116
Luskin, M R; Heil, D S; Tan, K S; Choi, S; Stadtmauer, E A; Schuster, S J; Porter, D L; Vonderheide, R H; Bagg, A; Heitjan, D F; Tsai, D E; Reshef, R
We examined the associations of Epstein-Barr virus (EBV) status with characteristics and outcomes of posttransplantation lymphoproliferative disorder (PTLD) by studying 176 adult solid organ transplant recipients diagnosed with PTLD between 1990 and 2013 (58 [33%] EBV-negative; 118 [67%] EBV-positive). The proportion of EBV-negative cases increased over time from 10% (1990-1995) to 48% (2008-2013) (p?0.001). EBV-negative PTLD had distinct characteristics (monomorphic histology, longer latency) though high-risk features (advanced stage, older age, high lactate dehydrogenase, central nervous system involvement) were not more common compared to EBV-positive PTLD. In multivariable analysis, EBV negativity was not significantly associated with worse response to initial therapy (adjusted odds ratio, 0.84; p?=?0.75). The likelihood of achieving a complete remission (CR) was not significantly different for EBV-negative versus EBV-positive PTLD including when therapy was reduction of immunosuppression alone (35% vs. 43%, respectively, p?=?0.60) or rituximab (43% vs. 47%, p?=?1.0). EBV negativity was also not associated with worse overall survival (adjusted hazard ratio, 0.91; p?=?0.71). Our findings indicate that EBV status is not prognostic or predictive of treatment response in adults with PTLD. The high proportion of EBV-negative disease diagnosed in recent years highlights the need for new strategies for prevention and management of EBV-negative PTLD. PMID:25988622
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
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
Mark Perazella; Peter McPhedran; Alan Kliger; Marc Lorber; Elliott Levy; Margaret J. Bia
To determine the mechanism of action by which angiotensin-converting enzyme (ACE) inhibitors lower hematocrit in patients with posttransplant erythrocytosis, indices of red blood cell production and red blood cell destruction were obtained serially for 6 months from 10 renal transplant patients receiving treatment with enalapril for this problem. Before treatment, five patients had an elevated red blood cell mass, four
Jeroen Aalten; Ellen K. Hoogeveen; Joke I. Roodnat; Willem Weimar; George F. Borm; Johan W. de Fijter; Andries J. Hoitsma
The prevalence of cardiovascular risk factors in renal transplant candidates is high. A better understanding of the relation between these risk factors and cardiovascular morbidity and mortality is mandatory to improve transplantation outcome. In this retrospective cohort study 2187 adult patients who received a first kidney transplant between 1984 and 1997 were included. We analyzed the incidence of post-transplant cardiovascular
Molnar, Miklos Z; Foster, Clarence E; Sim, John J; Remport, Adam; Krishnan, Mahesh; Kovesdy, Csaba P; Kalantar-zadeh, Kamyar
Background Previous studies have indicated U-shaped associations between blood pressure (BP) and mortality in dialysis patients. We hypothesized that a similar association exists between pre-transplant BP and post-transplant outcomes in dialysis patients who undergo successful kidney transplantation. Methods Data from the Scientific Registry of Transplant Recipients were linked to the 5-year cohort of a large dialysis organization in the United States. We identified all dialysis patients who received a kidney transplant during this period. Unadjusted and multivariate adjusted predictors of transplant outcomes were examined. Results The 13,881 patients included in our study were 47±14 years old and included 42% women. There was no association between pre-transplant systolic BP and post-transplant mortality, although a decreased risk trend was observed in those with low post-dialysis systolic BP. Compared to patients with pre-dialysis diastolic BP 70–<80 mmHg, patients with pre-dialysis diastolic BP<50 mmHg experienced lower risk of post-transplant death (HR:0.74, 95%CI:0.55–0.99). However, compared to patients with post-dialysis diastolic BP 70–<80 mmHg, patients with post-dialysis diastolic BP?100 mmHg experienced higher risk of death (HR: 3.50, 95%CI: 1.57–7.84). In addition, very low (
Klein, Susan D.; Simmons, Roberta G.
As part of a larger study of transplantation and chronic disease and the family, 124 children (10-18 years old) who were chronically ill with kidney disease (n=72) or were a year or more post-transplant (n=52) were included in a study focusing on the effects of chronic kidney disease and transplantation on children's psychosocial development. Ss…
Ok, Chi Young; Li, Ling; Young, Ken H
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
Esteves, I; Bonfim, C; Pasquini, R; Funke, V; Pereira, N F; Rocha, V; Novis, Y; Arrais, C; Colturato, V; de Souza, M P; Torres, M; Fernandes, J F; Kerbauy, F R; Ribeiro, A A F; Santos, F P S; Hamerschlak, N
Patients with refractory severe aplastic anemia (SAA) who lack a matched sibling or unrelated donor need new therapeutic approaches. Hematopoietic SCT (HSCT) using mismatched or haploidentical related donors has been used in the past, but was associated with a significant risk of GVHD and mortality. Recently, the use of post-transplant cyclophosphamide (Cy) has been shown to be an effective strategy to prevent GVHD in recipients of haploidentical HSCT, but the majority of reports have focused on patients with hematology malignancies. We describe the outcome of 16 patients who underwent haploidentical transplantation using a reduced-intensity conditioning regimen with post-transplant Cy. Stem cell sources were BM (N=13) or PBSCs (N=3). The rate of neutrophil engraftment was 94% and of platelet engraftment was 75%. Two patients had secondary graft failure and were successfully salvaged with another transplant. Three patients developed acute GVHD being grades 2-4 in two. Five patients have died and the 1-year OS was 67.1% (95% confidence interval: 36.5-86.4%). In our small series, the use of a reduced-intensity conditioning with post-transplant Cy in haploidentical BMT was associated with high rates of engraftment and low risk of GVHD in patients with relapsed/refractory SAA. PMID:25730184
Liu, Hong; McCarthy, Philip
Treatment of multiple myeloma (MM) has evolved significantly over the past two decades with high-dose chemotherapy and autologous stem cell transplant (ASCT), incorporating novel therapies such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) during induction and post-transplant maintenance therapies. We reviewed the evolution of maintenance therapy from traditional chemotherapy, interferon (IFN), and prednisone to the current use of thalidomide, lenalidomide, and bortezomib in the post-transplant maintenance setting. Based on existing literature, either thalidomide or lenalidomide can be recommended for maintenance therapy post-transplant resulting in improved progression- free survival (PFS) and overall survival (OS). Thalidomide is less tolerated than lenalidomide and does not improve survival in patient subgroups who had achieved at least a very good partial response (VGPR) or who had chromosome 13 deletion. Thalidomide maintenance may be even detrimental in patients with high-risk cytogenetics. Alternatively, lenalidomide maintenance improves PFS in all subgroups of patients including those achieving at least a VGPR and those with high-risk cytogenetics, and improves OS in one other study. Bortezomib maintenance improves PFS and OS as part of induction and maintenance when compared to thalidomide maintenance and it is uncertain as to whether this improvement was due to bortezomib used during induction. The future research in maintenance therapy may include incorporation of current novel agents and testing new oral agents such as pomalidomide, or ixazomib or antibody therapy with elotuzumab. PMID:24135405
Shi, Min; Savage, Natasha M; Salman, Huda; Morice, William G
Key Clinical Message Distinguishing chronic lymphoproliferative disorder of NK-cells from aggressive NK-cell leukemia is critical because they have distinct clinical course and management. Immunophenotyping plays a key role in distinguishing these two entities, however, it could not be used as sole criteria and clinical/laboratory findings are equally important. PMID:26401278
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...
Kohli, Vikas; Wadhawan, Manav; Gupta, Subhash; Roy, Vipul
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.
Gualco, Gabriela; van den Berg, Anke; Koopmans, Sicco; Bacchi, Lívia M; Carneiro, Siderley S; Ruiz, Everaldo; Vecchi, Ana Paula; Chan, John K C
We present a case of autoimmune lymphoproliferative syndrome (ALPS) caused by a previously undescribed minimal deletion in the death domain of the FAS gene. ALPS is an uncommon disease associated with an impaired Fas-mediated apoptosis. The patient presented with a history of splenomegaly since 4 months of age, associated with cervical lymphadenopathy, which improved with oral corticosteroid treatment. Relevant laboratory findings were the presence of anemia, thrombocytopenia, and positive direct and indirect Coombs tests. He was not an offspring of consanguineous parents. Two cervical lymph node biopsies were performed, at 4 years and at 6 years of age. In both lymph nodes, there was marked paracortical expansion by lymphocytes in variable stages of immunoblastic transformation and a very high cell proliferating index. Some clear cells were also present, raising the suspicion of malignant lymphoma. In one of the lymph nodes, there was also a focus rich in large histiocytes with round nuclei and emperipolesis, consistent with focal Rosai-Dorfman disease. Immunostaining showed numerous CD3+ cells, many of which were double-negative (CD4- CD8-) and expressed CD57, especially around the follicles. Molecular studies of the lymph node biopsy showed a point deletion (4-base pair deletion) in exon 9 of the FAS gene (930del TGCT), which results in 3 missense amino acids. PMID:18070632
Genomics and Immunogenetics Marek’s disease (MD), a lymphoproliferative disease caused by the highly oncogenic herpesvirus Marek's disease virus (MDV), continues to be a major disease concern to the poultry industry. The fear of MD is further enhanced by unpredictable vaccine breaks that result in ...
Winberg, C D; Sheibani, K; Burke, J S; Wu, A; Rappaport, H
To differentiate peripheral T-cell lymphomas (PTCL), the authors evaluated the results of T11 monoclonal antibody studies on consecutive cell suspensions prepared from 509 lymph nodes from various lymphoproliferative disorders (LPD). They used T11 (CD2) positivity to identify those LPD in which the content of T cells was high. There were 266 (52%) cell suspensions which contained more than 50% T11-positive cells. More than 75% of the following non-Hodgkin's lymphomas had over 50% T11-positive cells: diffuse mixed cell (DM), diffuse atypical poorly differentiated lymphocytic and lymphoblastic lymphomas; mycosis fungoides; and true histiocytic lymphoma. Eleven cell suspensions had more than 90% T11-positive cells; four were involved by B-cell lymphomas. The cell suspensions prepared from nine of 14 diffuse large cell lymphomas of the T-cell type had more than 50% T11-positive cells. Of these, three of five cases of the polymorphous subtype had fewer than 50% T11 cells, but six of seven lymph nodes of the clear-cell type had more than 50% T11-positive cells. Each of seven DM samples of the T-cell type contained over 50% T11 cells; none had a polymorphous appearance. In the 112 cases of reactive LPD studied, more than 75% of cases of necrotizing lymphadenitis, dermatopathic lymphadenitis, angioimmunoblastic lymphadenopathy, and those with lymph nodes with no specific reactive pattern had more than 50% T11-positive cells. The authors' findings indicate that T11 positivity is a reliable T-cell marker in reactive and neoplastic LPD except for those cases of PTCL with a polymorphous appearance; these tend to lose T11-expression. A multi-parameter diagnostic approach is required in the following LPD: (1) PTCL which are T11-negative; (2) PTCL of small lymphocytic type having an unremarkable T-cell phenotype; (3) SIg-negative B-cell lymphomas which are rich in nonneoplastic T cells; (4) non-Hodgkin's lymphomas with minimal disease which are rich in reactive T cells; and (5) polymorphous large cell proliferations. PMID:2901904
Omodho, Lorna; Francis, Annick; Vander Borght, Sara; Marine, Jean-Christophe; van den Oord, Joost; Amant, Frédéric
Patient-derived tumor xenograft (PDTX) approach is nowadays considered a reliable preclinical model to study in vivo cancer biology and therapeutic response. NOD scid and Il2rg-deficient mice represent the “gold standard” host for the generation of PDTXs. Compared to other immunocompromised murine lines, these mice offers several advantages including higher engraftment rate, longer lifespan and improved morphological and molecular preservation of patient-derived neoplasms. Here we describe a spectrum of previously uncharacterized post-transplant disorders affecting 14/116 (12%) NOD.Cg- Prkdcscid Il2rgtm1Sug/JicTac (NOG) mice subcutaneously engrafted with patient-derived metastatic melanomas. Affected mice exhibited extensive scaling/crusting dermatitis (13/14) associated with emaciation (13/14) and poor/unsuccessful tumor engraftment (14/14). In this context, the following pathological conditions have been recognized and characterized in details: (i) immunoinflammatory disorders with features of graft versus host disease (14/14); (ii) reactive lymphoid infiltrates effacing xenografted tumors (8/14); (iii) post-transplant B cell lymphomas associated with Epstein-Barr virus reactivation (2/14). We demonstrate that all these entities are driven by co-transplanted human immune cells populating patient-derived tumor samples. Since the exploding interest in the utilization of NOD scid and Il2rg-deficient mice for the establishment of PDTX platforms, it is of uppermost importance to raise the awareness of the limitations associated with this model. The disorders here described adversely impact tumor engraftment rate and animal lifespan, potentially representing a major confounding factor in the context of efficacy and personalized therapy studies. The occurrence of these conditions in the NOG model reflects the ability of this mouse line to promote efficient engraftment of human immune cells. Co-transplanted human lymphoid cells have indeed the potential to colonize the recipient mouse initiating the post-transplant conditions here reported. On the other hand, the evidence of an immune response of human origin against the xenotransplanted melanoma opens intriguing perspectives for the establishment of suitable preclinical models of anti-melanoma immunotherapy. PMID:25996609
Sugita, Yasuo; Ohta, Masaru; Ohshima, Koichi; Niino, Daisuke; Nakamura, Yukihiko; Okada, Yosuke; Nakashima, Shinji
This report describes a case of an immunocompetent 77-year-old male with Epstein-Barr virus (EBV)-positive lymphoproliferative disorder associated with calcified chronic subdural hematoma (CSH). On the day prior to consultation in our outpatient clinic, the patient fell from his bed, striking his frontal head on the floor. Magnetic resonance imaging showed ill-defined lesions in the right frontal-temporal subdural regions. At surgery, a hard and thickened outer membrane of a CSH and muddy organized subdural hematoma were observed. However, macroscopic neoplastic lesions were not apparent. Histologically, there were atypical lymphoid cells scattered or conglomerated in some areas of the thick outer membrane of the CSH. They were composed of occasional large atypical lymphoid cells. The lesions were accompanied by necrosis. Atypical lymphoid cells were immunopositive for B-cell markers but not for T-cell markers. EBNA2 was seen in the nuclei of tumor cells. Atypical lymphoid cells showed positive signals for EBV-encoded small RNAs (EBERs) on in situ hybridization. These findings were consistent with EBV-positive lymphoproliferative disorder associated with CSH. These results also suggested that EBV and the inflammatory reaction found in the CSH could be the etiological factors in the pathogenesis of lymphoproliferative disorder. PMID:22612510
Marek's disease (MD) is a highly contagious lymphoproliferative disease of chickens caused by MD virus (MDV). Therefore, the control of MD is of particular concern to the poultry industry. The poultry industry has been heavily relying on biosecurity and vaccination to control the spread and occurren...
Grenzi, Patricia C; Campos, Érika F; Silva, Hélio T; Felipe, Claudia R; Franco, Marcelo F; Soares, Maria F; Medina-Pestana, José O; Gerbase-DeLima, Maria
Several studies have shown association of high pre- or post-transplant levels of soluble CD30 (sCD30) with acute rejection and poor late kidney transplant outcome. Our goal was to investigate whether sCD30 levels at month-3 post-transplant are associated with subclinical rejection, presence of CD30(+) cells within the graft, and expression of immune response genes in peripheral blood mononuclear cells. The study comprised 118 adult first kidney graft recipients, transplanted at a single center, receiving tacrolimus in low concentration. All were submitted to a protocol biopsy at month-3. Subclinical rejection was identified in 10 biopsies and sCD30 levels ? 61.88 ng/mL (P = 0.004), younger recipient age (P = 0.030) and non-Caucasian ethnicity (P = 0.011) were independently associated with this outcome. Rare CD30(+) cells were present in only two biopsies. There was a correlation between sCD30 levels and CD30 gene expression in peripheral blood mononuclear cells (r = 0.385, P = 0.043). These results show that high sCD30 levels are independent predictors of graft dysfunction and may contribute to patient selection protocols by indicating those who could benefit from a more thorough evaluation. PMID:25698648
Innes, A; Pal, C R; Dennis, M J; Ryan, J J; Morgan, A G; Burden, R P
Review of 142 renal transplant recipients treated with cyclosporin and prednisolone revealed 23 patients with post-transplant erythrocytosis. The clinical characteristics of these patients were compared with 23 cyclosporin/prednisolone-treated control subjects matched for age, sex, and duration of transplant. Erythrocytosis developed between 6 weeks and 30 months (median 12 months) after transplant. It persisted in 16 patients and resolved spontaneously in five. In two patients the decrease in haematocrit was associated with acute leukaemia in one and sudden deterioration of renal function in the other. In the study group there were fewer HLA (A, B and DR) mismatches (P less than 0.05) and greater pretransplant haematocrit (P less than 0.01) than in the control group. Other clinical factors--previous allografts, panel reactive cytotoxic antibodies, duration and type of dialysis, transplant function, pre- and post-transplant blood pressure, number of rejection episodes, cyclosporin concentration and dose, smoking habits and use of diuretics--did not differ significantly between the two groups. In our experience, erythrocytosis in cyclosporin-treated patients is a relatively common phenomenon and does not, in general, resolve spontaneously. It is unrelated to transplant function or rejection episodes but affects patients with well-matched kidneys and elevated pretransplant haematocrit values. PMID:1956559
Schlegel, Patrick; Lang, Peter; Zugmaier, Gerhard; Ebinger, Martin; Kreyenberg, Hermann; Witte, Kai-Erik; Feucht, Judith; Pfeiffer, Matthias; Teltschik, Heiko-Manuel; Kyzirakos, Christina; Feuchtinger, Tobias; Handgretinger, Rupert
We report on posttransplant relapsed pediatric patients with B-precursor acute lymphoblastic leukemia with no further standard of care therapy who were treated with the T-cell engaging CD19/CD3-bispecific single-chain antibody construct blinatumomab on a compassionate use basis. Blast load was assessed prior to, during and after blinatumomab cycle using flow cytometry to detect minimal residual disease, quantitative polymerase chain reaction for rearrangements of the immunoglobulin or T-cell receptor genes, and bcr/abl mutation detection in one patient with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dosage of 5 or 15 ?g/m(2)/day. Nine patients received a total of 18 cycles. Four patients achieved complete remission after the first cycle of treatment; 2 patients showed a complete remission from the second cycle after previous reduction of blast load by chemotherapy. Three patients did not respond, of whom one patient proceeded to a second cycle without additional chemotherapy and again did not respond. Four patients were successfully retransplanted in molecular remission from haploidentical donors. After a median follow up of 398 days, the probability of hematologic event-free survival is 30%. Major toxicities were grade 3 seizures in one patient and grade 3 cytokine release syndrome in 2 patients. Blinatumomab can induce molecular remission in pediatric patients with posttransplant relapsed B-precursor acute lymphoblastic leukemia and facilitate subsequent allogeneic hematopoietic stem cell transplantation from haploidentical donor with subsequent long-term leukemia-free survival. PMID:24727818
With high-density chicken rearing, control of infectious diseases are critical for economic viability and maintaining public confidence in poultry products. Among poultry diseases, Marek’s disease (MD), a lymphoproliferative disease caused by the highly oncogenic herpesvirus Marek's disease virus (M...
Marek’s disease virus (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...
Tokuhira, Michihide; Hanzawa, Kyoko; Watanabe, Reiko; Sekiguchi, Yasunobu; Nemoto, Tomoe; Toyozumi, Yasuo; Tamaru, Jun-ichi; Itoyama, Shinji; Suzuki, Katsuya; Kameda, Hideto; Mori, Shigehisa; Kizaki, Masahiro
Rheumatoid arthritis (RA) is an autoimmune disease mediated by inflammatory processes mainly at the joints. Recently, awareness of Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder (T-LPD) has been heightened for its association with methotraxate usage in RA patients. In the contrary, acute myeloid leukemia with multilineage dysplasia (AML-MLD) has never been documented to be present concomitantly with the above two conditions. In this report we present a case of an autopsy-proven co-existence of AML-MLD and EBV-associated T-LPD in a patient with RA. PMID:19566938
Loupy, Alexandre; Vernerey, Dewi; Tinel, Claire; Aubert, Olivier; Duong van Huyen, Jean-Paul; Rabant, Marion; Verine, Jérôme; Nochy, Dominique; Empana, Jean-Philippe; Martinez, Frank; Glotz, Denis; Jouven, Xavier; Legendre, Christophe; Lefaucheur, Carmen
Kidney allograft rejection can occur in clinically stable patients, but long-term significance is unknown. We determined whether early recognition of subclinical rejection has long-term consequences for kidney allograft survival in an observational prospective cohort study of 1307 consecutive nonselected patients who underwent ABO-compatible, complement-dependent cytotoxicity-negative crossmatch kidney transplantation in Paris (2000-2010). Participants underwent prospective screening biopsies at 1 year post-transplant, with concurrent evaluations of graft complement deposition and circulating anti-HLA antibodies. The main analysis included 1001 patients. Three distinct groups of patients were identified at the 1-year screening: 727 (73%) patients without rejection, 132 (13%) patients with subclinical T cell-mediated rejection (TCMR), and 142 (14%) patients with subclinical antibody-mediated rejection (ABMR). Patients with subclinical ABMR had the poorest graft survival at 8 years post-transplant (56%) compared with subclinical TCMR (88%) and nonrejection (90%) groups (P<0.001). In a multivariate Cox model, subclinical ABMR at 1 year was independently associated with a 3.5-fold increase in graft loss (95% confidence interval, 2.1 to 5.7) along with eGFR and proteinuria (P<0.001). Subclinical ABMR was associated with more rapid progression to transplant glomerulopathy. Of patients with subclinical TCMR at 1 year, only those who further developed de novo donor-specific antibodies and transplant glomerulopathy showed higher risk of graft loss compared with patients without rejection. Our findings suggest that subclinical TCMR and subclinical ABMR have distinct effects on long-term graft loss. Subclinical ABMR detected at the 1-year screening biopsy carries a prognostic value independent of initial donor-specific antibody status, previous immunologic events, current eGFR, and proteinuria. PMID:25556173
Mareks disease (MD) is a lymphoproliferative disease in chickens caused by Marek's disease virus (MDV) and characterized by T cell lymphoma and infiltration of lymphoid cells into various organs such as liver, spleen, peripheral nerves and muscle. Resistance to MD and disease risk have long been tho...
Marek's disease (MD) is a contagious lymphoproliferative and neurotropic disease of poultry caused by the Marek's disease virus (MDV), an oncogenic alphaherpesvirus. Despite the use of vaccines, field strains of MDV continue to evolve resulting in unpredictable disease outbreaks. Therefore, understa...
Sasisekhar, B.; Aparna, M.; Augustin, D. J.; Kaliraj, P.; Kar, S. K.; Nutman, T. B.; Narayanan, R. B.
Antigen-specific hyporesponsiveness to filarial antigens is a phenomenon observed in patent infection with lymph-dwelling filarial parasites of humans. This phenomenon has been attributed to a multitude of factors, one of which is altered monocyte function. To examine the role played by monocytes in filarial infection, we assessed the responses of monocytes obtained from normal and filarial parasite-infected individuals to both crude filarial antigen and purified recombinant filarial antigen WbSXP-1 and attempted to relate these to the altered lymphoproliferative responses seen in filarial infection. Monocytes from microfilaremic (MF) patients demonstrated an inability to respond to lipopolysaccharide compared to monocytes from endemic normal persons or from lymphedema patients. Indeed, interleukin 1? (IL-1?) production was severely limited, a finding that did not extend to monocyte responses to filarial antigens. Serum from MF patients reduced adherence and spreading of normal monocytes, a finding not seen with serum from the other clinical groups. Interestingly, there was a significant correlation between the production of IL-1? and adherence. Moreover, the levels of spontaneous production of IL-1? correlated with high levels of spontaneous secretion of IL-10. The effects observed were not a result of diminished viability or alteration in the expression of the cell surface markers CD14 and HLA-DR. These data suggest that monocyte function is dampened in MF patients, a finding which could alter lymphoproliferative responses during patent infection. PMID:15908365
Sugita, Junichi; Kawashima, Naomi; Fujisaki, Tomoaki; Kakihana, Kazuhiko; Ota, Shuichi; Matsuo, Keitaro; Miyamoto, Toshihiro; Akashi, Koichi; Taniguchi, Shuichi; Harada, Mine; Teshima, Takanori
Allogeneic hematopoietic stem cell transplantation (allo-SCT) using post-transplant cyclophosphamide (PTCy) is increasingly performed. We conducted a multicenter phase II study to evaluate the safety and efficacy of PTCy-based HLA-haploidentical peripheral blood stem cell transplantation (PTCy-haploPBSCT) after busulfan-containing reduced-intensity conditioning. Thirty-one patients were enrolled; 61% patients were not in remission and 42% patients had a history of prior allo-SCT. Neutrophil engraftment was achieved in 87% patients with a median of 19 days. The cumulative incidence of grades II to IV and III to IV acute graft-versus-host disease (GVHD) and chronic GVHD at 1 year were 23%, 3%, and 15%, respectively. No patients developed severe chronic GVHD. Day 100 nonrelapse mortality (NRM) rate was 19.4%. Overall survival, relapse, and disease-free survival rates were 45%, 45%, and 34%, respectively, at 1 year. Subgroup analysis showed that patients who had a history of prior allo-SCT had lower engraftment, higher NRM, and lower overall survival than those not receiving a prior allo-SCT. Our results suggest that PTCy-haploPBSCT after busulfan-containing reduced-intensity conditioning achieved low incidences of acute and chronic GVHD and NRM and stable donor engraftment and low NRM, particularly in patients without a history of prior allo-SCT. PMID:26093044
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...
Martin, Archer Kilbourne; Stauffer, John A
Castleman's disease is a rare lymphoproliferative disorder. Multiple variants of the disease exist, with differentiation based on tissue pathology and number of masses within the body. We present the medical diagnostic and surgical treatment pathway of a retroperitoneal unicentric hyaline vascular variant complicated by close proximity to major vascular structures. PMID:25118641
Perito, Emily Rothbaum; Rhee, Sue; Glidden, Dave; Roberts, John Paul; Rosenthal, Philip
Introduction In adult liver transplant recipients, donor BMI is associated with post-transplant obesity but not graft or patient survival. Given the U.S. obesity epidemic and already-limited supply of liver donors, clarifying whether donor BMI affects pediatric outcomes is important. Methods UNOS data on pediatric U.S. liver transplants 1990-2010 was evaluated. Data on transplants 2004-2010 (n=3788) was used for survival analysis with Kaplan-Meier and Cox proportional hazards models and for post-transplant obesity analysis with generalized estimating equations. Results For children receiving adult donor livers, donor BMI 25-35 kg/m2 was not associated with graft or patient survival in univariate or multivariate analyses. Donor BMI>35 kg/m2 increased the risk of graft loss (HR 2.54, 95%CI 1.29-5.01, p=0.007) and death (HR 3.56, 95%CI 1.64-7.72, p=0.001). For pediatric donors, donor BMI was not associated with graft loss or mortality in univariate or multivariate analysis. Donor overweight/obesity was not a risk factor for post-transplant obesity. Conclusions Overweight/obesity is common among liver transplant donors. This analysis suggests that for adult donors, BMI 25-35 should not by itself be a contraindication to liver donation. Severe obesity (BMI>35) in adult donors increased the risk of graft loss and mortality, even after adjustment for recipient, donor, and transplant risk factors. Post-transplant obesity was not associated with donor BMI in this analysis. Further research is needed to clarify the impact of donor obesity on pediatric liver transplant recipients. PMID:22467594
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...
Piazza, Antonina; Poggi, Elvira; Ozzella, Giuseppina; Adorno, Domenico
The development of de novo human leukocyte antigen (HLA) donor specific antibodies (DSA), detected by both cytotoxic or solid phase assays, was considered the major risk factor for allograft failure in kidney transplantation. However, it was shown that not all patients with persistent production of DSA suffered loss of their grafts. Modified Luminex-Single Antigen assays, able to identify C1q-fixing antibodies, represent a new strategy in assessing the clinical relevance of detected DSA. This study demonstrated that C1q-fixing capability of de novo DSA is a clinically relevant marker of worse outcome and inferior graft survival in kidney transplantation. In fact, our findings evidenced a very low graft survival only in the patients who developed DSA able to fix C1q during post-transplant course, while patients producing C1q-negative DSA had good graft survival, which was comparable to that found in our previous study for DSA-negative patients. Moreover, anti-HLA class II antibodies had a higher incidence than anti-HLA class I, and the ability to fix C1q was significantly more frequent among anti-DQ DSA than anti-DR DSA. Monitoring of de novo C1q-DSA production represents a useful, non-invasive tool for risk stratification and prediction of graft outcome in kidney transplantation. PMID:25095531
Chan, P C; Wei, D C; Tam, S C; Chan, F L; Yeung, W C; Cheng, I K
Seventeen patients with post-renal transplant erythrocytosis and 17 non-erythrocytotic controls, matched in age, sex, serum creatinine and source of donor kidney, were studied to determine the role of erythropoietin, male sex hormones (testosterone, FSH, LH), and various patient risk factors in post-transplant erythrocytosis. Serum erythropoietin was significantly greater in erythrocytotic patients (35.6 +/- 5.7 mU/ml) than non-erythrocytotic patients (18.8 +/- 2.6 mU/ml) (P less than 0.05) and normal subjects (22.5 +/- 0.95 mU/ml) P less than 0.05). Serum testosterone was similar between the male study (13.2 +/- 6.2 nmol/l) and control (13.1 +/- 6.0 nmol/l) patients. This might be due to the greater basal LH in the male control subjects (13.9 +/- 11.7 IU/l versus 8.0 +/- 3.3 IU/l in erythrocytotic males, P = 0.084). Basal FSH in the male controls was greater than that in the study group (13.7 +/- 14 IU/l versus 6.8 +/- 2.9 IU/l, P = 0.067). Among the demographic risk factors, only the smoking history was important. There were more smokers among the erythrocytotic patients than controls (P = 0.051). PMID:1314974
Kim, Ji Hyun; Kim, Seon-Ok; Han, Duck Jong; Park, Su-Kil
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
Lodding, I.P.; Sengeløv, H.; da Cunha-Bang, C.; Iversen, M.; Rasmussen, A.; Gustafsson, F.; Downing, J.G.; Grarup, J.; Kirkby, N.; Frederiksen, C.M.; Mocroft, A.; Sørensen, S.S.; Lundgren, J.D.
Background Cytomegalovirus (CMV) infection in transplant recipients is reported to replicate with a doubling time of 1.2–2 days, and weekly screening is recommended for early diagnosis. We re-evaluated these features in our cohort of transplant recipients. Methods The CMV doubling time of the first CMV infection in the first year post-transplant could be calculated for 193 recipients of haematopoietic stem cell or solid organ transplantation. Factors determining the proportion of recipients with a high diagnostic CMV viral load (? 18,200 IU/mL) were explored using mathematical simulation. Findings The overall median doubling time was 4.3 days (IQR 2.5–7.8) and was not influenced by prior CMV immunity, or type of transplantation (p > 0.4). Assuming a fixed doubling time of 1.3 days and screening intervals of 7 or 10 days, 11.1% and 33.3% were projected to have a high CMV viral load at diagnosis, compared to 1.4% and 4.3% if the doubling time varies as observed in our cohort. Consistently, 1.9% of recipients screened weekly had a high diagnostic virus load. Interpretation Screening intervals can be extended to 10 days in cohorts with comparable CMV doubling time, whereas shorter than 7 days is required in cohorts with shorter doubling times to maintain pre-emptive screening quality.
Flynn, Katy; Daiches, Anna; Malpus, Zoey; Yonan, Nizar; Sanchez, Melissa
Exploring patients' narratives can lead to new understandings about perceived illness states. Intensive Care Unit delirium is when people experience transitory hallucinations, delusions or paranoia in the Intensive Care Unit and little is known about how this experience affects individuals who have had a heart or lung transplant. A total of 11 participants were recruited from two heart and lung transplant services and were invited to tell their story of transplant and Intensive Care Unit delirium. A narrative analysis was conducted and the findings were presented as a shared story. This shared story begins with death becoming prominent before the transplant: 'you live all the time with Mr Death on your shoulder'. Following the operation, death permeates all aspects of dream worlds, as dreams in intensive care 'tunes into the subconscious of your fears'. The next part of the shared story offers hope of restitution; however, this does not last as reality creeps in: 'I thought it was going to be like a miracle cure'. Finally, the restitution narrative is found to be insufficient and individuals differ in the extent to which they can achieve resolution. The societal discourse of a transplant being a 'gift', which gives life, leads to internalised responsibility for the 'success' or 'failure' of the transplant. Participants describe how their experiences impact their sense of self: 'a post-transplant person'. The clinical implications of these findings are discussed. PMID:24026357
Marek’s disease (MD) is a lymphoproliferative disease of the domestic chicken caused by a highly infectious, oncogenic herpesvirus commonly referred to as Marek’s disease virus (MDV). MD has been controlled by vaccination with non-oncogenic turkey herpesvirus (HVT), non-oncogenic chicken herpesvirus...
Marek’s disease (MD) is a lymphoproliferative disease of domestic chickens caused by an immunosupperessive alpha herpesvirus, Marek’s disease virus (MDV). Clinical signs of MD include bursal/thymic atrophy and neurological disorders. The cecal tonsils (CT) are the largest lymphoid aggregates of avia...
Marek’s disease (MD) is a lymphoproliferative disease of chickens caused by gallid herpesvirus type 2 (GaHV-2). The disease is controlled through mass vaccination with live-attenuated strains. Attenuation of oncogenic GaHV-2 involves the serial passage of a virulent field isolate in avian embryo fib...
Marek’s disease (MD) is a lymphoproliferative disease of chickens caused by gallid herpesvirus type 2 (GaHV-2). The disease is controlled through mass vaccination with live-attenuated strains. Attenuation of oncogenic GaHV-2 involves the serial passage of a virulent field isolate in avian embryo fib...
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) 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) 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...
Marek’s disease (MD), a lymphoproliferative disease of domestic chickens, is caused by an avian alpha-herpesvirus, Marek’s disease virus (MDV). MDV causes an early cytolytic infection in B cells followed by a latency infection in CD4+ T cells. The transcriptional analysis of a limited number of MD...
Yu, Gordon H; Vergara, Norge; Moore, Erika M; King, Rebecca L
The diagnostic evaluation of fluid specimens, including serous effusions and cerebrospinal fluids (CSFs), can be challenging for a number of reasons. The evaluation of lymphoid proliferations in these specimens can be particularly problematic, given the frequent presence of coexisting inflammatory conditions and the manner in which these specimens are processed. As a result, immunophenotypic analysis of hematopoietic cell populations by flow cytometry has emerged as a useful ancillary study in the diagnosis of these specimens, both in patients with and without a previous history of a lymphoproliferative disorder. In this study, we review our experience with flow cytometry in fluid specimens over a four-year period. Flow cytometry was performed in 184 of 6,925 total cases (2.7% of all fluids). Flow cytometry was performed in 4.8% of pleural fluids (positive findings in 38%, negative in 40%, and atypical in 18%), 1.1% of peritoneal fluids (positive in 40%, negative in 50%, and atypical in 10%), 1.9% of pericardial fluids (positive in 67%, negative in 33%), and 1.9% of CSFs (positive in 23%, negative in 55%, atypical in 3%). The specimen submitted was inadequate for analysis in 9.2% of cases, most commonly with CSF specimens, but was not related to the volume of fluid submitted. Atypical flow cytometry findings and atypical morphologic findings in the context of negative flow cytometry results led to the definitive diagnosis of a lymphoproliferative disorder in a significant number of cases when repeat procedures and ancillary studies were performed. PMID:24554583
Zhang, Xiuming; Wang, Zhaoming; Wang, Lijun; Yao, Hongtian
Epstein-Barr virus-positive T/natural killer (NK)-cell lymphoproliferative disorder (EBV+T/NK LPD) encompasses a heterogeneous group of disorders that have a common feature with excessive lymphoid proliferation of mainly T cells and/or NK cells. This disease is rare, predominantly affects children and young adults, and associated with high mortality. Herein, we report a case of EBV+T/NK LPD that occurred in an old woman with good outcome. The patient presented with fever, splenomegaly, and pancytopenia. Computed tomography (CT) scan of the abdomen showed splenomegaly. The clinical impression was a malignant tumor of spleen, so splenectomy was performed. Microscopically, the architecture of the spleen was preserved. The white pulp Malpighian corpuscles were atrophied. The red pulp showed intact sinusoids and pulp cords with increased cellular infiltrate. The proliferating lymphoid cells were mostly small lymphoid cells with minimal or no nuclear atypia, mixed with rare medium-sized or large cells. Immunohistochemical study and in-situ hybridization showed that the EBER-positive lymphoid cells were positive for CD3 and CD56. They were also positive for cytotoxic molecules, such as T-cell restricted intracellular antigen (TIA1), granzyme B. The case exhibited polyclonal rearrangement of T-cell receptor gene (TCR) by polymerase chain reaction (PCR) studies. Without radiotherapy and chemotherapy, the patient is alive and well with no evidence of disease 25 months after surgery. PMID:24228130
Katagiri, T; Urakawa, K; Yamanashi, Y; Semba, K; Takahashi, T; Toyoshima, K; Yamamoto, T; Kano, K
Overexpression of a src family gene, lck, has been associated with differentiation of the murine thymic lymphoma line LSTRA. Recent findings by several groups strongly suggest a functional role for the gene product p56lck protein-tyrosine kinase (PTK) in the activation of normal T cells. A single recessive gene, lpr or gld, induces a lymphoproliferative disorder concomitant with autoimmune disease in mice. In this study, a 10-fold elevated activity of PTK encoded by fyn, another src family gene, was demonstrated in CD4-CD8- T cells in mutant mice. The increased PTK activity was consistent with overexpression of fyn mRNA. The elevated fyn mRNA expression appeared to be a characteristic of CD4-CD8- T cells, since it was not observed in normal T cells at any stage of differentiation. The fact that fyn mRNA expression was markedly induced in normal T cells by mitogenic stimulation with anti-T3 epsilon antiserum supports the possibility that p59fyn PTK is a signal-generating molecule in T cells. Thus, our findings provide insight into the physiological role for a src gene family kinase in T-cell development and contribute to a better understanding of the molecular mechanisms of disease-inducing recessive genes. Images PMID:2513573
Venuto, Rocco C; Meaney, Calvin J; Chang, Shirley; Leca, Nicolae; Consiglio, Joseph D; Wilding, Gregory E; Brazeau, Daniel; Gundroo, Aijaz; Nainani, Neha; Morse, Sarah E; Cooper, Louise M; Tornatore, Kathleen M
Extrarenal adverse effects (AEs) associated with calcineurin inhibitor (CNI) and mycophenolic acid (MPA) occur frequently but are unpredictable posttransplant complications. AEs may result from intracellular CNI accumulation and low activity of P-glycoprotein, encoded by the ABCB1 gene. Since ABCB1 single nucleotide polymorphisms (SNPs) and sex influence P-glycoprotein, we investigated haplotypes and extrarenal AEs.A prospective, cross-sectional study evaluated 149 patients receiving tacrolimus and enteric coated mycophenolate sodium or cyclosporine and mycophenolate mofetil. Immunosuppressive AE assessment determined individual and composite gastrointestinal, neurologic, aesthetic, and cumulative AEs. Lipids were quantitated after 12-hour fast. ABCB1 SNPs: c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642) were determined with haplotype associations computed using the THESIAS program, and evaluated by immunosuppression, sex and race using multivariate general linear models.Tacrolimus patients exhibited more frequent and higher gastrointestinal AE scores compared with cyclosporine with association to CTT (P?=?0.018) and sex (P?=?0.01). Aesthetic AE score was 3 times greater for cyclosporine with TTC haplotype (P?=?0.005). Females had higher gastrointestinal (P?=?0.022), aesthetic (P?0.001), neurologic (P?=?0.022), and cumulative AE ratios (P?0.001). Total cholesterol (TCHOL), low-density lipoproteins (LDL), and triglycerides were higher with cyclosporine. The TTC haplotype had higher TCHOL (P?0.001) and LDL (P?=?0.005). Higher triglyceride (P?=?0.034) and lower high-density lipoproteins (P?=?0.057) were associated with TTT with sex-adjusted analysis.ABCB1 haplotypes and sex were associated with extrarenal AEs. Using haplotypes, certain female patients manifested more AEs regardless of CNI. Haplotype testing may identify patients with greater susceptibility to AEs and facilitate CNI individualization. PMID:26376376
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
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
Viruses that cause cancers are a great threat to human and animal health. Marek’s disease (MD) in chickens is a lymphoproliferative disease caused by Marek’s disease virus (MDV). The over-expression of Hodgkin’s disease antigen in MD makes it an ideal model to study the progression mechanism of Hodg...
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 (MD) is a lymphoproliferative disease of chickens caused by gallid herpesvirus type 2 (GaHV-2). The disease is controlled through mass vaccination with live-attenuated strains. Attenuation of oncogenic GaHV-2 involves the serial passage of a virulent field isolate in avian embryo fib...
The serotype 1 Marek’s disease virus (MDV) is the causative agent for Marek’s disease (MD), a lymphoproliferative disease of chickens of great concern to the poultry industry. CVI988, an attenuated serotype 1 MDV, is currently the most efficacious commercially available vaccine for preventing MD. Ho...
Salva, Katrin A; Bennett, Daniel; Longley, Jack; Guitart, Joan; Wood, Gary S
Expression of the pan B-cell marker CD20 by T-cell lymphoproliferative disorders is exceedingly rare. We present a 52-year-old man with a unilesional cutaneous CD20 T-cell lymphoproliferative disorder. Multispectral imaging analysis of CD3-CD20 double-stained lesional tissue sections allowed (1) the visualization of double-positive T lymphocytes in situ with sensitivity superior to that of conventional immunohistochemistry and (2) the quantitative assessment of marker coexpression. Here, 23% of CD3 signals in the patient's lesion were also CD20, whereas 38% of CD20 signals were also CD3. In contrast, both parameters were below 1% in the tonsil control. Overall, the percentage of double-positive cells in lesional skin was 35%, although only 0.4% of such cells were detected in the tonsil. This is the first demonstration of aberrant CD20 expression by skin-infiltrating T cells using multispectral imaging. PMID:26381030
R. M. Lowenthal; D. M. Tuck; I. C. Bray
Background: Studies have shown an association between electromagnetic fieldsandchildhoodleukaemia.Theaimofthisstudywastodeterminewhether there is an increased risk of lymphoproliferative disorders (LPD) or myelopro- liferative disorders (MPD) associated with residence 300 m from high-voltage power lines. Methods: Case-control study of 854 patients diagnosed with LPD or MPD (including leukaemia, lymphoma and related conditions) aged 0-94 years comprising all cases diagnosed in Tasmania between 1972
Leticia Quintanilla-Martinez; Shimareet Kumar; Falko Fend; Edgardo Reyes; Julie Teruya-Feldstein; Douglas W. Kingma; Lynn Sorbara; Mark Raffeld; Stephen E. Straus; Elaine S. Jaffe
This study describes the clinicopathologic features of 5 patients who developed a fulminant Epstein-Barr virus (EBV)-posi- tive clonal T-cell lymphoproliferative disor- der (LPD) after acute EBV infection. One additional patient developed a similar disorder in the setting of long-standing chronic active EBV infection. Detailed immunophenotyping, in situ hybridization for EBV early RNA-1 (EBER1) and polymer- ase chain reaction (PCR) analyses
K. Monier; X. Michalet; J. Lamartine; C. Schurra; F. Heitzmann; L. Yin; R. Cinti; B. S. Sylla; M. Creaven; G. Porta; C. Vourc’h; M. Robert-Nicoud; A. Bensimon; G. Romeo
X-linked lymphoproliferative syndrome is an inherited immunodeficiency for which the responsible gene is currently unknown. Several megabase-sized deleted regions mapping to Xq25 have been identified in XLP patients, and more recently a 130-kb deletion has been reported (Lamartine et al., 1996; Lanyi et al., 1996). To establish a physical map of this deleted region and to identify the XLP gene,
Masaru Kojima; Naoya Nakamura; Hideaki Itoh; Ken Shimizu; Kazuhiko Shimizu; Hazuki Matsuda; Yoshio Tamaki; Nobuhide Masawa; Shigeo Nakamura
Background and Study Aim: Because of the small biopsy specimens in the Waldeyer’s ring (WR) the differential diagnosis between Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (LPD) and malignant lymphoma is occasionally difficult. We report here clinicopathological, immunohistochemical and genotypic findings of 9 cases of EBV-associated LPDs in WR. Patients and Methods: Using formalin-fixed paraffin-embedded sections, histological analyses, immunohistochemistry, in situ hybridization
Gulez, Nesrin; Aksu, Guzide; Berdeli, Afig; Karaca, Neslihan; Tanr?verdi, Sema; Kutukculer, Necil; Azarsiz, Elif
The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency characterized by recurrent episodes of hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphomas. Recently, X-linked inhibitor of apoptosis (XIAP/BIRC4) gene defects, in families with XLP but without SH2D1A gene defects, has been defined. The distinction from primary immunodeficiencies with a defined genetic cause is mandatory. A six-year-old male patient was admitted with the complaints of persistent general lymphadenopathy, for two years had fever, bilateral cervical multiple microlymphadenopathy, hepatic/splenic enlargement with laboratory findings as decreased serum immunoglobulins, negative EBV VCA IgM (viral capsid antigen) and anti-EBV EA (antibody to early D antigen), positive EBV VCA IgG (viral capsid antigen) and EBV EBNA (antibody to nuclear antigen). SH2D1A gene analysis was negative. XIAP/BIRC4 sequencing revealed two novel single nucleotide variants (exon 7, 1978G > A, and 1996T > A) in the 3?UTR of the gene in both patient and mother which were not disease causing. XIAP protein expression was found to be normal. The clinical and laboratory resemblance, no gene mutations, and normal XIAP protein expression led us to think that there may be another responsible gene for XLP. The patient will to be followed up as CVID until he presents new diagnostic signs or until the identification of a new gene. PMID:21541208
Al-Matham, Khalid; Alabed, Iehab; Zaidi, Syed Z A; Qushmaq, Khalid A
Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia. Although it can occur secondary to lymphoproliferative disorders and autoimmune or infectious diseases, CAD is rarely reported as secondary to solid tumors. We report a case of a woman aged 18 years diagnosed with a well-differentiated hepatocellular carcinoma of the fibrolamellar subtype, who was shown to have CAD also. Her general condition, including CAD, improved after targeted therapy with sorafenib for the hepatocellular carcinoma and only conservative measures for the CAD that consisted of avoidance of cold. In summary, although it is an extremely rare association and less common than lymphoproliferative disorders, CAD can be associated with solid tumors. PMID:21293066
Roberts, C A; Ayers, L; Bateman, E A L; Sadler, R; Magerus-Chatinet, A; Rieux-Laucat, F; Misbah, S A; Ferry, B L
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of dysregulated lymphocyte homeostasis. Biomarkers including elevated CD3+TCR??+CD4-CD8- double negative T cells (TCR??+ DNT), IL-10, sCD95L and vitamin B12 can be used to differentiate between ALPS and common variable immunodeficiency (CVID) patients with an overlapping clinical phenotype. We investigated the utility of ALPS biomarkers in 13 CVID patients with lymphoproliferation and/or autoimmune cytopaenia with comparison to 33 healthy controls. Vitamin B12 (P < 0.01) and IL-10 (P < 0.0001), but not sCD95L or TCR??+ DNT, were increased in CVID compared to controls. The 95th percentile for TCR??+ DNT in healthy controls was used to define a normal range up to 2.3% of total lymphocytes or 3.4% of T cells. These frequencies lie markedly beyond the cut offs used in current ALPS diagnostic criteria (? 1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes), suggesting these limits may have poor specificity for ALPS. PMID:23993982
George, Suraj Konnath; Teng, Rong; You, Xuefen; Xu, Mengqi; Liu, Hong; Sun, Xiaoping; Amin, Hesham M.; Shi, Wenyu
The T-cell lymphoproliferative neoplasms (T-LPN) are characterized by a poor clinical outcome. Current therapeutics are mostly non-selective and may induce harmful side effects. It has been reported that NOTCH1 activation mutations frequently associate T-LPN. Because anti-Notch1 based therapies such as ?-secretase inhibitors (GSI) are less efficient and induce considerable side effects, we hypothesized that combining low concentrations of GSI and the proteasome inhibitor bortezomib (BTZ) may provide an effective and tolerable approach to treat T-LPN. Hence, we analyzed the in vitro and in vivo effects of GSI-I and BTZ, alone or in combination, against T-LPN. GSI-I and BTZ synergistically decreased cell viability, proliferation, and colony formation, and induced apoptosis in T-LPN cell lines. Furthermore, combining GSI-I and BTZ decreased the viability of primary T-LPN cells from patients. These effects were accompanied by deregulation of Notch1, AKT, ERK, JNK, p38 MAPK, and NF-?B survival pathways. Moreover, combination treatment inhibited T-LPN tumor growth in nude mice. In all experiments, combining low concentrations of GSI-I and BTZ was superior to using a single agent. Our data support that a synergistic antitumor activity exists between GSI-I and BTZ, and provide a rationale for successful utilization of dual Notch1 and proteasome inhibition to treat T-LPN. PMID:25879451
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
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
Marek’s disease (MD) is a lymphoproliferative disease of chicken caused by cell-associated alpha-herpesvirus, known as Marek’s disease virus (MDV). MD virus load in challenged chickens has been well studied, but the difference between the virus load in vaccinated MD resistant and susceptible chicken...
Marek’s disease (MD) is a lymphoproliferative disease of domestic chickens caused by Marek’s disease virus (MDV), an oncogenic and highly contagious a-herpesvirus. MD has been controlled by vaccination but sporadic outbreaks of MD still occur in some parts of the world. Efforts to improve vaccine ef...
Nichols, K E; Harkin, D P; Levitz, S; Krainer, M; Kolquist, K A; Genovese, C; Bernard, A; Ferguson, M; Zuo, L; Snyder, E; Buckler, A J; Wise, C; Ashley, J; Lovett, M; Valentine, M B; Look, A T; Gerald, W; Housman, D E; Haber, D A
X-linked lymphoproliferative syndrome (XLP) is an inherited immunodeficiency characterized by increased susceptibility to Epstein-Barr virus (EBV). In affected males, primary EBV infection leads to the uncontrolled proliferation of virus-containing B cells and reactive cytotoxic T cells, often culminating in the development of high-grade lymphoma. The XLP gene has been mapped to chromosome band Xq25 through linkage analysis and the discovery of patients harboring large constitutional genomic deletions. We describe here the presence of small deletions and intragenic mutations that specifically disrupt a gene named DSHP in 6 of 10 unrelated patients with XLP. This gene encodes a predicted protein of 128 amino acids composing a single SH2 domain with extensive homology to the SH2 domain of SHIP, an inositol polyphosphate 5-phosphatase that functions as a negative regulator of lymphocyte activation. DSHP is expressed in transformed T cell lines and is induced following in vitro activation of peripheral blood T lymphocytes. Expression of DSHP is restricted in vivo to lymphoid tissues, and RNA in situ hybridization demonstrates DSHP expression in activated T and B cell regions of reactive lymph nodes and in both T and B cell neoplasms. These observations confirm the identity of DSHP as the gene responsible for XLP, and suggest a role in the regulation of lymphocyte activation and proliferation. Induction of DSHP may sustain the immune response by interfering with SHIP-mediated inhibition of lymphocyte activation, while its inactivation in XLP patients results in a selective immunodeficiency to EBV. PMID:9811875
Nichols, Kim E.; Harkin, D. Paul; Levitz, Seth; Krainer, Michael; Kolquist, Kathryn Ann; Genovese, Cameo; Bernard, Amy; Ferguson, Martin; Zuo, Lin; Snyder, Eric; Buckler, Alan J.; Wise, Carol; Ashley, Jennifer; Lovett, Michael; Valentine, Marcus B.; Look, A. Thomas; Gerald, William; Housman, David E.; Haber, Daniel A.
X-linked lymphoproliferative syndrome (XLP) is an inherited immunodeficiency characterized by increased susceptibility to Epstein–Barr virus (EBV). In affected males, primary EBV infection leads to the uncontrolled proliferation of virus-containing B cells and reactive cytotoxic T cells, often culminating in the development of high-grade lymphoma. The XLP gene has been mapped to chromosome band Xq25 through linkage analysis and the discovery of patients harboring large constitutional genomic deletions. We describe here the presence of small deletions and intragenic mutations that specifically disrupt a gene named DSHP in 6 of 10 unrelated patients with XLP. This gene encodes a predicted protein of 128 amino acids composing a single SH2 domain with extensive homology to the SH2 domain of SHIP, an inositol polyphosphate 5-phosphatase that functions as a negative regulator of lymphocyte activation. DSHP is expressed in transformed T cell lines and is induced following in vitro activation of peripheral blood T lymphocytes. Expression of DSHP is restricted in vivo to lymphoid tissues, and RNA in situ hybridization demonstrates DSHP expression in activated T and B cell regions of reactive lymph nodes and in both T and B cell neoplasms. These observations confirm the identity of DSHP as the gene responsible for XLP, and suggest a role in the regulation of lymphocyte activation and proliferation. Induction of DSHP may sustain the immune response by interfering with SHIP-mediated inhibition of lymphocyte activation, while its inactivation in XLP patients results in a selective immunodeficiency to EBV. PMID:9811875
Salesi, Mahmoud; Rostami, Zohreh; Rahimi Foroushani, Abbas; Mehrazmay, Ali Reza; Mohammadi, Jamile; Einollahi, Behzad; Asgharian, Saeed; Eshraghian, Mohammad Reza
Background: Malignancy is a common complication after renal transplantation. Death with functioning graft and chronic graft loss are two competing outcomes in patients with post-transplant malignancies. Objectives: The purpose of our study was to evaluate the risk factors associated with cumulative incidence of these two outcomes. Patients and Methods: Fine-Gray model was used for 266 cases with post-transplant malignancy in Iran. These patients were followed-up from the diagnosis until the date of last visit, chronic graft loss, or death, subsequently. Results: At the end of the study, as competing events, chronic graft loss and death with functioning graft were seen in 27 (10.2%) and 53 cases (19.9%), respectively, while 186 cases (69.9%) were accounted as censored. The incidence rate of death was approximately two-time of the incidence rate of chronic graft loss (8.6 vs. 4.4 per 100 person-years). In multivariate analysis, significant risk factors associated with cumulative incidence of death included age (P < 0.007, subhazard ratio (SHR) = 1.03), type of cancer (P < 0.0001), and response to treatment (P < 0.0001, SHR = 0.027). The significant risk factors associated with cumulative incidence of chronic graft loss were gender (P = 0.05, SHR = 0.37), treatment modality (P < 0.0001), and response to treatment (P = 0.048, SHR = 0.47). Conclusions: Using these factors, nephrologists may predict the occurrence of graft loss or death. If the probability of graft loss was higher, physicians can decrease the immunosuppressive medications dosage to decrease the incidence of graft loss. PMID:25032129
A comparative evaluation of the protective efficacy of rMd5-delta-Meq and CV1988/Rispens against a vv+ strain of Marek's disease virus infection in a series of recombinant congenic strains of white leghorn chickens
Marek’s disease (MD) is a lymphoproliferative disease of domestic chickens caused by a highly infectious, oncogenic alpha-herpesvirus known as Marek’s disease virus (MDV). MD is presently controlled by vaccination. Current MD vaccines include attenuated serotype 1 strains (e.g. CVI988/Rispens), avir...
Gattazzo, Cristina; Teramo, Antonella; Passeri, Francesca; De March, Elena; Carraro, Samuela; Trimarco, Valentina; Frezzato, Federica; Berno, Tamara; Barilà, Gregorio; Martini, Veronica; Piazza, Francesco; Trentin, Livio; Facco, Monica; Semenzato, Gianpietro; Zambello, Renato
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
Dal Bo, Michele; Bomben, Riccardo; Hernández, Luis; Gattei, Valter
MicroRNAs (miRNAs) represent a class of small non-coding single-stranded RNA molecules acting as master regulators of gene expression post transcriptionally by inhibiting the translation or inducing the degradation of target messenger RNAs (mRNAs). In particular, the miR-17-92 cluster is widely expressed in many different cell types and is essential for many developmental and pathogenic processes. As a strong oncogene, miR-17-92 can regulate multiple cellular processes that favor malignant transformation, promoting cell survival, rapid cell proliferation, and increased angiogenesis. The miR-17-92 cluster has been reported to be involved in hematopoietic malignancies including diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, and chronic lymphocytic leukemia. Given the multiple and potent effects on cellular proliferation and apoptosis exerted by the miR-17-92 cluster, miRNAs belonging to the cluster surely represent attractive targets for cancer therapy also in the context of lymphoproliferative disorders. In the present review, we focus on the role of the miR-17-92 cluster in lymphoproliferative disorders, including diagnostic/prognostic implications, and on the potential applications of anti-miRNAs based therapies targeting miRNAs belonging to the cluster. PMID:26305986
Mancarelli, Maria Michela; Verzella, Daniela; Fischietti, Mariafausta; Di Tommaso, Ambra; Maccarone, Rita; Plebani, Sara; Di Ianni, Mauro; Gulino, Alberto; Alesse, Edoardo
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
Pace, Romina; Vinh, Donald C.
Background. Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte homeostasis due to defects in FAS-mediated apoptosis. ALPS is characterized by childhood onset of chronic lymphadenopathy and splenomegaly, autoimmunity, an expanded population of double-negative T cells (DNTCs), and an increased risk of lymphoma. This propensity for lymphoma in ALPS is not well understood. It is possible that lymphomagenesis in some of these patients may result from Epstein-Barr virus (EBV) infection exploiting the defective T-cell surveillance resulting from impaired FAS-mediated apoptosis. Case Presentation. We report the first case, to our knowledge, of lymphoma in a patient with ALPS that was clinically heralded by progressively increasing EBV viremia. We discuss its practical implications and the possible immune pathways involved in the increased risk for EBV-associated lymphoproliferative disorders in ALPS patients. Conclusion. In patients with ALPS, distinguishing chronic lymphadenopathy from emerging lymphoma is difficult, with few practical recommendations available. This case illustrates that, at least for some patients, monitoring for progressively increasing EBV viremia may be useful. PMID:25374737
Lanyi, A.; Li, B.F.; Li, S. [Univ. of Nebraska Medical Center, Omaha, NE (United States)] [and others
X-linked lymphoproliferative disease (XLP) is characterized by a marked vulnerability in Epstein-Barr virus (EBV) infection. Infection of XLP patients with EBV invariably results in fatal mononucleosis, agammaglobulinemia or B-cell lymphoma. The XLP gene lies within a 10 cM region in Xq25 between DXS42 and DXS10. Initial chromosome studies revealed an interstitial, cytogenetically visible deletion in Xq25 in one XLP family (43-004). We estimated the size of the Xq25 deletion by dual laser flow karyotyping to involve 2% of the X chromosome, or approximately 3 Mbp of DNA sequences. To further delineate the deletion we performed a series of pulsed field gel electrophoresis (PFGE) analyses which showed that DXS6 and DXS100, two Xq25-specific markers, are missing from 45-004 DNA. Five yeast artificial chromosomes (YACs) from a chromosome X specific YAC library containing sequences deleted in patient`s 43-004 DNA were isolated. These five YACs did not overlap, and their end fragments were used to screen the CEPH MegaYAC library. Seven YACs were isolated from the CEPH MegaYAC library. They could be arranged into a contig which spans between DXS6 and DXS100. The contig contains a minimum of 2.5 Mbp of human DNA. A total of 12 YAC end clone, lambda subclones and STS probes have been used to order clones within the contig. These reagents were also used in Southern blot and patients showed interstitial deletions in Xq25. The size of these deletions range between 0.5 and 2.5 Mbp. The shortest deletion probably represents the critical region for the XLP gene.
Canaud, Guillaume; Legendre, Christophe
Recurrence of disease after transplantation is frequent and represents the third cause of allograft loss. Recurrence of lupus nephritis after transplantation is rare. Kidney transplantation in patients with antiphospholipid syndrome or lupus anticoagulant is challenging due to the high risk of immediate post-transplant thrombosis and bleeding risk associated to the subsequent anticoagulation. Moreover, vascular changes associated to the presence of antiphospholipid antibodies negatively impact allograft rate survival. Recurrence of pauci immune glomerulonephritis or Goodpasture syndrome is exceptional. PMID:22244721
Marek’s disease (MD) is a lymphoproliferative disease of chicken caused by serotype 1 MD virus (MDV). Vaccination of commercial poultry has drastically reduced losses from MD and the poultry industry cannot be sustained without the use of vaccines. Retrovirus insertion into herpesviruses genome is a...
Zhang, Kun; Gao, Baoshan; Wang, Yuantao; Wang, Gang; Wang, Weigang; Zhu, Yaxiang; Yao, Liyu; Gu, Yiming; Chen, Mo; Zhou, Honglan; Fu, Yaowen
Since the association of serum uric acid and kidney transplant graft outcome remains disputable, we sought to evaluate the predictive value of uric acid level for graft survival/function and the factors could affect uric acid as time varies. A consecutive cohort of five hundred and seventy three recipients transplanted during January 2008 to December 2011 were recruited. Data and laboratory values of our interest were collected at 1, 3, 6, 12, 24 and 36 months post-transplant for analysis. Cox proportional hazard model, and multiple regression equation were built to adjust for the possible confounding variables and meet our goals as appropriate. The current cohort study lasts for 41.86 ± 15.49 months. Uric acid level is proven to be negatively associated with eGFR at different time point after adjustment for age, body mass index and male gender (standardized ? ranges from -0.15 to -0.30 with all P<0.001).Males with low eGFR but high level of TG were on CSA, diuretics and RAS inhibitors and experienced at least one episode of acute rejection and diabetic issue were associated with a higher mean uric acid level. Hyperuricemia was significantly an independent predictor of pure graft failure (hazard ratio=4.01, 95% CI: 1.25-12.91, P=0.02) after adjustment. But it was no longer an independent risk factor for graft loss after adjustment. Interestingly, higher triglyceride level can make incidence of graft loss (hazard ratio=1.442, for each unit increase millimoles per liter 95% CI: 1.008-2.061, P=0.045) and death (hazard ratio=1.717, 95% CI: 1.105-2.665, P=0.016) more likely. The results of our study suggest that post-transplant elevated serum uric acid level is an independent predictor of long-term graft survival and graft function. Together with the high TG level impact on poor outcomes, further investigations for therapeutic effect are needed. PMID:26208103
Havrdova, T; Jedinakova, T; Lipar, K; Skibova, J; Saudek, F
Diabetogenic effects of immunosuppressive agents are of great importance in pancreas or islet transplantation. The aim of our study was to compare the glucose metabolism in type 1 diabetic kidney and pancreas recipients on tacrolimus (Tacro) versus cyclosporine-based (Cyclo) immunosuppression in the late posttransplant period. We examined 26 insulin-independent patients with stabile good renal function. They were at least 7 years after simultaneous pancreas and kidney transplantation and with unchanged immunosuppressive therapy for at least 6 years. The mean follow-up in Tacro (n = 13) and Cyclo (n = 13) groups were 9.7 ± 1.9 and 10.9 ± 1.3 years, respectively (P = .08). Fasting glycemia, insulin levels, glycosylated hemoglobin (HbA(1c)), a standard intravenous glucose tolerance test (IVGTT) with coefficient of glucose assimilation (K(G)) calculation and trough Tacro/Cyclo levels were assessed. Insulin sensitivity and insulin secretion were evaluated using the homeostasis model assessment (HOMA-IR, HOMA-B). Total C-peptide and insulin secretions were calculated as areas under the curves (AUC) from the serum levels during the IVGTT. Tacro and Cyclo groups did not differ in age and body mass index. We did not find any significant difference in any examined parameters of glucose metabolism (fasting glycemia, insulin and C-peptide levels, HbA(1c,) IVGTT with K(G), HOMA-IR, HOMA-B, AUC of C-peptide and AUC of insulin; P > .05). Two patients in the Tacro group and none in the Cyclo group had K(G) <0.8%/min. Seven recipients in the Tacro group and eight in the Cyclo group had the normal glucose tolerance with K(G) ? 1.2%/min. Trough Tacro or Cyclo levels did not correlate with any of examined parameters. The use of different types of calcineurin inhibitors in type 1 diabetic pancreas and kidney recipients had no effect on glucose metabolism in the late posttransplant period. PMID:22099774
Johne’s disease in ruminants is a chronic infection of the intestines caused by Mycobacterium avium subsp. paratuberculosis. Economic losses associated with Johne’s disease arise due to premature culling, reduced production of milk and wool and mortalities. The disease is characterised by a long inc...
Parisi, Ioanna; Tsochatzis, Emmanuel; Wijewantha, Hasitha; Rodríguez-Perálvarez, Manuel; De Luca, Laura; Manousou, Pinelopi; Fatourou, Evangelia; Pieri, Giulia; Papastergiou, Vassilios; Davies, Neil; Yu, Dominic; Luong, TuVinh; Dhillon, Amar Paul; Thorburn, Douglas; Patch, David; O'Beirne, James; Meyer, Tim; Burroughs, Andrew K
Increased preoperative inflammation scores, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and inflammation-based index (IBI) have been related to post-transplant HCC recurrence. We evaluated the association between inflammation-based scores (NLR, PLR, IBI) and post-LT HCC recurrence as well as tumor necrosis after transarterial embolization. 150 consecutive patients who underwent transplantation for HCC within the Milan criteria between 1996 and 2010 were included; data regarding inflammatory markers, patient and tumor characteristics were analyzed. NLR, PLR, and IBI were not significantly associated with post-LT HCC recurrence or worse overall survival. Increased NLR and PLR were associated with complete tumor necrosis in the subset of patients who received preoperative transarterial embolization (P < 0.05). Cox regression analysis revealed that absence of neoadjuvant transarterial therapy (OR = 4.33, 95% CI = 1.28-14.64; P = 0.02) and no fulfillment of the Milan criteria in the explanted liver (OR = 3.34, 95% CI = 1.08-10.35; P = 0.04) were independently associated with post-LT HCC recurrence inflammation-based scores did not predict HCC recurrence post-LT in our group of patients. NLR and PLR were associated with better response to TAE, as this was recorded histologically in the explanted liver. Histological fulfillment of the Milan criteria and absence of neoadjuvant transarterial treatment were significantly associated with post-LT HCC recurrence. PMID:25088400
Perito, E. R.; Mohammad, S.; Rosenthal, P.; Alonso, E. M.; Ekong, U. D.; Lobritto, S. J.; Feng, S.
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
Suessmuth, Yvonne; Mukherjee, Rithun; Watkins, Benjamin; Koura, Divya T.; Finstermeier, Knut; Desmarais, Cindy; Stempora, Linda; Horan, John T.; Langston, Amelia; Qayed, Muna; Khoury, Hanna J.; Grizzle, Audrey; Cheeseman, Jennifer A.; Conger, Jason A.; Robertson, Jennifer; Garrett, Aneesah; Kirk, Allan D.; Waller, Edmund K.; Blazar, Bruce R.; Mehta, Aneesh K.; Robins, Harlan S.
Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme Bhigh/CD28low/CD57high/CD8+ effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31+/CD4+ putative thymic emigrants. T-cell receptor ? (TCR?) deep sequencing revealed a striking contraction of CD8+ Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials.gov as #NCT01012492. PMID:25852054
Marciano, Sebastián; Galdame, Omar Andrés; Barcan, Laura Alicia; Gadano, Adrián Carlos
Hepatitis C recurrence is the main cause of graft loss in liver transplant patients co-infected with human immunodeficiency virus (HII). These patients have higher risk of fibrosing cholestatic hepatitis, which is the most severe type of hepatitis C recurrence. Until direct antiviral agents were released, only a minority of patients could be satisfactorily treated. We describe the successful treatment with pegylated-interferon, ribavirin and telaprevir of an hepatitis C virus (HCV)/HIV co-infected patient who developed fibrosing cholestatic hepatitis after liver transplantation. A 40-year- old male (HCV genotype 1a; IL-28 CC) underwent liver transplantation for decompensated cirrhosis. On post-transplant day 60, he rapidly developed progressive jaundice, worsening of liver function tests and ascites. A transjugular liver biopsy confirmed the diagnosis of fibrosing cholestatic hepatitis. Treatment with peglated-interferon, ribavirin and telaprevir was indicated for 48 weeks, achieving sustained virological response at 12 weeks of follow-up. The rapid negativization of the viral load observed during the first 4 weeks of treatment was associated with regression of ascites andjaundice. Red blood cell transfusions, erythropoietin and filgrastim were required for the management of anemia and neutropenia. Triple therapy with telaprevir might be indicated for the treatment of severe HCV recurrence in selected HCV/HIV co-infected patients, especially in countries with limited access to pegylated-interferon-free regimens. PMID:26076519
Martin, D A; Zheng, L; Siegel, R M; Huang, B; Fisher, G H; Wang, J; Jackson, C E; Puck, J M; Dale, J; Straus, S E; Peter, M E; Krammer, P H; Fesik, S; Lenardo, M J
Heterozygous mutations in the CD95 (APO-1/Fas) receptor occur in most individuals with autoimmune lymphoproliferative syndrome (ALPS) and dominantly interfere with apoptosis by an unknown mechanism. We show that local or global alterations in the structure of the cytoplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a failure to bind the FADD/MORT1 signaling protein. Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking. These data suggest that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1. PMID:10200300
Maluf, Daniel G; Dumur, Catherine I; Suh, Jihee L; Scian, Mariano J; King, Anne L; Cathro, Helen; Lee, Jae K; Gehrau, Ricardo C; Brayman, Kenneth L; Gallon, Lorenzo; Mas, Valeria R
Non-invasive, cost-effective biomarkers that allow accurate monitoring of graft function are needed in kidney transplantation. Since microRNAs (miRNAs) have emerged as promising disease biomarkers we sought to establish an miRNA signature in urinary cell pellets comparing kidney transplant patients diagnosed with chronic allograft dysfunction (CAD) with interstitial fibrosis and tubular atrophy and those recipients with normal graft function. Overall, we evaluated 191 samples from 125 deceased donor primary kidney transplant recipients in the discovery, initial validation and the longitudinal validation studies for non-invasive monitoring of graft function. Of 1,733 mature miRNAs studied using microarrays, 22 were found to be differentially expressed between groups. Ontology and pathway analyses showed inflammation as the principal biological function associated with these miRNAs. Twelve selected miRNAs were longitudinally evaluated in urine samples of an independent set of 66 patients, at two time-points post-kidney transplant. A subset of these miRNAs was found to be differentially expressed between groups early post-kidney transplant before histological allograft injury was evident. Thus, a panel of urine miRNAs was identified as potential biomarkers for monitoring graft function and anticipating progression to CAD in kidney transplant patients. PMID:24025639
Maluf, Daniel G; Dumur, Catherine I; Suh, Jihee L; Scian, Mariano J; King, Anne L; Cathro, Helen; Lee, Jae K; Gehrau, Ricardo C; Brayman, Kenneth L; Gallon, Lorenzo; Mas, Valeria R
Noninvasive, cost-effective biomarkers that allow accurate monitoring of graft function are needed in kidney transplantation. Since microRNAs (miRNAs) have emerged as promising disease biomarkers, we sought to establish an miRNA signature in urinary cell pellets comparing kidney transplant patients diagnosed with chronic allograft dysfunction (CAD) with interstitial fibrosis and tubular atrophy and those recipients with normal graft function. Overall, we evaluated 191 samples from 125 deceased donor primary kidney transplant recipients in the discovery, initial validation, and the longitudinal validation studies for noninvasive monitoring of graft function. Of 1733 mature miRNAs studied using microarrays, 22 were found to be differentially expressed between groups. Ontology and pathway analyses showed inflammation as the principal biological function associated with these miRNAs. Twelve selected miRNAs were longitudinally evaluated in urine samples of an independent set of 66 patients, at two time points after kidney transplant. A subset of these miRNAs was found to be differentially expressed between groups early after kidney transplant before histological allograft injury was evident. Thus, a panel of urine miRNAs was identified as potential biomarkers for monitoring graft function and anticipating progression to CAD in kidney transplant patients. PMID:24025639
Ricciardelli, Ida; Blundell, Michael Patrick; Brewin, Jennifer; Thrasher, Adrian; Pule, Martin
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
E Meijer; ICM Slaper-Cortenbach; SFT Thijsen; AW Dekker; LF Verdonck
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
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
Fujii, Etsuko; Kato, Atsuhiko; Chen, Yu Jau; Matsubara, Koichi; Ohnishi, Yasuyuki; Suzuki, Masami
Human tumor tissue line models established in the severely immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Sug/Jic (NOD/Shi-scid, IL-2R?null or NOG) mouse are important tools for oncology research. During the establishment process, a lymphoproliferative lesion (LPL) that replaces the original tumor cells in the site of transplantation occurs. In the present study, we studied the impact of the LPL on the establishment process and the characteristics of the lesion, investigated the systemic distribution of the lesion in the mouse, and evaluated the potential of a simple identification method. The incidence of the lesion varied among tumor types, and the lesion was found to be the leading cause of unsuccessful establishment with gastric and colorectal cancer. The lesion consisted of a varying population of proliferating lymphoid cells that expressed CD20. The cells were positive for Epstein-Barr virus (EBV)-related antigens, and EBV DNA was detected. There was systemic distribution of the lesion within the NOG mouse, and the most consistent gross finding was splenomegaly. Additionally, identification of LPL-affected cases was possible by detecting splenomegaly in the 1st and 2nd generation mice at necropsy. From our findings the lesion was judged to arise from EBV-infected B cells originating from the donor, and monitoring splenomegaly at necropsy was thought effective as a simple method for identifying the lesion at an early stage of the establishment process. PMID:25077758
Monier, K; Michalet, X; Lamartine, J; Schurra, C; Heitzmann, F; Yin, L; Cinti, R; Sylla, B S; Creaven, M; Porta, G; Vourc'h, C; Robert-Nicoud, M; Bensimon, A; Romeo, G
X-linked lymphoproliferative syndrome is an inherited immunodeficiency for which the responsible gene is currently unknown. Several megabase-sized deleted regions mapping to Xq25 have been identified in XLP patients, and more recently a 130-kb deletion has been reported (Lamartine et al., 1996; Lanyi et al., 1996). To establish a physical map of this deleted region and to identify the XLP gene, two cosmid contigs were established (Lamartine et al., 1996). However, the physical map of this region is still uncompleted and controversial and three points remain unsolved: (1) the centromeric-telomeric orientation of the whole region, (2) the relative orientation of the two contigs, and (3) the size of the gap between the two contigs. To provide a definitive answer to these questions, high-resolution mapping by fluorescence in situ hybridization on combed DNA and molecular approaches were combined to establish the physical map of the XLP region over 600 kb. Our results identified a gap of 150 kb between the two contigs, established the relative orientation of one contig to the other, and determine the centromeric-telomeric orientation of the whole region. Our results show that the order of the marker over this region is: cen.1D10T7-DF83-DXS982.tel. PMID:9730614
Screpanti, I; Romani, L; Musiani, P; Modesti, A; Fattori, E; Lazzaro, D; Sellitto, C; Scarpa, S; Bellavia, D; Lattanzio, G
C/EBP beta is considered a key element of interleukin-6 (IL-6) signalling as well as an important transcriptional regulator of the IL-6 gene itself. We describe here how mice lacking C/EBP beta develop a pathology similar to mice overexpressing IL-6 and nearly identical to multicentric Castleman's disease in human patients, with marked splenomegaly, peripheral lymphadenopathy and enhanced haemopoiesis. Humoral, innate and cellular immunity are also profoundly distorted, as shown by the defective activation of splenic macrophages, the strong impairement of IL-12 production, the increased susceptibility to Candida albicans infection and the altered T-helper function. Our data show that C/EBP beta is crucial for the correct functional regulation and homeostatic control of haemopoietic and lymphoid compartments. Images PMID:7744000
De Re, Valli; Caggiari, Laura; De Zorzi, Mariangela; Repetto, Ombretta; Zignego, Anna Linda; Izzo, Francesco; Tornesello, Maria Lina; Buonaguro, Franco Maria; Mangia, Alessandra; Sansonno, Domenico; Racanelli, Vito; De Vita, Salvatore; Pioltelli, Pietro; Vaccher, Emanuela; Beretta, Massimiliano; Mazzaro, Cesare; Libra, Massimo; Gini, Andrea; Zucchetto, Antonella; Cannizzaro, Renato; De Paoli, Paolo
Background The variability in the association of host innate immune response to Hepatitis C virus (HCV) infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma (HCC) or lymphoproliferative disease progression. Methods and Findings We analyzed data from 396 HCV-positive patients with CHC (n = 125), HCC (118), and lymphoproliferative diseases (153), and 501 HCV-negative patients. All were HIV and HBV negative. KIR-SSO was used to determine the KIR typing. KIR2DL5 and KIR2DS4 variants were performed using PCR and GeneScan analysis. HLA/class-I genotyping was performed using PCR-sequence-based typing. The interaction between the KIR gene and ligand HLA molecules was investigated. Differences in frequencies were estimated using Fisher’s exact test, and Cochran-Armitage trend test. The non-random association of KIR alleles was estimated using the linkage disequilibrium test. We found an association of KIR2DS2/KIR2DL2 genes, with the HCV-related lymphoproliferative disorders. Furthermore, individuals with a HLA-Bw6 KIR3DL1+ combination of genes showed higher risk of developing lymphoma than cryoglobulinemia. KIR2DS3 gene was found to be the principal gene associated with chronic HCV infection, while a reduction of HLA-Bw4 + KIR3DS1+ was associated with an increased risk of developing HCC. Conclusions Our data highlight a role of the innate-system in developing HCV-related disorders and specifically KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression, and mainly towards lymphoproliferative disorders. Moreover the determination of KIR3D/HLA combination of genes direct the HCV progression towards a lymphoma rather than an hepatic disease. In this contest IFN-? therapy, a standard therapy for HCV-infection and lymphoproliferative diseases, known to be able to transiently enhance the cytotoxicity of NK-cells support the role of NK cells to counterstain HCV-related and lymphoproliferative diseases. PMID:25700262
Gupta, Nishant; Vassallo, Robert; Wikenheiser-Brokamp, Kathryn A; McCormack, Francis X
The diffuse cystic lung diseases (DCLDs) are a group of pathophysiologically heterogenous processes that are characterized by the presence of multiple spherical or irregularly shaped, thin-walled, air-filled spaces within the pulmonary parenchyma. Although the mechanisms of cyst formation remain incompletely defined for all DCLDs, in most cases lung remodeling associated with inflammatory or infiltrative processes results in displacement, destruction, or replacement of alveolar septa, distal airways, and small vessels within the secondary lobules of the lung. The DCLDs can be broadly classified according to underlying etiology as those caused by low-grade or high-grade metastasizing neoplasms, polyclonal or monoclonal lymphoproliferative disorders, infections, interstitial lung diseases, smoking, and congenital or developmental defects. In the first of a two-part series, we present an overview of the cystic lung diseases caused by neoplasms, infections, smoking-related diseases, and interstitial lung diseases, with a focus on lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis. PMID:25906089
Santos, Carlos A. Q.; Brennan, Daniel C.; Fraser, Victoria J.; Olsen, Margaret A.
Background Use of prophylactic anti-CMV therapy for 3 to 6 months after kidney transplantation can result in delayed-onset CMV disease. We hypothesized that delayed-onset CMV disease (occurring ? 100 days post-transplant) occurs more commonly than early-onset CMV disease, and that it is associated with death. Methods We assembled a retrospective cohort of 15,848 adult kidney transplant recipients using 2004 to 2010 administrative data from the California and Florida Healthcare Cost and Utilization Project State Inpatient Databases. We identified demographic data, comorbidities, CMV disease coded during readmission and inpatient death. We used multivariate Cox proportional hazards modeling to determine risk factors for delayed-onset CMV disease and inpatient death. Results Delayed-onset CMV disease was identified in 4.0% and early-onset CMV disease was identified in 1.2% of the kidney transplant recipients. Risk factors for delayed-onset CMV disease included previous transplant failure or rejection (HR 1.4) and residence in the lowest-income ZIP codes (HR 1.2). Inpatient death was associated with CMV disease occurring 101–365 days post-transplant (HR 1.5), CMV disease occurring > 365 days post-transplant (HR 2.1), increasing age (by decade: HR 1.5), non-white race (HR 1.2), residence in the lowest-income ZIP codes (HR 1.2), transplant failure or rejection (HR 3.2), prior solid organ transplant (HR 1.7) and several comorbidities. Conclusions These data showed that delayed-onset CMV disease occurred more commonly than early-onset CMV disease, and that transplant failure or rejection is a risk factor for delayed-onset CMV disease. Further research should be done to determine if delayed-onset CMV disease is independently associated with death. PMID:24621539
Bai, Xia; Yang, Hua; Zhuang, Hongming
The most commonly observed symptoms of posttransplantation lymphoproliferative disorder (PTLD) after a liver transplantation were diarrhea and fever. Although PTLD can involve bones, bone pain is a rare manifestation of PTLD, much less to say a sole presentation. We report a case of a pediatric patient with recurrent PTLD after liver transplantation, whose only complaint was right tibial pain. FDG PET/CT revealed not only hypermetabolic activity in the right proximal tibia but also in many other parts of the body. Recurrent PTLD was confirmed after bone biopsy. PMID:26098286
ESTHER BLANCO; MERCEDES GARCIA-BRIONES; ARANTZA SANZ-PARRA; PAULA GOMES; ELIANDRE DE OLIVEIRA; MARI LUZ VALERO; DAVID ANDREU; VICTORIA LEY; FRANCISCO SOBRINO
Porcine T-cell recognition of foot-and-mouth disease virus (FMDV) nonstructural proteins (NSP) was tested using in vitro lymphoproliferative responses. Lymphocytes were obtained from outbred pigs experimentally infected with FMDV. Of the different NSP, polypeptides 3A, 3B, and 3C gave the highest stimulations in the in vitro assays. The use of overlapping synthetic peptides allowed the identification of amino acid regions within
Wilflingseder, Julia; Sunzenauer, Judith; Toronyi, Eva; Heinzel, Andreas; Kainz, Alexander; Mayer, Bernd; Perco, Paul; Telkes, Gábor; Langer, Robert M.; Oberbauer, Rainer
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
Auguet Quintillá, T; Pedro-Botet Montoya, J; Planas Domingo, J; Gallén Castillo, M
Three patients with Hodgkin's disease, mixed cellularity subtype, plus infection by human immunodeficiency virus are presented. Two of them were intravenous drug abusers, and one had promiscuous heterosexual behaviour; they all presented B-type symptoms. One patient died because of infection, whereas the other two persisted in complete remission after treatment at 4 and 5 years of follow-up, respectively. None of the patients still alive has developed AIDS. The criteria for considering Hodgkin's disease as an AIDS-related lymphoproliferative disorder are discussed. PMID:1374934
Spartalis, Eleftherios; Charalampoudis, Petros; Kandilis, Apostolos; Athanasiou, Antonios; Tsaparas, Petros; Voutsarakis, Athanasios; Kostakis, Ioannis D.; Dimitroulis, Dimitrios; Svolou, Evanthia; Korkolopoulou, Penelope; Nikiteas, Nikolaos; Kouraklis, Gregory
Castleman's disease is a benign lymphoproliferative condition with three distinct histological subtypes. Clinically it presents in either a unicentric or multicentric manner and can affect various anatomic regions, the mediastinum being the most frequent location. We herein present a rare case of unifocal retroperitoneal mass proved to be hyaline vascular Castleman's disease. We perform a review of the current literature pertaining to such lesions, focusing on the management of the various clinical and histological variants of the disease. Surgical excision is the treatment of choice for unifocal Castleman's disease. PMID:25431731
Gupta, Nishant; Vassallo, Robert; Wikenheiser-Brokamp, Kathryn A; McCormack, Francis X
The diffuse cystic lung diseases have a broad differential diagnosis. A wide variety of pathophysiological processes spanning the spectrum from airway obstruction to lung remodeling can lead to multifocal cyst development in the lung. Although lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis are perhaps more frequently seen in the clinic, disorders such as Birt-Hogg-Dubé syndrome, lymphocytic interstitial pneumonia, follicular bronchiolitis, and light-chain deposition disease are increasingly being recognized. Obtaining an accurate diagnosis can be challenging, and management approaches are highly disease dependent. Unique imaging features, genetic tests, serum studies, and clinical features provide invaluable clues that help clinicians distinguish among the various etiologies, but biopsy is often required for definitive diagnosis. In part II of this review, we present an overview of the diffuse cystic lung diseases caused by lymphoproliferative disorders, genetic mutations, or aberrant lung development and provide an approach to aid in their diagnosis and management. PMID:25906201
Yang, Yu; Yu, Bo; Chen, Yun
Renal transplantation has become one of the most common surgical procedures performed to replace a diseased kidney with a healthy kidney from a donor. It can help patients with kidney failure live decades longer. However, renal transplantation also faces a risk of developing various blood disorders. The blood disorders typically associated with renal transplantation can be divided into two main categories: (1) Common disorders including post-transplant anemia (PTA), post-transplant lymphoproliferative disorder (PTLD), post-transplant erythrocytosis (PTE), and post-transplant cytopenias (PTC, leukopenia/neutropenia, thrombocytopenia, and pancytopenia); and (2) Uncommon but serious disorders including hemophagocytic syndrome (HPS), thrombotic microangiopathy (TMA), therapy-related myelodysplasia (t-MDS), and therapy-related acute myeloid leukemia (t-AML). Although many etiological factors involve the development of post-transplant blood disorders, immunosuppressive agents, and viral infections could be the two major contributors to most blood disorders and cause hematological abnormalities and immunodeficiency by suppressing hematopoietic function of bone marrow. Hematological abnormalities and immunodeficiency will result in severe clinical outcomes in renal transplant recipients. Understanding how blood disorders develop will help cure these life-threatening complications. A potential therapeutic strategy against post-transplant blood disorders should focus on tapering immunosuppression or replacing myelotoxic immunosuppressive drugs with lower toxic alternatives, recognizing and treating promptly the etiological virus, bacteria, or protozoan, restoring both hematopoietic function of bone marrow and normal blood counts, and improving kidney graft survival. PMID:25853131
Matloff, Robyn Greenfield; Arnon, Ronen
There is an intricate relationship between the liver and the kidney, with renal physiology and function intimately involved in many primary disorders of pediatric liver disease. The hemodynamic changes of progressive cirrhosis affect and are directly affected by changes in renal blood flow and renal handling of sodium and free water excretion. Resulting complications of worsening ascites, hyponatremia, and acute kidney injury frequently complicate the care of children with advanced liver disease and contribute significant morbidity and mortality. While liver transplantation may restore hemodynamic stability, nearly 40 % of pediatric liver transplant recipients develop chronic kidney disease post-transplant and approximately 25 % are left with clinical hypertension. This review seeks to provide a basic understanding of this relationship to enable the provision of optimal care to children with liver disease. PMID:26289614
Suh, Jong Hui; Hong, Sook Hee; Jeong, Seong Cheol; Park, Chan Beom; Choi, Kuk Bin; Shin, Ok Ran
Castleman’s disease (CD) is an uncommon benign lymphoproliferative disorder that usually presents as a single or multiple mediastinal mass. In unicentric CD, constitutional symptoms are rare, but are curable with surgical resection. However, serious intraoperative bleeding often requires conversion to thoracotomy. We present a case of unicentric CD in a 25-year-old woman with anemia, who was successfully treated by thoracoscopic resection. We describe the clinical course from the initial presentation to diagnosis and surgical cure. PMID:26380750
Berlakovich, Gabriela A
Transplantation for the treatment of alcoholic cirrhosis is more controversially discussed than it is for any other indication. The crucial aspect in this setting is abstinence before and after liver transplantation. We established pre-transplant selection criteria for potential transplant candidates. Provided that the underlying disease can be treated, there is no reason to withhold liver transplantation in a patient suffering from alcoholic cirrhosis. Evaluation of the patient by a multidisciplinary team, including an addiction specialist, is considered to be the gold standard. However, several centers demand a specified period of abstinence - usually 6 mo- irrespective of the specialist’s assessment. The 6-mo rule is viewed critically because liver transplantation was found to clearly benefit selected patients with acute alcoholic hepatitis; the benefit was similar to that achieved for other acute indications. However, the discussion may well be an academic one because the waiting time for liver transplantation exceeds six months at the majority of centers. The actual challenge in liver transplantation for alcoholic cirrhosis may well be the need for lifelong post-transplant follow-up rather than the patient’s pre-transplant evaluation. A small number of recipients experience a relapse of alcoholism; these patients are at risk for organ damage and graft-related death. Post-transplant surveillance protocols should demonstrate alcohol relapse at an early stage, thus permitting the initiation of adequate treatment. Patients with alcoholic cirrhosis are at high risk of developing head and neck, esophageal, or lung cancer. The higher risk of malignancies should be considered in the routine assessment of patients suffering from alcoholic cirrhosis. Tumor surveillance protocols for liver transplant recipients, currently being developed, should become a part of standard care; these will improve survival by permitting diagnosis at an early stage. In conclusion, the key factor determining the outcome of transplantation for alcoholic cirrhosis is intensive lifelong medical and psychological care. Post-transplant surveillance might be much more important than pre-transplant selection. PMID:25009374
Budmiger, H; Rhyner, K; Siegenthaler-Zuber, G; Bollinger, A
Clinical features, diagnostic procedure, therapy, course of the disease and prognosis in 6 patients with severe idiopathic chronic cold agglutinin disease are described. In 5 patients the main complaint was cold mediated acrocyanosis. The cold agglutinin in all patients was of anti-I type and belonged to IgM immunoglobulin. Keeping warm provided symptomatic relief and the hemolysis decreased to a milder form. Treatment with glucocorticoids alone failed in two patients but succeeded in combination with chlorambucil or cyclophosphamid. One patient developed a lymphoproliferative disorder 11 years after diagnosis of idiopathic chronic cold agglutinin disease. PMID:3344409
Nambirajan, Aruna; Bhowmik, Dipankar; Singh, Geetika; Agarwal, Sanjay Kumar; Dinda, Amit Kumar
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
SU, MAUREEN A.; ANDERSON, MARK S.
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
Mittal, Nupur; Zhu, Bing; Gaitonde, Sujata; Lu, Yang; Schmidt, Mary Lou
Extranodal Marginal zone lymphoma (EMZL) is a rare, usually localized disease in children. Advanced stage EMZL in adults is considered incurable, with prolonged remissions after chemotherapy. Gamma heavy chain disease (?HCD) is a rare disease of adults associated with lympho-proliferative processes with no comparable reports in children. A case of stage-IV EMZL with ?HCD in an adolescent is discussed including treatment with Bendamustine plus Rituximab. The patient remains disease free 18 months from diagnosis. This case highlights necessity for careful diagnostic work-up to identify indolent lymphomas in children which may respond to less toxic chemotherapy than used for common pediatric lymphomas. PMID:25663537
Koji, Hitoshi; Yazawa, Takuya; Nakabayashi, Kimimasa; Fujioka, Yasunori; Kamma, Hiroshi; Yamada, Akira
We report a 48-year-old female who developed lymphoproliferative disorder (LPD) during treatment of rheumatoid arthritis (RA) with methotrexate (MTX). She presented with multiple tumors in the cervical lymph nodes (LNs), multiple lung shadows and round shadows in both kidneys with pancytopenia and a high CRP level. The LN showed CD8-positive T-cell LPD associated with Epstein-Barr (EB) virus-infected B-cells. Clonality assays for immunoglobulin (Ig) heavy chain and T-cell receptor gamma (TCR?) were negative. The cessation of MTX without chemotherapy resulted in the complete disappearance of the tumors and abnormal clinical features. We compared this case with previously published ones and discuss the pathological findings, presuming that the proliferation of CD8 T-cells was a reactive manifestation to reactivated EB virus-infected B-cells. PMID:24386983
Wormser, C; Mariano, A; Holmes, E S; Aronson, L R; Volk, S W
The study objective was to compare the prevalence of malignant neoplasia in feline renal transplant recipients (n?=?111) with a control population of cats that did not receive transplantation (n?=?142); and to determine whether the development of post-transplant malignant neoplasia (PTMN) affects long-term survival. Twenty-five (22.5%) renal transplant recipients were diagnosed with PTMN, and of those 14 (56%) were diagnosed with lymphoma. The overall survival time in cats that developed PTMN following renal transplantation (median 646 days, IQR 433-1620 days) was not significantly different from the survival time in cats that did not develop PTMN (median 728 days, IQR 201-1942 days), although median survival after diagnosis of PTMN was only 13 days. Six control cats (4.2%) were diagnosed with malignant neoplasia. Compared to the control population, transplant cats had a 6.6 times higher odds of developing malignant neoplasia and a 6.7 times higher odds of developing lymphoma. PMID:25303015
Caroti, Leonardo; Di Maria, Lorenzo; Carta, Paolo; Moscarelli, Luciano; Cirami, Calogero; Minetti, Enrico Eugenio
Atypical haemolytic uraemic syndrome (aHUS) is a rare disease characterized by thrombocytopenia, microangiopathic haemolytic anaemia and renal impairment. Mutations in genes encoding inhibitors of the alternative pathway of the complement system are involved in ?50% of the cases. Thrombomodulin (THBD) gene mutations occur in ?3-5% of the cases. The risk of aHUS recurrence after kidney transplantation depends on the complement abnormality involved. In all three cases of THBD mutation reported to date, aHUS recurred after kidney transplantation (KT) with early graft loss. No data exist about therapeutic approaches before kidney transplantation to reduce the risk of recurrence in patients carrying this mutation. Favourable data on the use of eculizumab have been reported, in terms of plasmatherapy withdrawal and renal function recovery in aHUS recurrence after KT. To our knowledge, this case report presents the first case of successful kidney transplantation in a patient with aHUS due to THBD mutation who was treated with a single plasma-exchange immediately before surgery without recurrence of the disease 12 months after transplantation. PMID:26034596
Caroti, Leonardo; Di Maria, Lorenzo; Carta, Paolo; Moscarelli, Luciano; Cirami, Calogero; Minetti, Enrico Eugenio
Atypical haemolytic uraemic syndrome (aHUS) is a rare disease characterized by thrombocytopenia, microangiopathic haemolytic anaemia and renal impairment. Mutations in genes encoding inhibitors of the alternative pathway of the complement system are involved in ?50% of the cases. Thrombomodulin (THBD) gene mutations occur in ?3–5% of the cases. The risk of aHUS recurrence after kidney transplantation depends on the complement abnormality involved. In all three cases of THBD mutation reported to date, aHUS recurred after kidney transplantation (KT) with early graft loss. No data exist about therapeutic approaches before kidney transplantation to reduce the risk of recurrence in patients carrying this mutation. Favourable data on the use of eculizumab have been reported, in terms of plasmatherapy withdrawal and renal function recovery in aHUS recurrence after KT. To our knowledge, this case report presents the first case of successful kidney transplantation in a patient with aHUS due to THBD mutation who was treated with a single plasma-exchange immediately before surgery without recurrence of the disease 12 months after transplantation. PMID:26034596
Ueda, Tomoki; Iino, Rioko; Yokoyama, Kenji; Okamoto, Shinichiro; Asakura, Keiko; Tsukada, Yuiko; Ishizawa, Jo; Matsuki, Eri; Ikeda, Yasuo; Hattori, Yutaka
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
El-Osta, Hazem E.
Castleman's disease is a rare lymphoproliferative disorder in which there has been recent progress in elucidating underlying mechanisms with potential therapeutic implications. Unicentric Castleman's disease is an indolent condition that is often treated with local approaches. In contrast, patients with multicentric Castleman's disease (MCD) have a less favorable prognosis and require systemic treatment. Cytotoxic chemotherapy, with its attendant risk for toxicity, has been widely used to treat MCD, with variable efficacy. The discovery of putative etiologic factors and targets in MCD, particularly human herpes virus 8, CD20, and interleukin (IL)-6, has been translated into the use of rituximab and anti–IL-6-based therapy, as well as antiviral agents. In this article, we review the current state of the art of our understanding of Castleman's disease and its treatment and we provide insight into future treatment strategies based on disease biology. PMID:21441298
Taylor, Graham S; Long, Heather M; Brooks, Jill M; Rickinson, Alan B; Hislop, Andrew D
Epstein-Barr virus (EBV) is usually acquired silently early in life and carried thereafter as an asymptomatic infection of the B lymphoid system. However, many circumstances disturb the delicate EBV-host balance and cause the virus to display its pathogenic potential. Thus, primary infection in adolescence can manifest as infectious mononucleosis (IM), as a fatal illness that magnifies the immunopathology of IM in boys with the X-linked lymphoproliferative disease trait, and as a chronic active disease leading to life-threatening hemophagocytosis in rare cases of T or natural killer (NK) cell infection. Patients with primary immunodeficiencies affecting the NK and/or T cell systems, as well as immunosuppressed transplant recipients, handle EBV infections poorly, and many are at increased risk of virus-driven B-lymphoproliferative disease. By contrast, a range of other EBV-positive malignancies of lymphoid or epithelial origin arise in individuals with seemingly intact immune systems through mechanisms that remain to be understood. PMID:25706097
Kurzawski, Mateusz; Dziewanowski, Krzysztof; K?dzierska, Karolina; Wajda, Anna; Lapczuk, Joanna; Dro?dzik, Marek
New onset posttransplant diabetes mellitus (PTDM) has a high incidence after kidney transplantation in patients medicated with tacrolimus. PTDM can adversely affect patient and graft survival. The pathophysiology of PTDM closely mimics type 2 diabetes mellitus (T2DM). One of the possible genetic factors predisposing individuals to PTDM might be a polymorphism in the transcription factor 7-like 2 gene (TCF7L2). This polymorphism has previously been associated with increased risk of T2DM in the general population. Therefore, the present study aimed to evaluate TCF7L2 polymorphisms in PTDM in kidney transplant patients medicated with tacrolimus. Non-diabetic kidney transplant patients medicated with tacrolimus (n = 234) were genotyped for the presence of TCF7L2 gene variants (rs12255372 and rs7903146) using TaqMan probes. Of the 234 patients, 66 patients had developed PTDM and 168 had not. Frequencies of the studied single nucleotide polymorphisms (SNPs) did not differ significantly between the study groups. Moreover, haplotype analyses failed to detect any associations between TCF7L2 haplotypes and PTDM. However, in late-onset PTDM (developed later that 2 weeks from transplantation), frequencies of the rs7903146 TT genotype and T minor allele were significantly increased compared to non-PTDM controls (17.9% vs. 5.9%, p = 0.017, OR: 4.13, 95% CI: 1.19-14.33 for TT genotype, 39.3% vs. 25.9%, p = 0.038 for T allele). If the application of TCF7L2 rs7903146 SNPs as a marker for PTDM is confirmed by further independent studies, replacing tacrolimus with other immunosuppressants could be warranted in patients at high risk of PTDM, as diagnosed by TCF7L2 genotyping. PMID:21857094
Antibodies Elicited by Naked DNA Vaccination against the Complementary determining Region 3 Hypervariable Region of Immunoglobulin Heavy Chain Idiotypic Determinants of B-lymphoproliferative Disorders Specifically React with Patients' Tumor Cells 1
Monica Rinaldi; Francesco Ria; Paola Parrella; Emanuela Signori; Anna Serra; Silvia A. Ciafre; Isabella Vespignani; Marzia Lazzari; Maria Giulia Farace; Giuseppe Saglio; Vito M. Fazio
Several reports have suggested that the mechanism of protection in- duced by antiidiotypic vaccination against low-grade lymphoproliferative disorders is likely to be antibody mediated. Here we test the hypothesis that DNA vaccination with the short peptide encompassing the comple- mentary-determining region 3 hypervariable region of immunoglobulin heavy chain (VH-CDR3) may elicit a specific antibody immune response able to recognize the
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
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
Peters, T; Traboulsi, D; Tibbles, L A; Mydlarski, P R
Sirolimus, also known as rapamycin (SRL, Rapamune®), was approved in 1999 by the US Food and Drug Administration to prevent graft rejection in renal transplantation. As a member of the mammalian target of rapamycin (mTOR) inhibitor class, its potent immunosuppressant, anti-angiogenic and anti-proliferative properties are well recognized. When compared to other immunosuppressants, SRL has a lower risk of renal, neurologic and lymphoproliferative complications. It has become a promising treatment modality for angiofibromas, Kaposi's sarcoma and other inflammatory and malignant disorders of the skin. With the recent discovery that mTOR inhibitors extend the lifespan of mice, sirolimus and other rapamycin analogs (rapalogs) are emerging as therapeutic targets for the treatment and prevention of age-related diseases. PMID:25188522
Saghafi, Hossein; Aghaali, Mohammad; Haghighi, Samaneh
Castleman disease (CD) is a rare lymphoproliferative disorder, first described in 1956. This case report describes a 27-year-old man with hyaline vascular unicentric CD, first presented with edema and hypertension. On initial evaluation for edema, 24-hour urine collection revealed 8200 mg/24 h protein excretion. Pathologic examination of the kidney specimen showed diffuse mesangial lesions with segmental subepithelial deposition. On follow-up for nephrotic syndrome, the patient experienced a feeling of a mass in his pharynx and deterioration of previous snoring, documented by neck magnetic resonance imaging. Pathology report of the excisional biopsy showed CD. Treatment with corticosteroids and partial excision can be considered as an alternative to surgery for unresectable unicentric CD. The 5-year follow-up showed that this strategy could lead to remission. PMID:23880810
Primary chronic cold agglutinin disease (CAD) is a clonal lymphoproliferative disorder accounting for 13-15% of autoimmune haemolytic anaemias. Significant advances have been made in treatment, which was largely unsuccessful until recently. The essential clinical, immunological and pathological features are reviewed, focusing on their relevance for therapy. Non-pharmacological management still seems sufficient in some patients. With the recent improvements, however, drug therapy seems indicated more often than previously thought. Corticosteroids should not be used to treat CAD. Half of the patients respond to rituximab monotherapy; median response duration is 11 months. Fludarabine-rituximab combination therapy is very effective, resulting in 75% response rate, complete remissions in about 20%, and more than 66 months estimated response duration. Toxicity is a concern, and benefits should be carefully weighed against risks. An individualized approach is discussed regarding the choice of fludarabine-rituximab combination versus rituximab monotherapy. Patients requiring treatment should be considered for prospective trials. PMID:21385173
Montanaro, D; Gropuzzo, M; Tulissi, P; Boscutti, G; Risaliti, A; Baccarani, U; Adani, G L; Sainz, M; Bresadola, F; Mioni, G
Cardiovascular disease is the leading cause of morbidity and mortality following renal transplantation. Because many renal transplant recipients die with functioning grafts, deaths resulting from cardiovascular disease have became an increasingly important cause of graft loss, particularly after the first post-transplantation year. Moreover, a contribution of some cardiovascular risk factors to renal allograft dysfunction has been demonstrated. A number of observational studies suggest that cardiovascular disease is more common in renal transplant patients than in the general population. The excessive risk for cardiovascular disease is related to a high prevalence and accumulation of atherogenic risk factors before and after transplantation. Hypertension, post-transplantation diabetes and hyperlipidemia are well-recognized risk factors for the development of cardiovascular events after renal transplantation and are strongly associated with immunosuppressive therapy. Progressive renal dysfunction may also influence the risk of cardiovascular complications after renal transplantation. The elevated risk may also be caused by non- traditional risk factors such as anaemia, adhesion molecules, hyperhomocysteinemia, microinflammatory state, abnormal coagulation and oxidative stress. To prevent post-transplantation cardiovascular disease it is crucial to define the etiological risk factors. Some risk factors can be modified, and for some of these, there is strong evidence from studies in the general population that intervention improves survival. Given the significant morbidity and mortality of cardiovascular disease in renal transplant recipients, aggressive treatment intervention for potentially modifiable factors are strongly advocated after transplantation. In addition to treatment intervention, risk management should also involve tailoring the immunosuppressive regimen to minimize both direct and indirect cardiovascular risks. In this article we attempted to review and quantify the post-transplant risk factors for cardiovascular disease as well as offer suggestions on optimizing the therapy or treatment strategies to minimize the risk of cardiovascular complications in renal transplant patients. Reduction of cardiovascular morbidity and mortality can improve not only the life expectancy and quality of life of the transplant recipients but also their graft function and survival. PMID:15732047
Young, Sona; Kwarta, Elizabeth; Azzam, Ruba; Sentongo, Timothy
Malnutrition is a treatable complication in children with end-stage liver disease (ESLD). Biliary atresia and other cholestatic disorders are the most frequent cause of ESLD in children. No single variable provides adequate information about nutrition status, yet effective nutrition support is the one intervention known to improve pre- and posttransplant outcomes. A proactive approach consisting of screening anthropometry interpreted using appropriate growth references, recognition of clinical manifestations associated with micronutrient deficiency, and timely aggressive nutrition support is of a paramount importance to maximize anabolism and optimize outcomes. This article presents the principles of nutrition assessment, intervention, and monitoring in children with ESLD. PMID:23466471
Balasubramaniam, Saranya C; Raja, Harish; Nau, Cherie B; Shen, Joanne F; Schornack, Muriel M
Hematopoietic stem cell transplantation is important in the management of several lymphoproliferative and bone marrow disorders. Graft-versus-host disease (GVHD) involves inflammatory manifestations that arise after transplant and can affect many organs. Ocular manifestations of GVHD are common, and eye care providers must understand this disease entity. The ocular surface is most commonly involved, but GVHD can affect all parts of the eye. Ocular GVHD can be relapsing and remitting, can decrease quality of life, and can be challenging to diagnose and adequately treat. The diagnostic criteria for and grading of ocular GVHD continue to evolve. This review aims to summarize current definitions, clinical findings, diagnostic criteria, and management of ocular GVHD. The care of patients with ocular GVHD requires a multidisciplinary approach. PMID:26214529
Shah, Dharita; Darji, Parth; Lodha, Sambhav; Bolla, Soujanya
Castleman’s disease (CD) is a rare lymphoproliferative disease of uncertain etiology that affects lymph nodes. CD can be classified as a) unicentric vs. multicentric, based on clinical and radiological findings, b) hyaline vascular (80–90%) vs. plasmacytic (10–20%) vs. mixed cellularity variety based on histopathology. Unicentric disease is more common in the 3rd and 4th decade, whereas the multicentric form is more common in the 5th and 6th decade with no sex predilection. HIV seropositive individuals appear to be at an increased risk for multicentric castleman's disease (MCD) at a younger age due to the increased incidence of HHV- 8 infection. Diagnosis is usually based on histopathology features as imaging features show considerable overlap, thus posing diagnostic difficulties. Overall prognosis is good, particularly in the unicentric variety of disease. We have presented a case of the unicentric CD in a 40 year old male patient having abdominal pain and hematuria as chief complaints. PMID:23705043
Casper, Corey; Teltsch, Dana Y; Robinson, Don; Desrosiers, Marie-Pierre; Rotella, Philip; Dispenzieri, Angela; Qi, Ming; Habermann, Thomas; Reynolds, Matthew W
Multicentric Castleman disease (MCD) is a rare lymphoproliferative disease. Little is known about how patient clinical features and healthcare utilization varies by human immunodeficiency virus (HIV) status and disease subtype. Data of MCD patients identified between 2000 and 2009 were collected from medical records at two United States treatment centres. Clinical, demographic, and biochemical characteristics, drug therapies and medical utilization were descriptively reported by HIV status and cell histology, and statistically compared with the Fisher's Exact and Kruskal-Wallis tests. Patients (n = 59) had a pathologically and clinically confirmed MCD diagnosis: plasmacytic (42%), hyaline vascular (29%) and mixed (15%); 10% had HIV infection. In the first year after diagnosis, MCD patients on average saw a healthcare provider more than six times, were hospitalized at least once and underwent frequent radiological and laboratory testing. Rituximab was the most commonly used drug therapy, followed by corticosteroids and conventional chemotherapy. One- and 2-year survival was excellent in HIV-negative patients (100% and 97%, respectively) but inferior for HIV-positive cases (67% and 67%, respectively). Heterogeneous treatment decisions were observed in this MCD study; HIV status was the only distinguishing clinical criteria associated with pharmacotherapies. Additional research is necessary to guide treatment of this rare lymphoproliferative disorder. PMID:25208471
Tanaka, Hiroaki; Hashimoto, Shinichiro; Sugita, Yasumasa; Sakai, Shio; Takeda, Yusuke; Abe, Daijiro; Takagi, Toshiyuki; Nakaseko, Chiaki
Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia, classified into primary and secondary types. Secondary CAD accompanies infection or malignant disease, most often lymphoma, whereas primary CAD frequently represents a lymphoproliferative bone marrow disorder characterized by clonal expansion of B cells. Here, I describe a case of lymphoplasmacytic lymphoma (LPL) developed 6 years after amelioration of primary CAD by rituximab monotherapy. A 54-year-old Japanese woman was diagnosed with primary CAD characterized by a small fraction of B lymphocytes and kappa laterality in the peripheral blood. M-protein was not detected by immuno-electrophoresis. The patient achieved remission following two courses of rituximab monotherapy. The level of IgM was specifically decreased, although levels of IgG and IgA were slightly increased. Six years after rituximab monotherapy, she developed LPL without CAD recurrence. Flow cytometry performed on bone marrow specimens revealed that lymphoma cells were positive for CD19 and CD20 with kappa laterality. The lymphoma may have transformed from clonal B lymphocytes at presentation of CAD. Rituximab monotherapy induced remission of CAD by specific decrease of IgM level, but did not eliminate the clonal B lymphocytes that may have progressed to LPL. This experience may provide clues toward the understanding of the pathophysiology of primary CAD with clonal lymphoproliferative disease of the bone marrow. PMID:22878940
Tait, R.C.; Burnett, A.K.; Robertson, A.G.; McNee, S.; Riyami, B.M.; Carter, R.; Stevenson, R.D. )
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.
Cantillo, Jorge de Jesús; López, Rocío del Pilar; Andrade, Rafael Enrique
The nephropathy of monoclonal gammopathies is principally caused by light chain deposits of fragmented immunoglobins. Paraprotein-related renal diseases are associated with such deposits of intact (heavy chain) or fragmentary (light chain) immunoglobins. A condition of pathological light chain deposits is rare and characterized by deposits of fragments of monoclonal immunoglobulins in many organs. Renal deposits occur primarily in glomeruli and tubular basement membranes. This disease is frequently associated with lymphoproliferative disorders. The majority of cases are caused by deposits of kappa light chains. Whereas this disease is most frequently associated with hematologic malignancies, occasionally a case occurs without detectable hematological pathologies; these cases are called idiopathic or primary. They usually manifest themselves as severe renal insufficiencies with nephrotic-range proteinuria. No treatment regime has been clearly established and the prognosis is poor. Herein, the clinical and histological characteristics are described regarding the first case in Colombia of light chain deposit disease without symptoms of malignancy. PMID:20440451
Clinical and In Vitro Studies on Impact of High-Dose Etoposide Pharmacokinetics Prior Allogeneic Hematopoietic Stem Cell Transplantation for Childhood Acute Lymphoblastic Leukemia on the Risk of Post-Transplant Leukemia Relapse.
Sobiak, Joanna; Kazimierczak, Urszula; Kowalczyk, Dariusz W; Chrzanowska, Maria; Styczy?ski, Jan; Wysocki, Mariusz; Szpecht, Dawid; Wachowiak, Jacek
The impact of etoposide (VP-16) plasma concentrations on the day of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on leukemia-free survival in children with acute lymphoblastic leukemia (ALL) was studied. In addition, the in vitro effects of VP-16 on the lymphocytes proliferation, cytotoxic activity and on Th1/Th2 cytokine responses were assessed. In 31 children undergoing allo-HSCT, VP-16 plasma concentrations were determined up to 120 h after the infusion using the HPLC-UV method. For mentioned in vitro studies, VP-16 plasma concentrations observed on allo-HSCT day were used. In 84 % of children, VP-16 plasma concentrations (0.1-1.5 ?g/mL) were quantifiable 72 h after the end of the drug infusion, i.e. when allo-HSCT should be performed. In 20 (65 %) children allo-HSCT was performed 4 days after the end of the drug infusion, and VP-16 was still detectable (0.1-0.9 ?g/mL) in plasma of 12 (39 %) of them. Post-transplant ALL relapse occurred in four children, in all of them VP-16 was detectable in plasma (0.1-0.8 ?g/mL) on allo-HSCT day, while there was no relapse in children with undetectable VP-16. In in vitro studies, VP-16 demonstrated impact on the proliferation activity of stimulated lymphocytes depending on its concentration and exposition time. The presence of VP-16 in plasma on allo-HSCT day may demonstrate an adverse effect on graft-versus-leukemia (GvL) reaction and increase the risk of post-transplant ALL relapse. Therefore, if 72 h after VP-16 administration its plasma concentration is still above 0.1 ?g/mL then the postponement of transplantation for next 24 h should be considered to protect GvL effector cells from transplant material. PMID:26040247
Goswami, M; McGowan, K S; Lu, K; Jain, N; Candia, J; Hensel, N F; Tang, J; Calvo, K R; Battiwalla, M; Barrett, A J; Hourigan, C S
AML is a diagnosis encompassing a diverse group of myeloid malignancies. Heterogeneous genetic etiology, together with the potential for oligoclonality within the individual patient, have made the identification of a single high-sensitivity marker of disease burden challenging. We developed a multiple gene measurable residual disease (MG-MRD) RQ-PCR array for the high-sensitivity detection of AML, retrospectively tested on 74 patients who underwent allo-SCT at the NHLBI in the period 1994-2012. MG-MRD testing on peripheral blood samples prior to transplantation demonstrated excellent concordance with traditional BM-based evaluation and improved risk stratification for post-transplant relapse and OS outcomes. Pre-SCT assessment by MG-MRD predicted all clinical relapses occurring in the first 100 days after allo-SCT compared with 57% sensitivity using WT1 RQ-PCR alone. Nine patients who were negative for WT1 prior to transplantation were correctly reclassified into a high-risk MG-MRD-positive group, associated with 100% post-transplant mortality. This study provides proof of principle that a multiple gene approach may be superior to the use of WT1 expression alone for AML residual disease detection. PMID:25665046
Relapse after non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: early transplantation, use of an unrelated donor, and chronic graft-versus-host disease are protective.
Enright, H; Davies, S M; DeFor, T; Shu, X; Weisdorf, D; Miller, W; Ramsay, N K; Arthur, D; Verfaillie, C; Miller, J; Kersey, J; McGlave, P
We analyzed the incidence of posttransplant chronic myelogenous leukemia (CML) relapse in 283 consecutive related-donor (n = 177) and unrelated-donor (n = 106) allogeneic transplant recipients. Twenty-two of 165 related-donor recipients with stable or advanced disease at the time of transplant had hematologic relapse of CML following transplant (5-year Kaplan-Meier estimate of relapse, 20%; 95% confidence interval [CI], 11 to 30%). One of 12 patients transplanted in second stable phase following blast crisis also relapsed. Fifteen related-donor transplant recipients relapsed within 5 years of transplant; however, seven relapsed between 5 and 9 years after transplant. Factors independently associated with an increased risk of posttransplant relapse for related-donor recipients included prolonged interval between diagnosis and transplant (relative risk, [RR], 3.81; P = .009) and bone marrow basophilia (RR, 5.62; P = .01). Related-donor recipients with posttransplant chronic graft-versus-host disease (CGVHD) had a decreased risk of relapse (RR, 0.24; P = .005). Only two of 106 unrelated-donor transplant recipients relapsed following transplant (5-year Kaplan-Meier estimate of relapse, 3%; 95% CI, 0% to 7%). When both related- and unrelated-donor recipients were considered, the use of an unrelated donor was independently associated with a decreased risk of relapse (RR, 0.24; P = .07). Twelve of 16 relapsing patients who received further therapy (nine of 13 who underwent second transplant and three of three who received donor leukocyte infusions) remain alive. This analysis shows that relapse, sometimes occurring long after transplant, is an important adverse outcome in allogeneic transplantation for CML. Early transplant, posttransplant CGVHD, and use of an unrelated donor are associated with a reduced incidence of relapse, perhaps due to allogeneic disparities enhancing the graft-versus-leukemia effect. PMID:8695820
Viral infections are important causes of morbidity and mortality after allogeneic stem cell hematopoietic transplantation (allo-HSCT). Although most viral infections present with asymptomatic or subclinical manifestations, viruses may result in fatal complications in severe immunocompromised recipients. Reactivation of latent viruses, such as herpesviruses, is frequent during the immunosuppression that occurs with allo-HSCT. Viruses acquired from community, such as the respiratory and gastrointestinal viruses, are also important pathogens of post-transplant viral diseases. Currently, molecular diagnostic methods have replaced or supplemented traditional methods, such as viral culture and antigen detection, in diagnosis of viral infections. The utilization of polymerase chain reaction facilitates the early diagnosis. In view of lacking efficacious agents for treatment of viral diseases, prevention of viral infections is extremely valuable. Application of prophylactic strategies including preemptive therapy reduces viral infections and diseases. Adoptive cellular therapy for restoring virus-specific immunity is a promising method in the treatment of viral diseases. PMID:24341630
Hanson, C. A.; Frizzera, G.; Patton, D. F.; Peterson, B. A.; McClain, K. L.; Gajl-Peczalska, K. J.; Kersey, J. H.
Castleman's disease is a morphologically and clinically heterogeneous lymphoproliferative disorder. Both a localized benign variant and an aggressive form with systemic manifestations have been described. To investigate the differences between these variants of Castleman's disease, the authors analyzed lymph node DNA from 4 patients with the localized type and 4 with the systemic type of Castleman's disease for immunoglobulin and T-cell receptor gene rearrangements. The role of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) was also studied by viral genomic DNA probes. They detected clonal rearrangements in 3 of the 4 patients with the systemic variant of Castleman's; no patients with localized disease had rearrangements. Copies of EBV genome were also detected in 2 of the 3 patients with clonal rearrangements. These results suggest that systemic Castleman's disease is a disorder distinct from the classical localized variant in that it may evolve into a clonal lymphoproliferation. Images Figure 1 PMID:2833104
Huh, In Young; Lee, Sang Hyun; Kim, An Suk; Park, Se Hun; Kim, Dae-Young
Castleman's disease (CD) is a rare lymphoproliferative disorder of undetermined etiology. Unicentric Castleman's disease is confined to a single lymph node; it is usually asymptomatic though sometimes has local manifestations related to mass effects. In contrast, multicentric Castleman's disease (MCD) typically presents with lymphoid hyperplasia at multiple sites; it is associated with systemic symptoms and abnormal laboratory findings, with a less favorable prognosis. In case of anesthesia in CD, an exhaustive preanesthetic evaluation is essential to identify associated clinical manifestations which may influence the management of the anesthesia. Perioperative careful monitoring and proper anesthetic management are both important. We report a case of general anesthesia with anesthetic management in a patient with MCD that has not been documented in the literature. PMID:26045937
Abedin, Sameem; Yanik, Gregory A; Braun, Thomas; Pawarode, Attaphol; Magenau, John; Goldstein, Steven C; Levine, John E; Kitko, Carrie L; Couriel, Daniel R
Bronchiolitis obliterans syndrome (BOS) is a significant post-transplant complication with low survival. BOS stage 0p (BOS 0p) is a parameter detected on pulmonary function tests (PFTs) after lung transplantation to identify patients at risk to develop BOS. We performed a retrospective study on 442 patients who underwent allogeneic stem cell transplant from 2007 to 2011 to evaluate whether development of BOS 0p is a risk factor in this population for BOS. Patients who met criteria for BOS 0p were significantly more likely to develop BOS (hazard ratio [HR], 3.22; P < .001). BOS 0p was significantly associated with a history of lung disease pretransplant (HR, 2.48; P = .001) and chronic graft-versus-host disease (GVHD) outside the lung post-transplant (HR, 23; P < .001). Finally, BOS 0p criteria were adequately sensitive in predicting BOS (85%), with a high negative predictive value (98%). Our findings suggest a routine PFT screening strategy with the intent of detecting BOS 0p, especially among patients with prior lung disease and who developed chronic GVHD, could suitably identify an at-risk population for the development of BOS. PMID:25687798
Miltenyi, Zsofia; Toth, Judit; Gonda, Andrea; Tar, Ildiko; Remenyik, Eva; Illes, Arpad
Castleman disease is a rare lymphoproliferative disorder. The clinical signs and symptoms of the disease are primarily mediated by cytokines, especially interleukin-6. We presented the case of a young female. In May 2004, a 30-year-old otherwise healthy looking woman presented with oral ulcerations resistant to topical and systemic antibiotic and antimycotic treatment. Bullous mucosal lichen or pemphigus vulgaris were suspected. Histological examination and direct and indirect immunofluorescence confirmed the diagnosis of pemphigus. Search for neoplasm revealed a retroperitoneal Castleman tumour sized 15 x 6 x 5 cm in the abdominal MRI. The tumour was a bleeder, so the removal was partial. Histological examination showed hyalin hypervascular Castleman disease. Considering her young, fertile age and the multicentric Castleman disease, non-cytostatic immunomodulatory therapy was started including steroid, cyclosporine-A and thalidomide treatment. The control abdominal CT showed a small residual tumour on the bladder. The residual tumour was removed in repeated surgery. At this time the histological examination showed transient type tumour between plasma cell and vascular variant. Currently, i.e. 4 years after the onset of the disease. (18)FDG PET/CT examination showed low metabolic active mass in the right iliacal region, but our patient had no symptoms or complaints. She is on 200 mg thalidomide a day and no tumour progression can be seen. Castleman disease can be successfully treated with non-cytostatic immunomodulatory therapy. PMID:19067241
Chakupurakal, G; Leitzke, S; Langerbeins, P; Schiller, J; Schneider, P M; Holtick, U; Shimabukuro-Vornhagen, A; Theurich, S; Chemnitz, J; Hallek, M; von Bergwelt-Baildon, M; Scheid, C
Allogeneic stem cell transplantation is a treatment option for patients with poor risk CLL. We conducted a retrospective analysis of all CLL patients allografted at our institution, the University Hospital of Cologne, Germany. Data was collected on 40 patients from 2004 to 2012. The mean age was 54, and the majority were male (75 %). On average, the patients were diagnosed 6 years (range 2-12) prior to transplant with an average of 4 years (range 1-8) from time of first-line therapy to transplant. The remission states at the time of transplant were complete remission (CR) (n?=?4), stable disease (n?=?10), partial remission (n?=?20) and progressive disease (n?=?6). Only reduced intensity conditioning regimens were employed. The average CD34(+) cell dose was 4.16?×?10(6)/kg. Neutrophil engraftment was seen by day +17 (range 10-23) post-transplant, and 88 % achieved 95-100 % donor chimerism by day 100. Overall survival, progression-free survival and non-relapse mortality at 2 years post-transplant were 65, 52.5 and 27.5 %, respectively. A total of 51 % of patients were found to be minimal residual disease (MRD)-negative at 1 year post-transplant. Our single-centre experience confirms the valuable role of allogeneic stem cell transplantation (allo-SCT) in the treatment of poor risk CLL patients with promising long-term survival and acceptable transplant-related mortality. The advent of newer therapeutic agents should not hinder the consideration of allo-SCT for this patient cohort as it remains the only curative option for these patients. PMID:26259502
Jaffe, Elaine S.; Dale, Janet K.; Pittaluga, Stefania; Heslop, Helen E.; Rooney, Cliona M.; Gottschalk, Stephen; Bollard, Catherine M.; Rao, V. Koneti; Marques, Adriana; Burbelo, Peter D.; Turk, Siu-Ping; Fulton, Rachael; Wayne, Alan S.; Little, Richard F.; Cairo, Mitchell S.; El-Mallawany, Nader K.; Fowler, Daniel; Sportes, Claude; Bishop, Michael R.; Wilson, Wyndham; Straus, Stephen E.
Chronic active EBV disease (CAEBV) is a lymphoproliferative disorder characterized by markedly elevated levels of antibody to EBV or EBV DNA in the blood and EBV RNA or protein in lymphocytes in tissues. We present our experience with CAEBV during the last 28 years, including the first 8 cases treated with hematopoietic stem cell transplantation in the United States. Most cases of CAEBV have been reported from Japan. Unlike CAEBV in Japan, where EBV is nearly always found in T or natural killer (NK) cells in tissues, EBV was usually detected in B cells in tissues from our patients. Most patients presented with lymphadenopathy and splenomegaly; fever, hepatitis, and pancytopenia were common. Most patients died of infection or progressive lymphoproliferation. Unlike cases reported from Japan, our patients often showed a progressive loss of B cells and hypogammaglobulinemia. Although patients with CAEBV from Japan have normal or increased numbers of NK cells, many of our patients had reduced NK-cell numbers. Although immunosuppressive agents, rituximab, autologous cytotoxic T cells, or cytotoxic chemotherapy often resulted in short-term remissions, they were not curative. Hematopoietic stem cell transplantation was often curative for CAEBV, even in patients with active lymphoproliferative disease that was unresponsive to chemotherapy. These studies are registered at http://www.clinicaltrials.gov as NCT00032513 for CAEBV, NCT00062868 and NCT00058812 for EBV-specific T-cell studies, and NCT00578539 for the hematopoietic stem cell transplantation protocol. PMID:21454450
Warlick, Erica D.; O'Donnell, Paul V.; Borowitz, Michael; Grupka, Nichon; Decloe, Lauren; Garrett-Mayer, Elizabeth; Borrello, Ivan; Brodsky, Robert; Fuchs, Ephraim; Huff, Carol Ann; Luznik, Leo; Matsui, William; Ambinder, Richard; Jones, Richard J.; Smith, B. Douglas
Allogeneic blood and marrow transplantation (alloBMT) remains the only curative treatment for patients with myelodysplastic syndromes (MDS), but its application has been limited by the older age range of patients with this disease. T cell depletion decreases transplant-related toxicity related to graft-versus-host disease (GVHD), but does not improve overall survival because of increased risk for relapse and graft failure. Myeloid growth factors have been used to speed engraftment following alloBMT, but data suggest that they may also have anti-tumor properties. We treated 43 patients (median age 56) with MDS/AML with high risk features using a myeloablative T cell depleted alloBMT followed by prolonged systemic GM-CSF. The current event-free survival at 1 and 3 years was 47% and 34% respectively with a median follow-up of 22.8 months in surviving patients. The toxicities compared favorably with those seen using reduced intensity conditioning regimens and included grade III/IV GVHD (10%), graft failure (9%), and cumulative treatment related mortality (28%). The cumulative incidence of relapse remained high at 38%; however, 3/10 patients receiving donor lymphocyte infusions achieved durable complete remissions. These results suggest that it is possible to maintain treatment intensity while minimizing toxicity in older, high-risk MDS patients. PMID:18261793
Leboulanger, N; Coulomb L'hermine, A; Teissier, N; Rouillon, I; Zribi, S; Roger, G; Garabedian, E N
Castleman disease (CD) is a benign lymphoproliferative disorder, rare in children. Head and neck localizations are found only in 14 % of the cases. Two forms have been described: a hyaline vascular type and a plasma cell type. It can also be monocentric or multicentric. Both young patients were affected with an isolated neck localization of Castleman disease. Preoperative diagnosis can be difficult with a thymoma or a lymphoma. CT and MRI can help in the diagnosis, which is confirmed by histopathological assessment. The pathological features and the therapeutic management of CD are discussed. While surgery is the treatment for localized lesions, steroids and chemotherapy are indicated in the multicentric type. Because of the risk of relapse and malignant transformation, long-term follow-up is mandatory. PMID:20627489
Fosby, Bjarte; Melum, Espen; Bjøro, Kristian; Bennet, William; Rasmussen, Allan; Andersen, Ina Marie; Castedal, Maria; Olausson, Michael; Wibeck, Christina; Gotlieb, Mette; Gjertsen, Henrik; Toivonen, Leena; Foss, Stein; Makisalo, Heikki; Nordin, Arno; Sanengen, Truls; Bergquist, Annika; Larsson, Marie E.; Soderdahl, Gunnar; Nowak, Greg; Boberg, Kirsten Muri; Isoniemi, Helena; Keiding, Susanne; Foss, Aksel; Line, Pål-Dag; Friman, Styrbjörn; Schrumpf, Erik; Ericzon, Bo-Göran; Höckerstedt, Krister; Karlsen, Tom H.
Abstract Aim and background. The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013. Materials and methods. The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report. Results. Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004–2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively. Conclusion. The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR). PMID:25959101
El-Cheikh, Jean; Crocchiolo, Roberto; Vai, Andrea; Furst, Sabine; Bramanti, Stefania; Sarina, Barbara; Granata, Angela; Faucher, Catherine; Mohty, Bilal; Harbi, Samia; Bouabdallah, Reda; Vey, Norbert; Santoro, Armando; Chabannon, Christian; Castagna, Luca; Blaise, Didier
Over the past decade, invasive fungal infections (IFIs) have remained an important problem in patients undergoing allogeneic haematopoietic stem cell transplantation (Allo-HSCT). The optimal approach for prophylactic antifungal therapy has yet to bedetermined. We conducted a retrospective analysis, comparing the safety and efficacy of micafungin 50mg/day vs. fluconazole 400mg/day vs. itraconazole 200mg/day as prophylaxis for adult patients with various haematological diseases receiving haploidentical hematopoietic stem cell transplantation (haplo-HSCT) followed by high-dose cyclophosphamide (PT-Cy). Overall, 99 patients were identified: 30 patients received micafungin, 50 and 19 patients received itraconazole and fluconazole, respectively. After a median follow-up of 12 months (range: 1–51), proven or probable IFIs were reported in 3 patients (10%) in the micafungin, 5 patients in the itraconazole (10%) and 2 patients (11%) in the fluconazole group (p=0.998). Fewer patients in the micafungin group had invasive aspergillosis (1 [3%] vs. 3 [6%] in the itraconazole vs. 2 [11%] in the fluconazole group, p=0.589). Four patients (13%) in the micafungin group vs 13 (26%) patients in the itraconazole group and 10 (53%) patients in the fluconazole received empirical antifungal therapy (P = 0.19). No serious adverse events related to treatment were reported by patients, and there was no treatment discontinuation because of drug-related adverse events in both groups. The present analysis shows that micafungin did better than fluconazole in preventing invasive aspergillosis after transplant in these high-risk hematological diseases, as expected. In addition, micafungin was more effective than itraconazole in preventing all IFI episodes when also considering possible fungal infections. Future prospective studies would shed light on this issue, concerning this increasingly used transplant platform. PMID:26401237
The histopathologic changes of radiation dermatitis have been classified either as early effects (necrotic keratinocytes, fibrin thrombi, and hemorrhage) or as late effects (vacuolar changes at the dermal-epidermal junction, atypical radiation fibroblasts, and fibrosis). Two patients, one exposed to radiation therapeutically and one accidentally, are described. Skin biopsy specimens showed an interface dermatitis characterized by numerous dyskeratotic epidermal cells with lymphocytes in close apposition (satellite cell necrosis); that is, the epidermal changes were similar to those in acute graft-versus-host disease. Because recipients of bone marrow transplants frequently receive total body irradiation as part of their preparatory regimen, the ability of radiation to cause persistent epidermal changes similar to those in acute graft-versus-host disease could complicate the interpretation of posttransplant skin biopsy specimens.
Wang, Yu; Wu, De-Pei; Liu, Qi-Fa; Qin, Ya-Zhen; Wang, Jing-Bo; Xu, Lan-Ping; Liu, Yan-Rong; Zhu, Hong-Hu; Chen, Jia; Dai, Min; Huang, Xiao-Jun
We asked whether minimal residual disease (MRD) determined by RUNX1/RUNX1T1 transcript levels could identify allogeneic hematopoietic stem cell transplantation (allo- HSCT) t(8;21) (q22;q22) acute myeloid leukemia patients who are at high risk for relapse, together with the impact of c-KIT mutations. Ninety-two consecutive adult t(8;21) patients who received allo-HSCT in complete remission were enrolled. MRD status at 1, 2, and 3 months after HSCT identified relapse patients (P5.05, P < .001, P5.0001, respectively). The 2-year cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) was 32% vs 9% (P 5 .01) and 55% vs 70% (P 5 .12) for patients with and without c-KIT mutations, respectively. In multivariate analysis, MRD at the first 3 months after HSCT, rather than c-KIT mutations,was an independent factor for CIR (P5.001) and LFS(P5.001). In addition, 17 patients received donor lymphocyte infusion (DLI) as interventional therapy for MRD, and the 2-year CIR and LFS for patients with or without DLI was 24% vs 87% (P5.001) and 64%vs 0%(P < .001), respectively. In conclusion, MRD monitoring early after transplant allows further rapid identification of t(8;21) patients at high risk of relapse and was more predictive of relapse risk than c-KIT mutations. PMID:25082877
Rajabiani, Afsaneh; Abdollahi, Alireza; Farahani, Zahra
Castleman’s disease, giant lymph node hyperplasia, is a kind of benign lymphoproliferative disease with gentle behavior. Its etiology and prevalence are unclear. This rare disease is usually found in mediastinal area asymptomatically and incidentally. It is also rare to see this tumor in the retroperitoneum. In this study, we have introduced a 34-year-old woman who referred just with occasional abdominal pain caused by compressive symptoms. Laboratory findings only reported microcytic anemia (MCH: 18.5, MCV: 63, Hemoglobin 10.2 g/dl). Chest and abdominal X-ray imaging showed no remarkable point. In abdominal ultrasonography, a solid and firm tumor with 12.2×5.3×6.6 cm was reported in patient’s retroperitoneum. Patient’s surgery was done and the tumor (covered by a fibrous thick capsule, with no bizarre appearance and bleeding) was completely removed. Pathologic examination indicated a Castleman’s tumor, type of unicentric and hyaline-vascular. This item had been one of the rare reported items of Castleman’s disease in the retroperitoneal space.
Kikuchi, Kentaro; Ishige, Toshiyuki; Ide, Fumio; Ito, Yumi; Saito, Ichiro; Hoshino, Miyako; Inoue, Harumi; Miyazaki, Yuji; Nozaki, Tadashige; Kojima, Masaru; Kusama, Kaoru
Recent research has shown that activation-induced cytidine deaminase (AID) triggers somatic hypermutation and recombination, in turn contributing to lymphomagenesis. Such aberrant AID expression is seen in B-cell leukemia/lymphomas, including Burkitt lymphoma which is associated with c-myc translocation. Moreover, Epstein-Barr virus (EBV) latent membrane protein-1 (LMP-1) increases genomic instability through early growth transcription response-1 (Egr-1) mediated upregulation of AID in B-cell lymphoma. However, few clinicopathological studies have focused on AID expression in lymphoproliferative disorders (LPDs). Therefore, we conducted an immunohistochemical study to investigate the relationship between AID and LMP-1 expression in LPDs (MTX-/Age-related EBV-associated), including diffuse large B-cell lymphomas (DLBCLs). More intense AID expression was detected in LPDs (89.5%) than in DLBCLs (20.0%), and the expression of LMP-1 and EBER was more intense in LPDs (68.4% and 94.7%) than in DLBCLs (10.0% and 20.0%). Furthermore, stronger Egr-1 expression was found in MTX/Age-EBV-LPDs (83.3%) than in DLBCLs (30.0%). AID expression was significantly constitutively overexpressed in LPDs as compared with DLBCLs. These results suggest that increased AID expression in LPDs may be one of the processes involved in lymphomagenesis, thereby further increasing the survival of genetically destabilized B-cells. AID expression may be a useful indicator for differentiation between LPDs and DLBCLs. PMID:25834572
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
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Taydas, Eren; Malik, Mohammad U; Dhingra, Abhinav; Russell, Stuart; Chacko, Matthews; Cameron, Andrew M; Alqahtani, Saleh; Gurakar, Ahmet
Coronary artery disease may affect cirrhotic patients regardless of age and etiology of the underlying liver disease. Early identification of coronary artery disease is important to be able to achieve the best posttransplant outcomes and survival. The coronary artery calcium score can be used as a screening tool to supplement the results of cardiac stress tests to identify a subgroup of patients who may benefit from further investigation with coronary arteriogram. Arteriogram is an invasive test and may cause renal compromise and risk of bleeding associated with coagulopathy. The present retrospective study showed that coronary artery calcium score > 250 Agatston units may help select the subgroup of patients who will benefit from further investigation with cardiac catheterization, and determining this score may limit the risks of catheterization. PMID:25894124
Stickel, Felix; Inderbitzin, Daniel; Candinas, Daniel
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
Major lentil diseases around the world have been described and reviewed. The major diseases include Ascochyta blight, Fusarium wilt, Botrytis Gray Mold, Lentil rust, Stemphylium blight, Anthracnose, and virus diseases. The management practices for these diseases are also presented....
NINDS Huntington's Disease Information Page Condensed from Huntington's Disease: Hope Through Research Table of Contents (click to jump to sections) ... Trials Organizations Additional resources from MedlinePlus ... is Huntington's Disease? Huntington's disease (HD) results from genetically programmed degeneration ...
Stenger, Elizabeth O; Chiang, Kuang-Yueh; Haight, Ann; Qayed, Muna; Kean, Leslie; Horan, John
Transfusion-related alloimmunization is a potent barrier to the engraftment of allogeneic hematopoietic stem cells in patients with nonmalignant diseases (NMDs). Memory T cells, which drive alloimmunization, are relatively resistant to commonly used conditioning agents. Alefacept, a recombinant leukocyte function antigen-3/IgG1 fusion protein, targets CD2 and selectively depletes memory versus naive T cells. Three multiply transfused pediatric patients with NMD received a short course of high-dose i.v. alefacept (.25 mg/kg/dose on days -40 and -9 and .5 mg/kg/dose on days -33, -26, -19, and -12) before undergoing unrelated allogeneic transplant in the setting of reduced-intensity pretransplant conditioning and calcineurin inhibitor-based post-transplant graft-versus-host disease (GVHD) prophylaxis. Alefacept infusions were well tolerated in all patients. Peripheral blood flow cytometry was performed at baseline and during and after alefacept treatment. As expected, after the 5 weekly alefacept doses, each patient demonstrated selective loss of CD2(hi)/CCR7(-)/CD45RA(-) effector memory (Tem) and CD2(hi)/CCR7(+)/CD45RA(-) central memory (Tcm) CD4(+) and CD8(+) T cells with relative preservation of the CD2(lo) Tem and Tcm subpopulations. In addition, depletion of CD2(+) natural killer (NK) cells also occurred. Neutrophil recovery was rapid, and all 3 patients had 100% sorted (CD3/CD33) peripheral blood donor chimerism by day +100. Immune reconstitution (by absolute neutrophil, monocyte, and lymphocyte counts) was comparable with a cohort of historical control patients. All 3 patients developed GVHD but are all now off immune suppression and >2 years post-transplant with stable full-donor engraftment. These results suggest that alefacept at higher dosing can deplete both memory T cells and NK cells and that incorporating CD2-targeted depletion into a reduced-intensity transplant regimen is feasible and safe in heavily transfused patients. PMID:26095669
Kanaoka, Miwa; Matsukura, Setsuko; Ishikawa, Hideyuki; Matsuura, Midori; Ishii, Norito; Hashimoto, Takashi; Aihara, Michiko
Paraneoplastic pemphigus (PNP) is an autoimmune bullous disease, which associates mainly with lymphoproliferative neoplasms. Bronchiolitis obliterans (BO) with progressive respiratory failure is a significant cause of death in PNP. We report a case of PNP associated with follicular lymphoma and BO, which showed findings suggesting coexistence of bullous pemphigoid (BP). The patient showed bullous and ulcerative lesions on the lips and oral cavity, and flaccid blisters on the trunk and thighs associated with anti-desmoglein (Dsg)3 antibodies. At later disease stage after commencement of treatment, anti-BP180 antibodies and tense blister formation were observed. It was proposed that persistent interface dermatitis is the first event in PNP, and subsequently induce the production of autoantibodies to Dsg and components of the basement membrane zone, resulting in both intraepidermal and subepidermal blisters. We speculate that interface dermatitis caused by autoreactive T cells induced autoantibody production against Dsg3, and subsequently against BP180. PMID:24985544
Bretagnol, Anne; Halimi, Jean Michel; Roland, Mélanie; Barbet, Christelle; Machet, Laurent; Al Najjar, Azmi; Marlière, Jean Frédéric; Badin, Julie; Nivet, Hubert; Lebranchu, Yvon; Büchler, Matthias
Nonmelanoma skin cancers (NMSC) are the most common malignant tumors following solid organ transplantation. Risk factors for NMSC mainly include immunosuppression, age, sun exposure and patient phototype. Recent findings have suggested that autosomal dominant polycystic kidney disease (ADPKD) may increase the risk of developing NMSC. We performed a monocenter retrospective study including all kidney recipients between 1985 and 2006 (n = 1019). We studied the incidence of NMSC, solid cancers and post-transplantation lymphoproliferative disease (PTLD), and analyzed the following parameters: age, gender, phototype, time on dialysis, graft rank, immunosuppressive regimen, history of cancer and kidney disease (ADPKD versus others). Median follow-up was 5.5 years (range: 0.02-20.6; 79 838 patient-years). The cumulated incidence of NMSC 10 years after transplantation was 12.7% (9.3% for solid cancers and 3.5% for PTLD). Autosomal dominant polycystic kidney disease and age were risk factors for NMSC (HR 2.63; P < 0.0001 and HR 2.21; P < 0.001, respectively) using univariate analysis. The association between ADPKD and NMSC remained significant after adjustments for age, gender and phototype using multivariate analysis (HR 1.71; P = 0.0145) and for immunosuppressive regimens (P < 0.0001). Autosomal dominant polycystic kidney disease was not a risk factor for the occurrence of solid cancers after transplantation (HR 0.96; P = 0.89). Our findings suggest that ADPKD is an independent risk factor for developing NMSC after kidney transplantation. PMID:20230542
Tschan-Plessl, A; Halter, J P; Heim, D; Medinger, M; Passweg, J R; Gerull, S
The multikinase inhibitor sorafenib has shown a strong anti-leukemic effect in FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML); however, remission is often transient. To better understand the role of sorafenib, we performed a retrospective analysis of all patients who received sorafenib in combination with allogeneic hematopoietic stem cell transplantation (HSCT) at our center. Seventeen patients with FLT3-ITD positive AML were treated with sorafenib in combination with allogeneic HSCT. Seven patients received sorafenib therapy pre- and posttransplant, and 10 patients were given sorafenib only posttransplant. Median duration of sorafenib treatment was 13 months (range 1-42); median dose was 600 mg (range 100-1200). Fourteen patients (82 %) achieved a complete remission (CR), while 5 patients (29 %) eventually developed progressive disease. Developing chronic graft-versus-host disease (GvHD) had a strong protective influence on the risk of sorafenib resistance (p?=?0.028, HR 0.08, 95 % CI 0.01-0.76). In a total of 8 patients, sorafenib had to be stopped, paused or dose-reduced due to toxicity. In 5 patients with pronounced toxicity, we switched to an alternating dosing schedule with 1 month on/1 month off sorafenib. These patients subsequently remained in sustained complete molecular remission, with a median follow-up of 20 months. Our data indicate that sorafenib can achieve high rates of sustained remission in high-risk patients treated in combination with HSCT. PMID:26233683
... Health Division of Parasitic Diseases and Malaria CS226359 Chagas Disease Fact Sheet What is Chagas disease? ? A disease that can cause serious heart ... benchuca,” “vinchuca,” “chinche,” or “barbeiro” Who can get Chagas disease? Anyone. However, people have a greater chance ...
... Binswanger's Disease? Binswanger's disease (BD), also called subcortical vascular dementia , is a type of dementia caused by widespread, ... Hope Through Research Information booklet about Alzheimer's disease, vascular dementia, and other types of dementia compiled by the ...
NINDS Kennedy's Disease Information Page Synonym(s): Bulbospinal Muscular Atrophy, X-Linked Spinal and Bulbar Muscular Atrophy Table of Contents ( ... is being done? Clinical Trials Organizations What is Kennedy's Disease? Kennedy's disease is an inherited motor neuron ...
Infectious diseases kill more people worldwide than any other single cause. Infectious diseases are caused by germs. Germs are tiny living ... live NIH: National Institute of Allergy and Infectious Diseases
Huntington's disease (HD) is an inherited disease that causes certain nerve cells in the brain to waste away. ... express emotions. If one of your parents has Huntington's disease, you have a 50 percent chance of getting ...
... chest pain, heart attacks, and strokes . What Is Heart Disease? The heart is the center of the ... burst blood vessel. Continue How Do You Get Heart Disease? Heart disease isn't contagious — you can' ...
Hartlage, Alex S; Liu, Tom; Patton, John T; Garman, Sabrina L; Zhang, Xiaoli; Kurt, Habibe; Lozanski, Gerard; Lustberg, Mark E; Caligiuri, Michael A; Baiocchi, Robert A
The Epstein-Barr virus (EBV) is an oncogenic, ?-herpesvirus associated with a broad spectrum of disease. Although most immune-competent individuals can effectivley develop efficient adaptive immune responses to EBV, immunocompromised individuals are at serious risk for developing life-threatening diseases, such as Hodgkin lymphoma and posttransplant lymphoproliferative disorder (PTLD). Given the significant morbidity associated with EBV infection in high-risk populations, there is a need to develop vaccine strategies that restore or enhance EBV-specific immune responses. Here, we identify the EBV immediate-early protein BZLF1 as a potential target antigen for vaccine development. Primary tumors from patients with PTLD and a chimeric human-murine model of EBV-driven lymphoproliferative disorder (EBV-LPD) express BZLF1 protein. Pulsing human dendritic cells (DC) with recombinant BZLF1 followed by incubation with autologous mononuclear cells led to expansion of BZLF1-specific CD8(+) T cells in vitro and primed BZLF1-specific T-cell responses in vivo. In addition, vaccination of hu-PBL-SCID mice with BZLF1-transduced DCs induced specific cellular immunity and significantly prolonged survival from fatal EBV-LPD. These findings identify BZLF1 as a candidate target protein in the immunosurveillance of EBV and provide a rationale for considering BZLF1 in vaccine strategies to enhance primary and recall immune responses and potentially prevent EBV-associated diseases. Cancer Immunol Res; 3(7); 787-94. ©2015 AACR. PMID:25735952
... frequent, urgent urination Bladder cancer Doctors diagnose bladder diseases using different tests. These include urine tests, x- ... National Institute of Diabetes and Digestive and Kidney Diseases
Columnaris disease is caused by the Gram-negative bacterium, Flavobacterium columnare. The disease was first described in 1917-1919 in the United States and the bacterium was not successfully isolated and grown in the laboratory until 1944. Columnaris disease continues to be a prevalent disease of...
NINDS Alzheimer's Disease Information Page Table of Contents (click to jump to sections) What is Alzheimer's Disease? Is there any ... Trials Organizations Additional resources from MedlinePlus What is Alzheimer's Disease? Alzheimer's disease (AD) is an age-related, non- ...
... you're like most people, you think that heart disease is a problem for others. But heart disease is the number one killer in the ... of disability. There are many different forms of heart disease. The most common cause of heart disease ...
Puri, K; Kocoshis, S; Risma, K; Perez, L; Hart, C; Chin, C; Ryan, T D; Jefferies, J L; Schumacher, K R; Castleberry, C
Autoimmune-mediated bowel disease has been reported after pediatric heart transplantation. Recognition and treatment of these patients has been difficult. We describe a patient who responded to steroids and basiliximab therapy after an inflammatory process secondary to abnormal T-cell activation. Our patient is a 28-month-old female who received a heart transplant at five wk of age. At 24 months post-transplant, she developed fever and bloody stools. Initial investigations were significant for an elevated ESR (>120) and CRP (15.2). Symptoms persisted despite bowel rest and mycophenolate discontinuation. Endoscopic evaluation revealed discontinuous ulcerative disease involving esophagus, terminal ileum, right and left colon, necessitating extensive bowel resection. She had additional airway inflammation leading to a TEF at the site of esophageal ulceration, requiring tracheostomy. Immune evaluation revealed autoimmune dysregulation that responded to parenteral methylprednisolone. Chronic basiliximab therapy allowed for successful weaning of steroids with sustained remission. She has been transitioned to sirolimus and tacrolimus maintenance immunosuppression with plans to discontinue basiliximab once off steroids. In conclusion, bowel disease in the setting of pediatric heart transplantation can be severe and refractory to traditional treatment methods. Tailoring immune therapy to activated T cells can result in remission. Basiliximab therapy was used in our patient to maintain steroid-induced remission, but long-term complications of this disease process are unknown. PMID:26374667
Avsar, Yesim; Cicinnati, Vito R; Kabar, Iyad; Wolters, Heiner; Anthoni, Christoph; Schmidt, Hartmut H J; Beckebaum, Susanne
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
Costa, Rubens; 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
Niemiec, Brook A
Periodontal disease is the most commonly diagnosed problem in small animal veterinary medicine. In the vast majority of cases, however, there are little to no outward clinical signs of the disease process, and, therefore, therapy often comes very late in the disease course. Consequently, periodontal disease is also the most undertreated animal health problem. In addition, unchecked periodontal disease has numerous dire consequences both locally and systemically. These consequences are detailed in the article and should be utilized to educate clients and encourage compliance of therapeutic recommendations. The local consequences include oronasal fistulas, class II perio-endo lesions, pathologic fractures, ocular problems, osteomyelitis, and an increased incidence of oral cancer. Systemic diseases linked to periodontal disease include: renal, hepatic, pulmonary, and cardiac diseases; osteoporosis, adverse pregnancy effects, and diabetes mellitus. Before the discussion of consequences, this article covers the pathogenesis of periodontal disease, followed by clinical features and diagnostic tests. PMID:18482707
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
the donor was chronically infected, such as Epstein-Barr (EBV) or other herpes viruses. Some evidence has suggested that the lympho-proliferative disorder associ- ated with EBV infection may be less severe if the post-transplant immunosuppressant used is rapamycin, which can also suppress the growth of EBV
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
Muhsein, Khairul Abdullah; Liew, Ngoh-Chin; Shaker, Abdul Rahman Hikmet; Shahrin, Iskandar Abdul Wahab
Castleman's disease is a rare lymphoproliferative disorder of unknown aetiology. The presentation is varied, diagnosis is difficult, and optimum management is still unknown. We report our experience with a case of Castleman's disease in a 34-year old woman who presented with pallor, hepatosplenomegaly, and a right iliac fossa mass that was 5 cm in diameter. this was initially diagnosed as a soft tissue sarcoma and preoperative tumour embolization was planned before excision. Mesenteric arteriogram revealed that the feeder arteries arose from the superior mesenteric artery and embolization was aborted for fear of causing bowel ischaemia. On laparotomy, lymphoid enlargement was found between the leaves of the jejunal mesentery. The tumour was relatively avascular and the overlying mesenteric vessels contributed to teh duplex ultrasound and computerized tomography appearance of hypervascularity. The tumour with the mesentery and the overlying segment of jejunum was excised completely. Histopathology confirmed Castleman's disease. The purpose of this report is to present this rare case that caused a diagnostic dilemma and to review the management of this disorder. PMID:14719517
Delforge, M L
Serology testing allows the determination of immunity against different infecting organisms via the dosage of IgG. When the direct detection of a pathogen is not possible, detection of specific IgM antibodies or antigens may also help to diagnose an acute infection. This article describes the usefulness of serological testing for the diagnosis or the follow-up of some infectious pathologies: Lyme disease, sexually transmitted diseases (STD) and Epstein-Barr virus (EBV). Serological diagnosis of Lyme disease is difficult. Results must always be interpreted in correlation with clinical symptoms: on the one hand, the presence of antibodies could be correlated either with a recent or a past infection; and on the other hand, sensitivity of Lyme serology is low in the early stages. Concerning STD, the direct detection of the pathogen must be preferred for Herpes simplex, Chlamydia, mycoplasma and gonorrhoea infections. For detection of HIV, HCV, HBV and syphilis, serological testing is the method of choice. The diagnosis of infectious mononucleosis is based on the detection of specific EBV IgM antibodies and should be preferred to the detection of heterophilic antibodies such as Paul and Bunnel test. EBV reactivation are very rare in immunocompetent patients, but can occur in immunocompromised, particularly transplanted patients and can lead to a lymphoproliferative disorder. Surveillance of these patients can be followed with the monitoring of EBV viral load. Serological testing in this case is generally not useful. PMID:22034758
... not harmful. 5 The seeds in tomatoes, zucchini, cucumbers, strawberries, and raspberries, as well as poppy seeds, ... diseases, including diverticular disease. Clinical trials are research studies involving people. Clinical trials look at safe and ...
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... You may have seen the actor Michael J. Fox on TV talking about Parkinson's disease. He has ... and help find a cure. Mostly adults (like Fox and boxer Muhammad Ali) get Parkinson's disease. It's ...
Parkinson disease causes certain brain cells to die. These are the cells that help control movement and coordination. ... called dopamine to help control muscle movement. With Parkinson disease, the brain cells that make dopamine slowly die. ...
... our online catalog. Additional Links Hashimoto's Disease Hyperthyroidism Hypothyroidism Pregnancy & Thyroid Disease Thyroid Tests Find a Specialist ... everyone who receives radioactive iodine treatment eventually develops hypothyroidism, which occurs when the thyroid does not make ...
... print versions from our online catalog. Additional Links Hypothyroidism Pregnancy and Thyroid Disease Thyroid Tests Find a ... disease often leads to reduced thyroid function, or hypothyroidism. Hypothyroidism is a disorder that occurs when the ...
... and Parkinson’s disease illustrates value of exposome studies (Mar. 2014) Exploring the haunting legacy – benomyl and Parkinson’s ( ... 2011) Deciphering a Core Process in Parkinson's Disease (Mar. 2011) Workshop Examines the Role of Air Pollution ...
... developing celiac disease increase when his or her genes—traits passed from parent to child—have variants, or changes. In celiac disease, certain gene variants and other factors, such as a person's ...
... southern Italians, but it may occur in any group. Wilson disease typically appears in people under 40 ... Wilson disease support groups can be found at www.wilsonsdisease.org and www.geneticalliance.org .
... take place on hard surfaces, such as track, basketball, soccer, and gymnastics. Sever's disease also can result ... THIS TOPIC Jumper's Knee (Patellar Tendonitis) Growth Plate Injuries Osgood-Schlatter Disease Knee Injuries Common Childhood Orthopedic ...
... Sandhoff Disease? Sandhoff disease is a rare, inherited lipid storage disorder that progressively destroys nerve cells in ... results in the harmful accumulation of certain fats (lipids) in the brain and other organs of the ...
Lyme disease is a bacterial infection you get from the bite of an infected tick. The first symptom ... Muscle and joint aches A stiff neck Fatigue Lyme disease can be hard to diagnose because you may ...
... greater risk for kidney disease if you have diabetes, high blood pressure, or a close family member ... your kidneys normally do. NIH: National Institute of Diabetes and Digestive and Kidney Diseases
... The Most Common Types of Prostate Diseases Benign prostatic hyperplasia (BPH) Prostatitis Prostate cancer For men over the ... the prostate disease most often encountered is benign prostatic hyperplasia (BPH). If you have BPH, your prostate has ...
... make a report by phone. Examples are rubeola (measles) and pertussis (whooping cough). Report of total number ... related infant deaths Legionellosis Listeriosis Lyme disease Malaria Measles Meningococcal disease Mumps Novel influenza A virus infections ...
Krabbe disease is a rare genetic disorder of the nervous system. It is a type of leukodystrophy. ... A defect in the GALC gene causes Krabbe disease. Persons with this gene ... (galactosylceramidase). The body needs this substance to ...
Chagas disease is an illness spread by insects. It is common in South and Central America. ... Chagas disease is caused by the parasite Trypanosoma cruzi. It is spread by the bite of reduviid bugs ...
... can make a person more likely to get Alzheimer disease. But that doesn't mean everyone related to someone who has it will get the disease. Other factors, combined with genes, may make it more likely that someone will ...
... It is most common in the Ashkenazi Jewish population. Type 2 disease usually begins in infancy with severe neurologic involvement. This form can lead to rapid, early death. Type 3 disease may cause liver, ...
Fifth disease is a viral infection caused by parvovirus B19. The virus only infects humans; it's not the same parvovirus that dogs and cats can get. Fifth disease mostly affects children. Symptoms can include a low ...
Chagas disease is caused by a parasite. It is common in Latin America but not in the United States. ... nose, the bite wound or a cut. The disease can also spread through contaminated food, a blood ...
... blood pressure and water and salt balance. Addison disease happens if the adrenal glands don't make ... problem with your immune system usually causes Addison disease. The immune system mistakenly attacks your own tissues, ...
... where your body makes and stores stool. Many disorders affect the colon's ability to work properly. Some ... abdominal cramping and other symptoms Treatment for colonic diseases varies greatly depending on the disease and its ...
... For Kids For Parents MORE ON THIS TOPIC Digestive System Irritable Bowel Syndrome (IBS) Inflammatory Bowel Disease X- ... GI) Irritable Bowel Syndrome Inflammatory Bowel Disease Your Digestive System Constipation Upper GI (Video) Digestive System Irritable Bowel ...
... and remove poisons. There are many kinds of liver diseases. Viruses cause some of them, like hepatitis A, ... of the skin, can be one sign of liver disease. Cancer can affect the liver. You could also ...
Huntington disease is a disorder in which nerve cells in certain parts of the brain waste away, or ... Huntington disease is caused by a genetic defect on chromosome 4. The defect causes a part of DNA, ...
Parkinson's disease (PD) is a type of movement disorder. It happens when nerve cells in the brain don't ... coordination As symptoms get worse, people with the disease may have trouble walking, talking, or doing simple ...
Raynaud's disease is a rare disorder of the blood vessels, usually in the fingers and toes. It causes the ... secondary Raynaud's, which is caused by injuries, other diseases, or certain medicines. People in colder climates are ...
... the back of the eye Macular degeneration - a disease that destroys sharp, central vision Diabetic eye problems ... defense is to have regular checkups, because eye diseases do not always have symptoms. Early detection and ...
Lyme disease is a bacterial infection that is spread through the bite of one of several types of ... Lyme disease is caused by bacteria called Borrelia burgdorferi ( B. burgdorferi) . Blacklegged ticks and other species of ticks ...
... Share External Link Disclaimer Digestive Diseases Wilson Disease Alternate Versions PDF Version? (444 KB) You can also ... things psychosis—when a person loses contact with reality Other Signs and Symptoms Other signs and symptoms ...
... Disease Information Page Table of Contents (click to jump to sections) What is Gaucher Disease? Is there ... Column2 National Gaucher Foundation, Inc. 61 General Early Drive Harpers Ferry, WV 25425 firstname.lastname@example.org http:// ...
... Disease Information Page Table of Contents (click to jump to sections) What is Leigh's Disease? Is there ... called adenosine triphosphate ( ATP). The energy in ATP drives virtually all of a cell's metabolic functions. Genetic ...
... Disease Information Page Table of Contents (click to jump to sections) What is Behcet's Disease? Is there ... NEI) National Institutes of Health, DHHS 31 Center Drive, Rm. 6A32 MSC 2510 Bethesda, MD 20892-2510 ...
... Disease Information Page Table of Contents (click to jump to sections) What is Moyamoya Disease? Is there ... Column2 National Rehabilitation Information Center (NARIC) 8400 Corporate Drive Suite 500 Landover, MD 20785 email@example.com ...
Legionnaires' disease is a type of pneumonia caused by bacteria. You usually get it by breathing in ... t spread from person to person. Symptoms of Legionnaires' disease include high fever, chills, a cough, and ...
Parvovirus B19; Erythema infectiosum; Slapped cheek rash ... Fifth disease is caused by human parvovirus B19. It often affects preschoolers or school-age children during the spring. The disease spreads through the fluids in the nose and ...
Amador, Jose; Berry, Robert W.; Frederiksen, Richard A.; Horne, C. Wendell; Thames, Walter H.; Toler, Robert W.
. THAMES, Professor, Department of Plant Sciences ROBERT W. TOLER, Associate Professor, Depart- ment of Plant Sciences Texas AM University SORGHUM DISEASES GRAIN SORGHUM ACREAGE has increased rapidly since introduction of hybrids, and disease has.... Plants infected in the foliar cycle may become systemically diseased. Leaves of systemically infected plants will become striped with white bands sometimes running the whole length of the leaf. At this stage, the disease possibly may be confused...
Jones, Roger K.
(Blank P~ge in O .... a1-BUUetinl ? ~" -: . . r ". ./ RICE DISEASES Roger K. Jones * Rice diseases reduce yields in Texas by an average of 12 percent each year. The yield loss in certain fields with a history of disease may exceed 30... percent in some seasons. Disease development in individual fields depends upon the interaction of several factors including the genetic resistance of the variety planted, cropping practices, environmental conditions (such as temperature, dew periods...
Concise information about Newcastle disease (ND) is provided for a book that serves as a quick reference guide to the infectious, parasitic, metabolic, nutritional, and toxic diseases of domesticated animals and birds as well some exotic species that a veterinarian might encounter. Newcastle disease...
... very complex Are often caused by changes in genes It can be hard to find a specialist who knows how to treat your rare disease. Disease advocacy groups, rare disease organizations, and genetics clinics may help you to find one. NIH: National Institutes of Health
Gaucher disease is an autosomal recessive disorder caused by congenital deficiency of lysosomal glucocerebrosidase. Gaucher disease is classified into three types. In addition to enzyme replacement therapy, substrate reduction therapy, chemical chaperon therapy, and hematopoietic stem cell transplantation therapy are considered for the effective treatment of Gaucher disease. PMID:26329151
Taylor, George C.
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…
Schessel, David A.
Meniere's disease is characterized by unpredictable spells of severe vertigo and fluctuations in hearing and tinnitus. This article discusses the incidence of Meniere's disease, the present status of our understanding of this disease, controversies in its diagnosis, and the multiple therapeutic modalities recruited in its treatment. (Contains…
NINDS Krabbe Disease Information Page Synonym(s): Globoid Cell Leukodystrophy Table of Contents (click to jump to sections) What is Krabbe ... Trials Organizations Additional resources from MedlinePlus What is Krabbe Disease? Krabbe disease is a rare, inherited degenerative disorder ...
Alzheimer's disease (AD) is the most common form of dementia among older people. Dementia is a brain disorder that seriously affects a person's ability to carry ... higher if a family member has had the disease. No treatment can stop the disease. However, some ...
... of brain function that occurs with certain diseases. Alzheimer disease (AD) is one form of dementia. It affects ... The exact cause of Alzheimer disease (AD) is not known. Research shows that certain changes in the brain lead to AD developing. You are more likely ...
... hours or more before attaching to the skin. Diagnosis & Tests How can my doctor tell if I have Lyme disease? The best way to find out if you ... tests aren't always necessary to make the diagnosis. They can often give ... in early-stage Lyme disease. People who have been sick with Lyme disease ...
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
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
Kim, Jun Suk; Oh, Seak Hee; Kim, Hyun Jin; Cho, Jin Min; Yoo, Han-Wook; Namgoong, Jung-Man; Kim, Dae Yeon; Kim, Ki-Hun; Hwang, Shin; Lee, Sung-Gyu
Purpose Metabolic liver disease (MLD) often progresses to life-threatening conditions. This study intends to describe the outcomes of liver transplantation (LTx) for MLD at a living donor-dominant transplantation center where potentially heterozygous carrier grafts are employed. Methods We retrospectively evaluated the medical records of 54 patients with MLD who underwent LTx between November 1995 and February 2012 at Asan Medical Center in Seoul, Korea. The cumulative graft and patient survival rates were analyzed according to patient age, and living or deceased donor LTx. Recurrence of the original disease was also investigated. Results The post-transplant cumulative patient survival rates at one, five, and 10 years were 90.7%, 87.5% and 87.5%, and the graft survival rates were 88.8%, 85.5%, and 85.5%, respectively. There were no differences in the patient survival rates according to the recipient age, human leukocyte antigen matching, and living or deceased donor LTx. There were also no differences in the patient survival rates between the MLD and the non-MLD groups for children. Recurrence of the original metabolic disease was not observed in any patient during the follow-up period. Conclusion Our results suggest that the living donor-dominant transplantation program is well-tolerated in MLD without recurrence of the original MLD using all types of transplantation. PMID:25866733
Sundel, Robert P
Kawasaki disease (KD) is the archetypal pediatric vasculitis, exemplifying the unique aspects and challenges of vascular inflammation in children. The condition is almost unheard of in adults, is closely associated with infections, and is self-limited, with fever resolving after an average of 12 days even without treatment. Yet KD is also a potentially fatal disease and the most common cause of acquired heart disease in the developed world. Unraveling of the developmental, immunologic, and genetic secrets of Kawasaki disease promises to improve our understanding of vasculitis in particular, and perhaps also to provide a window on the fundamental mysteries of inflammatory diseases in general. PMID:25399940
Takada, Leonel T; Geschwind, Michael D
Prion diseases are a group of diseases caused by abnormally conformed infectious proteins, called prions. They can be sporadic (Jakob-Creutzfeldt disease [JCD]), genetic (genetic JCD, Gerstmann-Sträussler-Scheinker, and familial fatal insomnia), or acquired (kuru, variant JCD, and iatrogenic JCD). The clinical features associated with each form of prion disease, the neuroimaging findings, cerebrospinal fluid markers, and neuropathological findings are reviewed. Sporadic JCD is the most common form of human prion disease, and will be discussed in detail. Genetic prion diseases are caused by mutations in the prion-related protein gene (PRNP), and they are classified based on the mutation, clinical phenotype, and neuropathological features. Acquired prion diseases fortunately are becoming rarer, as awareness of transmission risk has led to implementation of measures to prevent such occurrences, but continued surveillance is necessary to prevent future cases. Treatment and management issues are also discussed. PMID:24234356
Knight, Tyler; Schaefer, Caroline; Krasa, Holly; Oberdhan, Dorothee; Chapman, Arlene; Perrone, Ronald D
Background Autosomal dominant polycystic kidney disease (ADPKD) results in kidney cyst development and enlargement, resulting in chronic kidney disease (CKD) leading to renal failure. This study sought to determine if ADPKD patients in the early stages of CKD contribute to a sizable economic burden for the US health care system. Methods This was a retrospective, matched cohort study, reviewing medical resource utilization (MRU) and costs for adults in a US private-payer claims database with a diagnosis code of ADPKD (ICD-9-CM 753.13). ADPKD patients were matched by age grouping (0–17, 18–34, 35–44, 45–54, 55–64, and 65+ years) and sex to controls to understand the burden of ADPKD. Descriptive statistics on 6-month MRU and costs were assessed by CKD stages, dialysis use, or previous renal transplant. Results The analysis included ADPKD patients in CKD stages 1–5 (n=316 to n=860), dialysis (n=586), and post-transplant (n=615). Mean ages did not differ across CKD stages (range 43–56 years). Men were the majority in the later stages but the minority in the early stages. The proportion of patients with at least one hospitalization increased with CKD stage, (12% to >40% CKD stage 2 to stage 5, dialysis or post-transplant). The majority had at least one hospital outpatient visit and at least one pharmacy claim. Total 6-month per-patient costs were greater among ADPKD patients than in age-matched and sex-matched healthy non-ADPKD controls (P<0.001 for all comparisons). Conclusion ADPKD patients with normal kidney function are associated with a significant economic burden to the health care system relative to the general population. Any treatments that delay progression to later stages of CKD may provide potential health care cost offsets. PMID:25759590
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.
Pierson, Duane L.
This is a collection of viewgraphs on the Johnson Space Center's work on infectious disease. It addresses their major concern over outbreaks of infectious disease that could jeopardize the health, safety and/or performance of crew members engaged in long duration space missions. The Antarctic environment is seen as an analogous location on Earth and a good place to carry out such infectious disease studies and methods for proposed studies as suggested.
Edward McKintosh; Sarah J. Tabrizi; John Collinge
Prion diseases are incurable neurodegenerative conditions affecting both animals and humans. They may be sporadic, infectious,\\u000a or inherited in origin. Human prion diseases include Creutzfeldt—Jakob desease (CJD), Gerstmann—Straussler—Scheinker disease,\\u000a kuru, and fatal familial insomnia. The appearance of variant CJD, and the demonstration that is caused by strains indistinguishable\\u000a from bovine spongiform encephalopathy (BSE) in cattle, has led to the threat
Dr. Leslie Nader (MSMR)
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.
... Funding About NIAID News & Events NIAID > Health & Research Topics > Whipworm Disease Skip Website Tools Website Tools Print this page Get email updates Order publications Volunteer for Clinical ...
Bhargava, Parul; Rushin, Jeanne M; Rusnock, Eileen J; Hefter, Lawrence G; Franks, Teri J; Sabnis, Sharda G; Travis, William D
Light chain deposition disease (LCDD) in the lung is a rare occurrence. We describe 5 new cases of this entity, review the literature, and compare pulmonary light chain deposits to pulmonary amyloidosis. In addition, we identified 17 patients with pulmonary LCDD in the literature with sufficient clinical information to allow evaluation of clinical presentation, laboratory findings, histologic appearance, and disease progression. In these 22 patients, 2 different histologic patterns were appreciated: diffuse and nodular. A parallel with the diffuse and nodular forms of pulmonary amyloidosis is suggested. The 10 patients with nodular LCDD had an overall better prognosis compared with the 12 patients with diffuse pulmonary LCDD. However, when compared to what is reported in the literature for nodular pulmonary amyloidosis, the patients with nodular LCDD had a higher incidence of an associated lymphoproliferative and/or plasma cell dyscrasia and renal failure. Light chain deposits in the lung are histologically similar to amyloid but are not Congophilic. Their electron microscopic appearance is distinctly different with fibrils in amyloid and granular deposits in LCDD. As the diffuse forms of LCDD and amyloidosis have a similarly poor prognosis, differentiating the 2 entities is probably not critical. However, when present as nodules, LCDD is more frequently associated with an underlying plasma cell dyscrasia or renal failure than is amyloidosis, and therefore the distinction may be clinically important. PMID:17255772
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 focus of this chapter, are viruses of avian paramyxovirus serotype-1 (APMV-1). All isolates of APMV-1 are of one serotype and are referred to as Newcastle disease viruses (NDV). Newcastle disease (ND) is caused only by infections with virulent isolates of APMV-1 (virulent NDV or vNDV). Virulent ...
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...
Karen E. Anderson
Huntington's disease (HD) is an inherited disorder that causes neurological, cognitive, and psychiatric symptoms. Most patients with HD develop symptoms in all three of these domains, often concurrently. Problems in one area can impact and magnify symptoms in another domain. Limited treatment options exist for neurological and cognitive symptoms at this time, and no treatment exists to slow disease progression.
... 605-14. 3. Donsante, A. et. al. ATPTA gene addition to the choroid plexus results in long-term rescue of the lethal copper transport defect in a Menkes disease mouse model. Molecular Therapy (in press as of August 2011). NIH Patient Recruitment for Menkes Disease Clinical Trials ...
... inflamed tissue) on individuals with little or no lung or nervous system complications, or may be surgically removed in older individuals. What is the prognosis? Most children with the classic form of Farber’s disease die by age 2, usually from lung disease. Children born with the most severe form ...
Meniere's disease is a disorder of the inner ear. It can cause severe dizziness, a roaring sound in your ears called tinnitus, hearing loss that ... together over several days. Some people with Meniere's disease have "drop attacks" during which the dizziness is ...
Kalia, Lorraine V; Lang, Anthony E
Parkinson's disease is a neurological disorder with evolving layers of complexity. It has long been characterised by the classical motor features of parkinsonism associated with Lewy bodies and loss of dopaminergic neurons in the substantia nigra. However, the symptomatology of Parkinson's disease is now recognised as heterogeneous, with clinically significant non-motor features. Similarly, its pathology involves extensive regions of the nervous system, various neurotransmitters, and protein aggregates other than just Lewy bodies. The cause of Parkinson's disease remains unknown, but risk of developing Parkinson's disease is no longer viewed as primarily due to environmental factors. Instead, Parkinson's disease seems to result from a complicated interplay of genetic and environmental factors affecting numerous fundamental cellular processes. The complexity of Parkinson's disease is accompanied by clinical challenges, including an inability to make a definitive diagnosis at the earliest stages of the disease and difficulties in the management of symptoms at later stages. Furthermore, there are no treatments that slow the neurodegenerative process. In this Seminar, we review these complexities and challenges of Parkinson's disease. PMID:25904081
Soilborne pathogens that cause root diseases spend most of their life cycle in or on the soil. Soil management decisions will influence the survival, growth of these pathogens and severity of disease. Many of the cultural methods that growers have relied on in the past to reduce the impact of the...
Legionnaire disease is an infection of the lungs and airways. It is caused by Legionella bacteria. ... The bacteria that cause Legionnaire disease have been found in water delivery systems. They can survive in the warm, moist air conditioning systems of large ...
Taylor, Frederick L; Levine, Laurence A
Peyronie's disease is a psychologically and physically devastating disorder that is manifest by a fibrous inelastic scar of the tunica albuginea, resulting in palpable penile scar in the flaccid condition and causing penile deformity, including penile curvature, hinging, narrowing, shortening, and painful erections. Peyronie's disease remains a considerable therapeutic dilemma even to today's practicing physicians. PMID:17983892
W. Jones Williams
The increasing use of beryllium in a variety of industries continues to be a hazard. New cases are still being reported to the UK Beryllium Case Registry, now numbering 60 in the period 1945-1988. The majority of cases follow inhalation which results in acute beryllium disease (chemical pneumonitis) or more commonly chronic beryllium disease--a granulomatous pneumonitis. Granulomatous skin nodules also
Seekatz, Anna M; Theriot, Casey M; Molloy, Caitlyn T; Wozniak, Katherine L; Bergin, Ingrid L; Young, Vincent B
Recurrent Clostridium difficile infection (CDI) is of particular concern among health care-associated infections. The role of the microbiota in disease recovery is apparent given the success of fecal microbiota transplantation (FMT) for recurrent CDI. Here, we present a murine model of CDI relapse to further define the microbiota recovery following FMT. Cefoperazone-treated mice were infected with C. difficile 630 spores and treated with vancomycin after development of clinical disease. Vancomycin treatment suppressed both C. difficile colonization and cytotoxin titers. However, C. difficile counts increased within 7 days of completing treatment, accompanied by relapse of clinical signs. The administration of FMT immediately after vancomycin cleared C. difficile and decreased cytotoxicity within 1 week. The effects of FMT on the gut microbiota community were detectable in recipients 1-day posttransplant. Conversely, mice not treated with FMT remained persistently colonized with high levels of C. difficile, and the gut microbiota in these mice persisted at low diversity. These results suggest that full recovery of colonization resistance against C. difficile requires the restoration of a specific community structure. PMID:26169276
Chinnock, Richard E; Bailey, Leonard L
Successful infant heart transplantation has now been performed for over 25 years. Assessment of long term outcomes is now possible. We report clinical outcomes for322 patients who received their heart transplant during infancy. Actuarial graft survival for newborn recipients is 59% at 25 years. Survival has improved in the most recent era. Cardiac allograft vasculopathy is the most important late cause of death with an actuarial incidence at 25 years of 35%. Post-transplant lymphoma is estimated to occur in 20% of infant recipients by25 years. Chronic kidney disease grade 3 or worse is present in 31% of survivors. The epidemiology of infant heart transplantation has changed through the years as the results for staged repair improved and donor resources remained stagnant. Most centers now employ staged repair for hypoplastic left heart syndrome and similar extreme forms of congenital heart disease. Techniques for staged repair, including the hybrid procedure, are described. The lack of donors is described with particular note regarding decreased donors due to newer programs for appropriate infant sleep positioning and infant car seats. ABO incompatible donors are a newer resource for maximizing donor resources, as is donation after circulatory determination of death and techniques to properly utilize more donors by expanding the criteria for what is an acceptable donor. An immunological advantage for the youngest recipients has long been postulated, and evaluation of this phenomenon may provide clues to the development of accommodation and/or tolerance. PMID:22548030
Markey, Kate A.; MacDonald, Kelli P. A.
The last 6 decades have seen major advances in the understanding of immunologic diseases, driven by preclinical animal models. Indeed, bone marrow transplantation (BMT) has its genesis in rodent models dating back to the 1950s. Allogeneic BMT and its major complication, graft-versus-host disease (GVHD), represent a paradigm for the translation of preclinical concepts into clinical practice. The appreciation that GVHD can be thought of as a stepwise escalation in immune activation characterized by eventual massive target tissue apoptosis has allowed the design of rational approaches to better manage patients. Here, we describe the pathophysiology of GVHD as defined in preclinical models, focusing on the successes and failures of this research to instruct and translate clinical practice. We also provide a commentary on the limitations of these models so that they may be better appreciated and addressed in future studies. Notable preclinical successes include the definition of modern immune suppression, reductions in conditioning intensity, posttransplant cyclophosphamide, and the promotion of regulatory T-cell reconstitution. New strategies including naïve T-cell depletion, focused cytokine and chemokine inhibition, and the blockade of costimulation now also appear highly promising and very likely to translate into patients in the near future. PMID:24914137
Sakellari, I; Barbouti, A; Bamichas, G; Mallouri, D; Kaloyannidis, P; Fragidis, S; Batsis, I; Apostolou, C; Karpouza, A; Yannaki, E; Smias, C; Sombolos, K; Anagnostopoulos, A
Chronic kidney disease (CKD) has been related to allogeneic haematopoietic cell transplantation (HCT) as a late effect caused by a variety of factors. We retrospectively evaluated the development of CKD in 230 patients, aged 34 (5-65) years, who had undergone allogeneic HCT for haematological disease, using sibling or unrelated donors and myeloablative or reduced conditioning regimens. Pre-HCT glomerular filtration rate (GFR) was within normal limits (108±28?mL/min/1.73?m(2)) in patients who did not develop CKD and 95±24?mL/min/1.73?m(2) in those with CKD postHCT, while the GFR 12 months post transplant declined to 104±26 and 69±19?mL/min/1.73?m(2), respectively. CKD incidence was 20.4%, with a median time of development of 6 (3-18) months post transplant. On multivariate analysis, risk factors for CKD were the presence of chronic GVHD (cGVHD; P=0.001), unrelated donor transplantation (P=0.008), post-transplant event of acute kidney injury (AKI) (P=0.002) and older age (P=0.002). In long-term survivors stable significant predictors for CKD were older age at transplantation, cGVHD and AKI. CKD did not influence non-relapse mortality. In our study, cGVHD emerges as an important cause of kidney injury in HCT survivors, regardless of administration of nephrotoxic agents. PMID:23584436
Marvin, Michael R; Ferguson, Nicole; Cannon, Robert M; Jones, Christopher M; Brock, Guy N
Multiple studies have demonstrated an advantage for hepatocellular carcinoma (HCC) patients under the current liver allocation system, such that the United Network for Organ Sharing (UNOS) recently voted in support of a proposal to delay granting Model for End-Stage Liver Disease (MELD) exception points to all HCC patients for 6 months, independently of a candidate's native MELD score or alpha-fetoprotein (AFP) level. We obtained UNOS data on adult patients who were added to the wait list between January 22, 2005 and September 30, 2009, and we explored the relationship between HCC, MELD, AFP, and other factors that contribute to not only dropout on the wait list but posttransplant survival as well. The aim was to establish an equivalent Model for End-Stage Liver Disease (MELDEQ ) score for HCC patients that would reduce the disparity in access to transplantation between HCC and non-HCC patients. We determined risk groups for HCC patients with dropout hazards equivalent to those of non-HCC patients, and we evaluated projections for HCC wait-list dropout/transplantation probabilities on the basis of the MELDEQ prioritization scheme. Projections indicate that lower risk HCC patients (MELDEQ ???18) would have dropout probabilities similar to those of non-HCC patients in the same MELD score range, whereas dropout probabilities for higher risk HCC patients would actually be improved. The posttransplant survival of all HCC risk groups is lower than that of their non-HCC counterparts, with 1-year survival of 0.77 (95% CI, 0.70-0.85) for MELDEQ scores???31. These results suggest that HCC patients with a combination of a low biochemical MELD score and a low AFP level (MELDEQ ???15) would receive a marked advantage in comparison with patients with chemical MELD scores in a similar range and that a delay of 6 months for listing may be appropriate. In contrast, patients with MELDEQ scores?>?15 would likely be adversely affected by a universal 6-month delay in listing. PMID:25694099
Thanthrige-Don, Niroshan; Abdul-Careem, Mohamed F. [Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada); Shack, L. Allen; Burgess, Shane C. [Department of Basic Sciences, Mississippi State University (United States); Sharif, Shayan, E-mail: firstname.lastname@example.org [Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada)
Marek's disease virus (MDV), which causes a lymphoproliferative disease in chickens, is known to induce host responses leading to protection against disease in a manner dependent on genetic background of chickens and virulence of the virus. In the present study, changes in the spleen proteome at 7, 14 and 21 days post-infection in response to MDV infection were studied using two-dimensional polyacrylamide gel electrophoresis. Differentially expressed proteins were identified using one-dimensional liquid chromatography electrospray ionization tandem mass spectrometry (1D LC ESI MS/MS). Comparative analysis of multiple gels revealed that the majority of changes had occurred at early stages of the disease. In total, 61 protein spots representing 48 host proteins were detected as either quantitatively (false discovery rate (FDR) <= 0.05 and fold change >= 2) or qualitatively differentially expressed at least once during different sampling points. Overall, the proteins identified in the present study are involved in a variety of cellular processes such as the antigen processing and presentation, ubiquitin-proteasome protein degradation (UPP), formation of the cytoskeleton, cellular metabolism, signal transduction and regulation of translation. Notably, early stages of the disease were characterized by changes in the UPP, and antigen presentation. Furthermore, changes indicative of active cell proliferation as well as apoptosis together with significant changes in cytoskeletal components that were observed throughout the experimental period suggested the complexity of the pathogenesis. The present findings provide a basis for further studies aimed at elucidation of the role of these proteins in MDV interactions with its host.
Martins, Sofia S; Buscatti, Izabel M; Freire, Pricilla S; Cavalcante, Erica G; Sallum, Adriana M; Campos, Lucia M A; Silva, Clovis A
Kikuchi-Fujimoto disease (KFD) is a self-limiting histiocytic necrotizing lymphadenitis of unknown origin. Of note, KFD was infrequently reported in adult systemic lupus erythematosus (SLE), with rare occurrence in childhood-SLE (C-SLE) patients. To our knowledge, the prevalence of KFD in the paediatric lupus population was not studied. Therefore, in a period of 29 consecutive years, 5,682 patients were followed at our institution and 289 (5%) met the American College of Rheumatology classification criteria for SLE, one had isolated KFD (0.03) and only one had KFD associated to C-SLE diagnoses, which case was reported herein. A 12 year-old female patient had high fever, fatigue and cervical and axillary lymphadenopathy. The antinuclear antibodies (ANA) were negative, with positive IgM and IgG herpes simplex virus type 1 and type 2 serologies. Fluorine-18-fluoro-deoxy-glucose positron emission tomography/computed tomography (PET/CT) imaging demonstrated diffuse lymphadenopathy. The axillary lymph node biopsy showed necrotizing lymphadenitis with histiocytes, without lymphoproliferative disease, compatible with KFD. After 30 days, she presented spontaneous regression and no therapy was required. Nine months later, she developed malar rash, photosensitivity, oral ulcers, lymphopenia and ANA 1:320 (homogeneous nuclear pattern). At that moment the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score was 10 and she was treated with prednisone (1.0mg/kg/day) and hidroxychloroquine showing progressive improvement of hers signs and symptoms. In conclusion, KFD is a benign and rare disease in our paediatric lupus population. We also would like to reinforce the relevance of autoimmune diseases diagnosis during the follow-up of patients with KFD. PMID:25627306
Nat, Laura Bogdana; Simiti, Adriana Liana; Poanta, Laura Irina
Lyme disease (Borreliosis), also called the "disease of 1000 faces", is produced by a bacterium called Borrelia burgdorferi, transmitted by the Ixodes tick. The clinical picture is non-specific and polymorph, with multisystemic involvement. Diagnosis is most often one of exclusion, and certain diagnosis is based on the presence of Borellia antibodies. The treatment is done differently depending on the stage of the disease and the severity of injuries, being used antibiotics like Doxycycline, Amoxicillin, Erythromycin or Penicillin. Under treatment the disease quickly heals without sequel, in the early stages, but advanced stages are usually resistant to treatment and chronic injuries can occur. Symptoms get worse without treatment and become chronic. We present the case of a woman of 66-year-old with a complex history of disease, which began one year prior to admission, through multiple and nonspecific symptoms; she presented herself in numerous medical services (gastroenterology, rheumatology--where an immunosuppressive treatment was initiated, hematology) without determining a final diagnosis. She was admitted in our service with altered general state and worsening symptoms, predominantly fever, muscle pain, joint pain, the patient being immobilized in bed. After multiple investigations and the problem of differential diagnosis with multiple pathologies, we finally established the diagnosis of Lyme disease. The peculiarities of the case are represented by the severity of the clinical manifestations and fulminant disease evolution under the unjustified administration of immunosuppressive treatment, and atypical joint involvement regarding localization and evolution that raised the issue of differential diagnosis with osteosarcoma or bone tuberculosis. PMID:25726630
Nickell, Larry T; Schucany, William G; Opatowsky, Michael J
Kummell disease, or avascular necrosis of a vertebral body, presents as vertebral osteonecrosis typically affecting a thoracic vertebra with compression deformity, intravertebral vacuum cleft, and exaggerated kyphosis weeks to months after a minor traumatic injury. This rare disease is increasing in prevalence secondary to an aging population and the associated rise in osteoporosis. Treatment with vertebroplasty or surgical decompression and fusion is often required. We present a classic case of Kummell disease to illustrate the salient features of the condition, with associated imaging findings on computed tomography and magnetic resonance imaging. PMID:23814399
Chapuis-Taillard, Caroline; de Vallière, Serge; Bochud, Pierre-Yves
In 2008, several publications have highlighted the role of climate change and globalization on the epidemiology of infectious diseases. Studies have shown the extension towards Europe of diseases such as Crimea-Congo fever (Kosovo, Turkey and Bulgaria), leismaniosis (Cyprus) and chikungunya virus infection (Italy). The article also contains comments on Plasmodium knowlesi, a newly identified cause of severe malaria in humans, as well as an update on human transmission of the H5NI avian influenza virus. It also mentions new data on Bell's palsy as well as two vaccines (varicella-zoster and pneumococcus), and provides a list of recent guidelines for the treatment of common infectious diseases. PMID:19216322
Ruiter, Annebeth E C; Meuleman, Eric J H
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
... lung diseases, like asthma and emphysema Dictionary of Environmental Health , involve a narrowing or blockage of the airways ... health/health-topics/topics/ipf/ , pneumonia Dictionary of Environmental Health and lung cancer, are caused by a loss ...
... Infections, such as influenza and pneumonia Lung cancer Sarcoidosis (sar-KOY-doh-sis) and pulmonary fibrosis Lung ... and can reduce oxygen flow into the blood. Sarcoidosis and pulmonary fibrosis. These inflammatory diseases cause stiffening ...
... is called hyperthyroidism. (An underactive thyroid leads to hypothyroidism .) Graves disease is the most common cause of ... radioactive iodine usually will cause an underactive thyroid (hypothyroidism). Without getting the correct dosage of thyroid hormone ...
... copper diet is also recommended, which involves avoiding mushrooms, nuts, chocolate, dried fruit, liver, and shellfish. In ... and/or support research related to Wilson disease. Growing knowledge of the copper transporting gene ATP7B, which ...
... The disease is caused by a bacterium called Borrelia burgdorferi that's usually found in animals like mice and ... on mice, deer, and other animals that carry Borrelia burgdorferi . When the tick feeds on infected animals, then ...
... disease — especially if you grab fries and a soda after school and aren't able to brush immediately after eating them. You probably know that sugar is bad for your teeth, but you may not know that starchy foods ...
... affect a person’s health in any way. What causes Rh disease? An Rh-negative mother and an ... abdominal trauma. Does cleft lip or cleft palate cause dental problems? A cleft lip or cleft palate ...
Your endocrine system includes eight major glands throughout your body. These glands make hormones. Hormones are chemical messengers. They ... levels. In the United States, the most common endocrine disease is diabetes. There are many others. They ...
... Mumps Pertussis (Whooping Cough) Pneumococcal Disease Rubella (German Measles) Shingles (Herpes Zoster) Tetanus (Lockjaw) You May Also Like Meningococcal Serogroup B Cases and Outbreaks on US College Campuses NFID Announces Recipients of ...
... tick. Be careful not to leave the head embedded in the skin. Clean the area thoroughly with ... E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of ...
... more likely include Family history of vascular or heart diseases Pregnancy Illness or injury Long periods of sitting or standing still Any condition that affects the heart and blood vessels, such as diabetes or high ...
... Publications, web features, podcasts, e-Cards, print materials... World Scout Jamboree Four cases of meningococcal disease have ... among Scottish and Swedish participants who attended the World Scout Jamboree held in Japan from July 28 ...
... Email: email@example.com Internet: www.gluten.net National Foundation for Celiac Awareness 224 South Maple Street Ambler, ... Hospital Medical Center; Walter Reed Army Medical Center; National Foundation for Celiac Awareness; Celiac Disease Foundation; Celiac Sprue ...
... there may be liver and spleen enlargement. The brain is gradually affected. It usually starts in childhood or adolescence. Gaucher disease has no cure. Treatment options for types 1 and 3 include ...
... of Parkinson's disease in people who live in rural areas and in those who work in certain professions, suggesting that environmental factors may play a role in the disorder. Researchers are focusing on additional ...
... disease. It ranges from simple gum inflammation, called gingivitis, to serious damage to the tissue and bone ... the worst cases, you can lose teeth. In gingivitis, the gums become red and swollen. They can ...
... Progressive Sclerosing Poliodystrophy Table of Contents (click to jump to sections) What is Alpers' Disease? Is there ... NIDDK) National Institutes of Health, DHHS 31 Center Drive, Rm. 9A06 MSC 2560 Bethesda, MD 20892-2560 ...
... the lungs to take in oxygen and release carbon dioxide. People with this type of lung disorder often ... the lungs to take up oxygen and release carbon dioxide. These diseases may also affect heart function. An ...
Portillo, Aránzazu; Santibáñez, Sonia; Oteo, José A
Lyme disease (LD) is a worldwide-distributed multisystemic process caused by Borrelia burgdorferi sensu lato (s.l.) and transmitted by hard ticks. In fact, it is the most common tick-borne infectious disease in the northern hemisphere. In Spain it is transmitted by Ixodes ricinus ticks and Borrelia garinii is the genoespecies of B. burgdorferi s.l. mostly involved in our area. LD is known as "the last great imitator" due to the broad clinical spectrum that may cause. Except in the case of erythema migrans (pathognomonic feature of the disease), the remaining clinical manifestations should be confirmed using microbiological tests. This review is intended to provide readers a current vision of the etiology, epidemiology, clinical manifestations, laboratory diagnosis and treatment of Lyme disease in our environment. Controversial aspects arising from the use of non-validated microbiological tests that are being used without scientific rigor are highlighted. PMID:24630582
Texas Wildlife Services
disease prevention methods. Rabies Rabies, sometimes called ?hydrophobia,? is a viral disease that affects the central nervous sys- tem. Rabies is normally transmitted to humans from the bite of a rabid animal or from the sali- va of a rabid animal... entering the blood stream through open cuts or scratches. Only warm- blooded animals are susceptible to the rabies virus. In Texas, the most commonly infected wild animals are skunks, bats, coyotes, raccoons and foxes. Rabid animals cannot always...
With continuing worldwide growth in travel, timely information about the epidemiology of post-travel illness is important. Various travel-related surveillance systems have been established that provide these data. Knowledge about prevalences of important diseases in travelers and migrants can help in the differential diagnosis. On the other hand it has be kept in mind that also rare, but life-threatening diseases can be imported like leptospirosis, viral hemorrhagic fever or amebic liver abcess. PMID:26080718
Shankar, P R; Subish, P
Convincing healthy people that they are sick and require medicines can enormously expand the market. Disease mongering can turn ordinary ailments like baldness into medical problems, consider risk factors such as hypertension and osteoporosis as diseases and frame prevalence estimates to increase potential markets. In Asia, conditions like erectile dysfunction, male pattern baldness, attention deficit hyperactivity disorder and irritable bowel syndrome, and the drugs to treat them, are widely promoted. Fairness creams and traditional medicines are also widely used. The cost of disease mongering to the individual and the community is expected to be high. Some authors have argued that medicalisation of illnesses may not be a problem and the real problem may be the lack of medicines. Doctors will play a key role in combating disease mongering. Disentanglement from the pharmaceutical industry and development of a capacity for critical analysis are required. Educating patients and empowering them to make decisions are important. Several initiatives have been undertaken to combat disease mongering. Initiatives at the level of the patient and the physician are especially important. Studies on the extent and knowledge of disease mongering among doctors and medical students, and their economic and social consequences are urgently required. PMID:17384871
Cardiovascular Diseases; Coronary Disease; Cerebrovascular Accident; Heart Diseases; Myocardial Infarction; Infection; Chlamydia Infections; Cytomegalovirus Infections; Helicobacter Infections; Atherosclerosis
Dai, Lu; Noverr, Mairi C.; Parsons, Chris; Kaleeba, Johnan A. R.; Qin, Zhiqiang
Expression of xCT, a component of the xc– amino-acid transporter, is essential for the uptake of cystine required for intracellular glutathione (GSH) synthesis and maintenance of the intracellular redox balance. Therefore, xCT plays an important role not only in the survival of somatic and immune cells, but also in other aspects of tumorigenesis, including the growth and malignant progression of cancer cells, resistance to anticancer drugs, and protection of normal cells against oxidative damage induced by carcinogens. xCT also functions as a factor required for infection by Kaposi’s sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi’s sarcoma (KS) and other lymphoproliferative diseases associated with HIV/AIDS. In spite of these advances, our understanding of the role of xCT in the pathogenesis of infectious diseases is still limited. Therefore, this review will summarize recent findings about the functions of xCT in diseases associated with microbial (bacterial or viral) infections, in particular KSHV-associated malignancies. We will also discuss the remaining questions, future directions, as well as evidence that supports the potential benefits of exploring system xc– as a target for prevention and clinical management of microbial diseases and cancer. PMID:25745420
Crotty, Shane; McCausland, Megan M; Aubert, Rachael D; Wherry, E John; Ahmed, Rafi
The human genetic disease X-linked lymphoproliferative disease (XLP), which is caused by mutations in SH2D1A/SAP that encode SLAM-associated protein (SAP), is characterized by an inability to control Epstein-Barr virus (EBV) and hypogammaglobulinemia. It is unclear which aspects of XLP disease are specific to herpesvirus infection and which reflect general immunologic functions performed by SAP. We examined SAP- mice during a chronic LCMV infection, specifically to address the following question: Which SAP deficiency immunologic problems are general, and which are EBV specific? Illness, weight loss, and prolonged viral replication were much more severe in SAP- mice. Aggressive immunopathology was observed. This inability to control chronic LCMV was associated with both CD8 T-cell and B-cell response defects. Importantly, we demonstrate that SAP- CD8 T cells are the primary cause of the immunopathology and clinical illness, because depletion of CD8 T cells blocked disease. This is the first direct demonstration of SAP- CD8 T-cell-mediated immunopathology, confirming 30 years of XLP clinical observations and indirect experimentation. In addition, germinal center formation was extremely defective in chronically infected SAP- animals, and hypogammaglobulinemia was observed. These findings in a chronic viral infection mouse model recapitulate key features of human XLP and clarify SAP's critical role regulating both cellular and humoral immunity. PMID:16788096
Gracia-Ahufinger, I; Ferrando-Martínez, S; Montejo, M; Muñoz-Villanueva, M C; Cantisán, S; Rivero, A; Solana, R; Leal, M; Torre-Cisneros, J
Cytomegalovirus (CMV) disease is an important complication in solid organ transplant recipients. Thymic function in adults is associated with specific T-cell immunity. Pre-transplant thymic function was analysed in 75 solid organ transplant patients by the use of nested PCR. The primary outcome was the incidence of CMV disease 12 months after transplantation. Using multivariable logistic regression, we studied whether pre-transplant thymic function is an independent risk factor for CMV disease after transplantation. Thymic function was related to the risk of CMV disease in CMV-seropositive recipients. In these recipients, pre-transplant thymic function of <9.5 (OR 11.27, 95% CI 1.11-114.43, p 0.040) and the use of thymoglobulin (OR 8.21, 95% CI 1.09-61.84, p 0.041) were independent risk factors for CMV disease at 12 months after transplantation. Patients with pre-transplant thymic function values of <9.5 had a higher subsequent incidence of CMV disease (24%) than patients with values of ?9.5 (3%) (log-rank test: 5.727; p 0.017). The positive and negative predictive values of these pre-transplant thymic function cut-offs were 0.24 (95% CI 0.10-0.45) and 0.97 (95% CI 0.82-1.00), respectively. Pre-transplant thymic function in CMV-seropositive candidates could be useful in determining the risk of post-transplant CMV disease in solid organ transplant patients, selecting a group of low-risk candidates. PMID:25682299
Rooney, C M; Roskrow, M A; Suzuki, N; Ng, C Y; Brenner, M K; Heslop, H
Donor-derived Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTL) are successful in the prevention and treatment of Epstein-Barr virus (EBV)-associated lymphoproliferative disease (LPD) in allogeneic bone marrow transplant (BMT) recipients [1, 2]. This finding prompted us to use a similar approach to the treatment of relapsed EBV-positive Hodgkin's disease . Autologous EBV-specific CTL lines could be generated on the first or second attempt from 11 of 15 patients with Hodgkin's disease. Peripheral blood TCR zeta-chain levels were low, but increased in the activated CTL lines. Three patients have received gene-marked autologous CTL. The first two patients experienced alleviation of stage B symptoms and a drop in peripheral blood EBV load. However, this situation reversed between 6 and 12 weeks after infusion, when chemotherapy and radiation were reinstated. Both patients eventually progressed and died. The third patient had a pleural effusion, which increased after CTL infusion. Analysis of the pleural effusion revealed both tumor cells and levels of marker gene over 100 fold greater than in peripheral blood. The infused CTL line showed activity against LMP2. The patient initially improved and then remained stable for over eight months after CTL infusion, but now has progressive disease. We currently are evaluating methods for introducing the LMP2 gene into dendritic cells and using these to present LMP2 to autologous T cells. Using both retrovirus and herpesvirus vectors to express LMP2 in dendritic cells, LMP2-specific CTL were successfully generated from individuals who were EBV-seronegative or who were non-responsive to LMP2 when presented on autologous LCL. In future protocols, LMP2-specific CTL will be used for treatment. PMID:9926252
Plontke, S K; Gürkov, R
Menière`s disease is one of the most common inner ear and vestibular disorders. It is defined as the idiopathic syndrome of endolymphatic hydrops (ELH). Despite the development of several different animal models of ELH, its etiology and pathogenesis is still unresolved. In humans, endolymphatic hydrops may occur spontaneously or as a consequence of specific disorders with distinct inner ear pathologies, e.?g., infectious labyrinthitis, noise induced hearing loss or vestibular schwannoma. Recent imaging studies using MRI have shown that hydropic ear disease is associated not only with the full triad of vertigo, hearing, loss and tinnitus/aural pressure, but also with inner ear symptoms that do not fulfill the clinical criteria of definite Menière's disease as set forth by the AAO-HNS. Therefore, terms like "atypical" or "cochlear"/"vestibular" Menière's disease or "forme fruste" should be avoided and the term "Menière's disease" should universally be applied according only to these guidelines. Besides that, the recent possibility of visualizing endolymphatic hydrops on MRI and thereby ascertaining the diagnosis in difficult cases and new audiovestibular function tests for the indirect detection of endolymphatic hydrops show promising results. Evidenced based reviews of currently available therapeutic options still reveal many uncertainties with regard to efficacy, with the exception of the ablative therapies, e.?g., intratympanic gentamicin application. PMID:26243634
Kötter, I; Xenitidis, T; Fierlbeck, G; Schanz, S; Melms, A; Horger, M; Ernemann, U; Deuter, C
Behçet's disease is a systemic disorder with the histopathological correlate of leukocytoclastic vasculitis. Pathogenetically, besides a strong genetic component participation of the innate immune system and an autoinflammatory component are discussed. The disease is most common in countries along the former silk route but in Germany the disease is rare (prevalence approximately 0.6/100,000). Oral aphthous ulcers are the main symptom, followed by skin manifestations, genital ulcers and oligoarthritis of large joints. Severe manifestations, threatening quality of life and even life itself, are the gastrointestinal manifestations which often perforate, arterial, mainly pulmonary arterial aneurysms which cause life-threatening bleeding, CNS manifestations and ocular disease, which with occlusive retinal vasculitis often leads to blindness. For milder manifestations low-dose steroids and colchicine are used, for moderate manifestations such as arthritis or ocular disease not immediately threatening visual acuity, azathioprin or cyclosporin A are combined with steroids. For severe manifestations, interferon-alpha, TNF-antagonists or cytotoxic drugs are recommended. Interleukin 1 (IL-1) antagonists are currently being examined in clinical studies. PMID:23052559
. · But there is a genetic test for this disease that can tell you not only if you have the disease, and if you do, when you. The classical (pre-genetic) differential diagnosis of the disease 4. The classical (pre-genetic) treatment of the disease 5. A description of genetics of the disease including world and ethnic distribution of the disease
Deneau, Mark; Wallentine, Jeremy; Guthery, Stephen; O'Gorman, Molly; Bohnsack, John; Fluchel, Mark; Bezzant, John; Pohl, John F
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
Rezaei, Nima; Hedayat, Mona; Aghamohammadi, Asghar; Nichols, Kim E
Primary immunodeficiencies (PIDs) are commonly characterized by an increased susceptibility to specific infections and, in certain instances, a higher than usual incidence of malignancies. Although improved diagnosis and early treatment of PIDs have reduced early morbidity and mortality from infection, the development of cancer remains a significant cause of premature death. The emergence of cancer in patients with PIDs often results from impairments in the immune response that lead to weakened surveillance against oncogenic viruses, premalignant or malignant cells, or both. Here we review the clinical and biologic features of several PIDs associated with enhanced susceptibility to viral infections and cancer, including X-linked lymphoproliferative disease; IL-2-inducible T-cell kinase deficiency; epidermodysplasia verruciformis; warts, hypogammaglobulinemia, infections, and myelokathexis syndrome; autosomal recessive hyper-IgE syndrome; X-linked agammaglobulinemia; and common variable immunodeficiency. It is of importance that we gain in-depth insights into the fundamental molecular nature of these unique PIDs to better understand the pathogenesis of virus-associated malignancies and to develop innovative therapeutic strategies. PMID:21514636
Devuyst, Olivier; Thakker, Rajesh V
Dent's disease is a renal tubular disorder characterized by manifestations of proximal tubule dysfunction, including low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. These features are generally found in males only, and may be present in early childhood, whereas female carriers may show a milder phenotype. Prevalence is unknown; the disorder has been reported in around 250 families to date. Complications such as rickets or osteomalacia may occur. The disease is caused by mutations in either the CLCN5 (Dent disease 1) or OCRL1 (Dent disease 2) genes that are located on chromosome Xp11.22 and Xq25, respectively. CLCN5 encodes the electrogenic Cl?/H(+) exchanger ClC-5, which belongs to the CLC family of Cl? channels/transporters. OCRL1 encodes a phosphatidylinositol bisphosphate (PIP?) 5-phosphatase and mutations are also associated with Lowe Syndrome. The phenotype of Dent's disease is explained by the predominant expression of ClC-5 in the proximal tubule segments of the kidney. No genotype-phenotype correlation has been described thus far, and there is considerable intra-familial variability in disease severity. A few patients with Dent's disease do not harbour mutations in CLCN5 and OCRL1, pointing to the involvement of other genes. Diagnosis is based on the presence of all three of the following criteria: low-molecular-weight proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia or renal insufficiency. Molecular genetic testing confirms the diagnosis. The differential diagnosis includes other causes of generalized dysfunction of the proximal tubules (renal Fanconi syndrome), hereditary, acquired, or caused by exogenous substances. Antenatal diagnosis and pre-implantation genetic testing is not advised. The care of patients with Dent's disease is supportive, focusing on the treatment of hypercalciuria and the prevention of nephrolithiasis. The vital prognosis is good in the majority of patients. Progression to end-stage renal failure occurs between the 3rd and 5th decades of life in 30-80% of affected males. PMID:20946626
Kontogiannis, V; Powell, R
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
Duchosal, M. A.; Eming, S. A.; McConahey, P. J.; Dixon, F. J.
A chimeric model consisting of severe combined immune deficiency (SCID) mice populated with human peripheral blood leukocytes (PBL) has recently been described (bu-PBL-SCID mice). These reports indicated a limited reconstruction of the transferred human immune system and functionality of the human graft. Herein we described modifications of the PBL transfer method that minimize transfer time and cellular manipulations, leading to a more effective population of SCID mouse recipients. Severe combined immune deficiency mice given 15 x 10(6) PBL had human IgG serum levels reaching 2 to 5 g/l, and all mice had detectable human anti-tetanus toxoid antibody levels when they received cells from donors with such levels. These transfers were associated also with clinical and histologic evidence of graft-versus-host disease, suggesting responsiveness of the human graft in the recipients. When Epstein-Barr virus seropositive (EBV+) donors were used, the chimeric mice also showed a high incidence of fatal lymphoproliferative disease 1 to 3 months after transfer of 15 x 10(6) PBL. The high level of immunoglobulin synthesis and immunoresponsiveness of the human cells with this transfer procedure may expand the use of these chimeric mice for the manipulations of human immune cells in vivo. Images Figure 3 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 PMID:1332484
Chou, C.L. (Columbia Univ., New York, NY (United States)); Morrison, S.L. (Univ. of California, Los Angeles (United States))
The analysis of spontaneous somatic mutants gives insights into the regulation of gene expression. Human heavy-chain disease (HCD) is a monoclonal lymphoproliferative disorder characterized by the presence of truncated immunoglobulin (Ig) heavy chains without associated light chains. To better understand the molecular mechanisms leading to the loss of light-chain production, the authors have examined a murine cell line model of heavy-chain disease. R15, a spontaneous mutant of the IgA, [kappa]-producing myeloma cell line W3129, produces heavy chain but no light chain. The variant [Delta]15 derived from R15 resembles human HCD in that it secretes a shortened heavy chain with no associated light chain. Cloning and analysis of the R15 [kappa] light-chain gene revealed that a 358-nucleotide insertion of unknown origin replaced 22 bases of the wild-type leader-variable region (L-V) intron (IVS). Although this genomic change left the light-chain exons and known regulatory elements intact, it altered the mRNA processing pathway, yielding two alternative RNA products, neither of which encodes a functional protein. This mutant therefore provides new insights into how genomic changes can influence gene expression. 32 refs., 6 figs.
... smooth and consistent in color. Specific types of nail discoloration and changes in growth rate can be signs of lung, heart, kidney, and liver diseases, as well as diabetes and anemia. White spots and vertical ridges are harmless. Nail problems that sometimes require treatment include Bacterial and ...
... intestines become thickened. Factors that may play a role in Crohn's disease include: Your genes and family history (People of Jewish descent are at higher risk.) Environmental factors Tendency of your body to over-react to normal bacteria in the ...
A COMPREHENSIVE REVIEW OF MOST ASPECTS OF COMMON BUNT AND DWARF BUNT DISEASES OF WHEAT IS PRESENTED. INCLUDED ARE SECTIONS ON HISTORY, DISTRIBUTION AND ECONOMIC IMPORTANCE, TAXONOMY, MORPHOLOGY, SPORE GERMINATION, CULTURE, AND PHYSIOLOGY. EXTENSIVE SECTIONS DEAL WITH RESEARCH METHODOLOGY AND DISEA...
... addition to gamma globulin, the child should receive aspirin, initially in high doses. Aspirin can decrease the tendency of blood to clot ... damaged blood vessels. Although it’s appropriate to use aspirin to treat Kawasaki disease, treating children with minor ...
The sunflower disease chapter is part of the Sunflower Oilseeds Monograph, which will be a new publication in the AOCS Oilseeds Monograph series. The monograph contains an overview and history of sunflower crop development, how the oilseed is cultivated, how the oilseed is produced, how the seed is...
Green, Peter H R; Lebwohl, Benjamin; Greywoode, Ruby
This review will focus on the pathogenesis, clinical manifestations, diagnosis, and management of celiac disease (CD). Given an increasing awareness of gluten-related disorders, medical professionals of all varieties are encountering patients with a diagnosis of CD or who are thought to have food intolerance to gluten. The prevalence of CD among the general population is estimated to be 1% in Western nations, and there is growing evidence for underdiagnosis of the disease, especially in non-Western nations that were traditionally believed to be unaffected. The development of serologic markers specific to CD has revolutionized the ability both to diagnose and monitor patients with the disease. Additionally, understanding of the clinical presentations of CD has undergone a major shift over the past half century. Although it is well understood that CD develops in genetically predisposed subjects exposed to gluten, the extent of other environmental factors in the pathogenesis of the disease is an area of continued research. Currently, the main therapeutic intervention for CD is a gluten-free diet; however, novel nondietary agents are under active investigation. Future areas of research should also help us understand the relationship of CD to other gluten-related disorders. PMID:25956012
... 4 to 14 days (sometimes up to 20 days) after getting infected with parvovirus B19. About 20% of children and adults who get infected with this virus will not have any symptoms. Signs & Symptoms The first symptoms of fifth disease are usually mild and ...
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
... determine whether you have Addison’s disease: Blood tests: Tests that measure the levels of certain minerals and hormones in your blood ... your blood before and after an injection. These tests help your doctor know ... levels of certain hormones, such as adrenocorticotrophic hormone (ACTH) ...
... parasitic diseases occur in the United States. Contaminated water supplies can lead to Giardia infections. Cats can transmit toxoplasmosis, which is dangerous for pregnant women. Others, like malaria, are ... to drink only water you know is safe. Prevention is especially important. ...
... time during surgery. In some patients, surgeons can repair or replace heart valves using minimally invasive techniques, but it will be ... invasive surgery. See also on this site: Valve Repair or Replacement Surgery Center for Heart Valve Disease Limited-Access Heart Surgery Search for previous ...
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
... from the NHLBI on Twitter. What Is Diabetic Heart Disease? The term "diabetic heart disease" (DHD) refers ... Kidney Diseases' Introduction to Diabetes Web page. What Heart Diseases Are Involved in Diabetic Heart Disease? DHD ...
Heart disease, Coronary heart disease, Coronary artery disease; Arteriosclerotic heart disease; CHD; CAD ... Coronary heart disease (CHD) is the leading cause of death in the United States for men and women. Coronary ...
Onitilo, A A; Lazarchick, J; Brunson, C Y; Frei-Lahr, D; Stuart, R K
As the life expectancy of patients with homozygous sickle cell anemia (SCA) improves, SCA care providers are confronted with diseases of the adult SCA population rarely seen before. We report here a 40-year-old woman with SCA who developed diffuse large B-cell non-Hodgkin's lymphoma (NHL) that was treated with eight cycles of chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE), without complete remission. She subsequently underwent high-dose cyclophosphamide and total-body irradiation followed by autologous bone marrow transplantation (BMT). To reduce the risk of sickle cell crisis precipitated by G-CSF, she underwent hypertransfusion to maintain a low % hemoglobin S throughout her treatment course. Although she has required iron chelation therapy and shows no sign of modification of her underlying SCA, she remains in remission from NHL 12 years posttransplant. To our knowledge, this is the first reported case of autologous BMT in a patient with SCA. Our patient illustrates that SCA in itself does not preclude autologous stem cell transplantation for lymphoma in selected patients, and this report should encourage others to consider autologous BMT in adults with SCA where it represents a lifesaving therapy for malignant diseases. PMID:14697986
Rossi, A P; Bone, B A; Edwards, A R; Parker, M K; Delos Santos, R B; Hagopian, J; Lockwood, C; Musiek, A; Klein, C L; Brennan, D C
Graft-versus-host disease (GVHD) after solid organ transplantation is rare and usually fatal. We present, to our knowledge, the second successfully treated case in a simultaneous pancreas-kidney (SPK) transplant recipient. A 29-year-old female with end-stage renal disease from type 1 diabetes mellitus received an SPK transplant from a male donor, with rabbit-antithymocyte globulin induction. Twelve days posttransplant, she was readmitted with abdominal pain, nausea and vomiting. She developed leukopenia, abnormal liver enzymes, fever and a skin rash. Skin biopsy showed interface dermatitis consistent with allergic reaction versus GVHD. Fluorescence in situ hybridization of the skin biopsy showed 28% of cells had a Y chromosome confirming GVHD. Short tandem repeats (STR) enriched for CD3+ cells from peripheral blood showed a mixed chimerism. She was successfully treated with a single plasmapheresis to remove antithymocyte globulin, high-dose steroids, photopheresis and high tacrolimus levels (12-15?ng/mL). Five months after transplantation, she has normal renal function and white blood cell count, normal hemoglobin A1C and no evidence of peripheral blood donor chimerism. In conclusion, early diagnosis of GVHD after SPK transplantation may allow successful treatment. STR enriched for CD3+ may be useful to evaluate the response to therapy. PMID:25219902
Tümer, Zeynep; Møller, Lisbeth B
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 mutations are intragenic mutations or partial gene deletions. ATP7A is an energy dependent transmembrane protein, which is involved in the delivery of copper to the secreted copper enzymes and in the export of surplus copper from cells. Severely affected MD patients die usually before the third year of life. A cure for the disease does not exist, but very early copper-histidine treatment may correct some of the neurological symptoms. PMID:19888294
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.
Sullivan, P B
Current evidence on the pathogenesis of Hirschprung's disease, then, favours the 'abnormal microenvironment' hypothesis wherein the developing and migrating normal neural crest cells confront a segmentally abnormal and hostile microenvironment in the colon. This hypothesis would account both for the congenital absence of ganglion cells in the wall of colon and also for the range of enteric neuronal abnormalities encountered including neuronal dysplasia, hypoganglionosis, and zonal aganglionosis. The abnormal constitution of the mesenchymal and basement membrane extracellular matrix in the affected segment of colon is presumably genetically determined and further understanding of the pathogenesis of this disorder will emerge as molecular geneticists characterise the specific genes and gene products associated with Hirschprung's disease. Advances in this field should permit gene probes to be developed to facilitate prenatal and postnatal diagnosis. PMID:8660047
Accordino, Robert E; Engler, Danielle; Ginsburg, Iona H; Koo, John
Morgellons disease, a pattern of dermatologic symptoms very similar, if not identical, to those of delusions of parasitosis, was first described many centuries ago, but has recently been given much attention on the internet and in the mass media. The present authors present a history of Morgellons disease, in addition to which they discuss the potential benefit of using this diagnostic term as a means of building trust and rapport with patients to maximize treatment benefit. The present authors also suggest "meeting the patient halfway" and creating a therapeutic alliance when providing dermatologic treatment by taking their cutaneous symptoms seriously enough to provide both topical ointments as well as antipsychotic medications, which can be therapeutic in these patients. PMID:18318880
O'Reilly, L A; Hughes, P; Lin, A; Waring, P; Siebenlist, U; Jain, R; Gray, D H D; Gerondakis, S; Strasser, A
FASL/FAS signaling imposes a critical barrier against autoimmune disease and lymphadenopathy. Mutant mice unable to produce membrane-bound FASL (FasL(?m/?m)), a prerequisite for FAS-induced apoptosis, develop lymphadenopathy and systemic autoimmune disease with immune complex-mediated glomerulonephritis. Prior to disease onset, FasL(?m/?m) mice contain abnormally high numbers of leukocytes displaying activated and elevated NF-?B-regulated cytokine levels, indicating that NF-?B-dependent inflammation may be a key pathological driver in this multifaceted autoimmune disease. We tested this hypothesis by genetically impairing canonical or non-canonical NF-?B signaling in FasL(?m/?m) mice by deleting the c-Rel or NF-?B2 genes, respectively. Although the loss of NF-?B2 reduced the levels of inflammatory cytokines and autoantibodies, the impact on animal survival was minor due to substantially accelerated and exacerbated lymphoproliferative disease. In contrast, a marked increase in lifespan resulting from the loss of c-REL coincided with a striking reduction in classical parameters of autoimmune pathology, including the levels of cytokines and antinuclear autoantibodies. Notably, the decrease in regulatory T-cell numbers associated with loss of c-REL did not exacerbate autoimmunity in FasL(?m/?m)c-rel(-/-) mice. These findings indicate that selective inhibition of c-REL may be an attractive strategy for the treatment of autoimmune pathologies driven by defects in FASL/FAS signaling that would be expected to circumvent many of the complications caused by pan-NF-?B inhibition. PMID:25361085
Fausto de Souza, Dominique; Micaelo, Lilian; Cuzzi, Tullia
Plantar fibromatosis, or Ledderhose disease, is a rare hyperproliferative disorder of the plantar aponeurosis. It may occur at any age with the greatest prevalence at middle age and beyond. This disorder is more common in men than woman and it is sometimes associated with other forms of fibromatosis. A 28-year-old Brazilian woman with a six-year history of painless bilateral plantar nodules is described in this article. PMID:20877526
Obst, Wilfried; von Arnim, Ulrike; Malfertheiner, Peter
Summary Background Whipple's disease (WD) is rarely the cause of a malabsorption syndrome. The disease is a chronic infection of the intestinal mucosa with the bacterium Tropheryma whipplei, which leads to a lymphostasis with an impaired absorption of the nutrition. Due to its low incidence (1:1,000,000) and the non-specific early symptoms, the disease is often diagnosed only after many years. Methods Based on a selective literature review and the clinical experience of the authors, the current knowledge of WD regarding pathogenesis, clinical presentation, diagnosis, and therapy are presented in this paper. Results Recent studies suggest that a host-specific dysfunction of the intestinal macrophages is responsible for the chronic infection with T. whipplei. Prior to patients reporting symptoms of a malabsorption syndrome (chronic diarrhea/steatorhea, weight loss), they often suffer from non-specific symptoms (polyarthralgia, fever, fatigue) for many years. Misdiagnoses such as seronegative polyarthritis are frequent. Furthermore, neurological, cardiac, ocular, or dermatological symptoms may occur. The standard method concerning diagnosis is the detection of PAS(periodic acid-Schiff)-positive macrophages in the affected tissues. Immunohistochemical staining and PCR(polymerase chain reaction)-based genetic analysis increase the sensitivity and specificity of conventional detection methods. Endoscopically, the intestinal mucosa appears edematous with lymphangiectasias, enlarged villi, and white-yellowish ring-like structures. The German treatment recommendations include a two-week intravenous induction therapy with ceftriaxone, which is followed by a three-month oral maintenance therapy with trimethoprim/sulfamethoxazole. Conclusion WD is rarely responsible for a malabsorption syndrome. However, if WD is not recognized, the disease can be lethal. New diagnostic methods and prospectively approved therapeutic concepts allow an adequate treatment of the patient. Due to the host-specific susceptibility to T. whipplei, a lifelong follow-up is necessary.
David A. Sirois; Riva Touger-Decker
Several autoimmune diseases are particularly important to oral health and nutrition because of their direct impact on the\\u000a oral mucosa, masticatory apparatus, salivary glands, teeth and supporting structures, oral pain, or mechanical ability to\\u000a chew. For some disorders, the earliest signs of systemic illness are found in the oral cavity, and these remain as significant\\u000a manifestations of the primary immune
Oboudiyat, Carly; Glazer, Hilary; Seifan, Alon; Greer, Christine; Isaacson, Richard S
Alzheimer's disease (AD) is the most common neurodegenerative cause of dementia and is responsible for significant individual morbidity and mortality, and economic impact on the health care system. Neurodegeneration (including neuronal atrophy and/or loss) are attributed to extraneuronal toxic amyloid oligomers and proteins, intraneuronal neurofibrillary tangles consisting of hyperphosphorylated tau, region-specific diminished cerebral glucose metabolism, synaptic dysfunction, and mitochondrial dysfunction. Several of these pathologic changes may occur decades before symptom onset, leaving ample time for implementing prevention strategies that target the earliest stages of the disease. In recent years, a myriad of modifiable and nonmodifiable risk factors have been elucidated. We describe the latest criteria for the diagnosis of AD, including earliest diagnostic stage of preclinical AD, which has the highest potential for research, including diagnosis and disease modification. We discuss both FDA-approved pharmacologic treatments, as well as nonpharmacologic strategies for AD therapeutics, including prevention via evidence-based, low-risk interventions. Genotype is an important consideration in managing patients on the AD continuum, as presence of the APOE ?4 allele may influence response to treatment. We present the most current evidence relating to pharmacogenomics, nutrigenomics, and distinctive nutritional requirements targeted toward AD. PMID:24234352
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.
Eric L. Davis (North Carolina State University; )
This plant disease lesson on Lesion nematode disease (caused by Pratylenchus) includes information on symptoms and signs, pathogen biology, disease cycle and epidemiology, disease management, and the significance of the disease. Selected references are listed and a glossary is also available for use with this resource.
Eric L. Davis (North Carolina State University; )
This plant disease lesson on Soybean cyst nematode disease (caused by Heterodera glycines) includes information on symptoms and signs, pathogen biology, disease cycle and epidemiology, disease management, and the significance of the disease. Selected references are listed and a glossary is also available for use with this resource.
Cleora J. D'Arcy (University of Illinois; )
This plant disease lesson on Dutch elm disease (caused by the fungus Ophiostoma ulmi) includes information on symptoms and signs, pathogen biology, disease cycle and epidemiology, disease management, and the significance of the disease. Selected references are listed and a glossary is also available for use with this resource.
Morishima, Yasuo; Kawase, Takakazu; Malkki, Mari; Morishima, Satoko; Spellman, Stephen; Kashiwase, Koichi; Kato, Shunichi; Cesbron, Anne; Tiercy, Jean-Marie; Senitzer, David; Velardi, Andrea; Petersdorf, Effie W.
The significance of patient and donor ethnicity on risk of acute graft-versus-host disease (GVHD) and disease relapse after unrelated donor hematopoietic cell transplantation (HCT) is not known. A total of 4335 patient/donor pairs from the International Histocompatibility Working Group in HCT met the following three criteria: (1) HLA-A, B, C, DRB1 and DQB1 allele matched donor; (2) diagnosis of leukemia, and (3) non-T cell depleted GVHD prophylaxis. Post-transplant risks of acute GVHD and leukemia relapse were defined in Asian/Pacific Islander, Caucasian, African American, Hispanic, and Native American patients transplanted from donors with the same self-described background. Asian patients had a significantly lower incidence of acute GVHD (Japanese patients: 40.0% grades II-IV and 15.3% grades III-IV; non-Japanese Asian patients: 42.1% grades II-IV and 15.7% grades III-IV) compared to Caucasian patients (56.5% grades II-IV and 22.6% grades III-IV) (p< 0.001). The hazard ratio (HR) of acute GVHD for Caucasian patients was significantly higher than for Japanese patients. Unexpectedly, the HR of leukemia relapse in Caucasian patients with early disease status was also significantly higher than that in Japanese patients. These results provide a platform for future investigation into the genetic factors for unrelated donor HCT and clinical implications of diverse ethnic background. PMID:23747601
Maev, I V; Andreev, D N; Samsonov, A A
Menetrier disease (MD) is a very rare stomach pathology of unknown etiology characterized by manifest hypertrophy of gastric mucosa. The main causes of MD are believed to be Helicobacter pylori and cytomegalovirus infections. The most frequent symptom is epigastric pain. Also common are peripheral oedema due to hypoalbuminemia and increased permeability of gastric mucosa. The main diagnostic signs of MD include diffusive enhancement of mucosal folds, foveolar hyperplasia and glandular atrophy with a decrease in the number of main and parietal cells, hypoalbuminemia and peripheral oedema. MD being a very rare condition, the optimal methodfor its treatment is unknown. PMID:26155704
Tanowitz, H B; Kirchhoff, L V; Simon, D; Morris, S A; Weiss, L M; Wittner, M
Chagas' disease, caused by Trypanosoma cruzi, is an important cause of morbidity in many countries in Latin America. The important modes of transmission are by the bite of the reduviid bug and blood transfusion. The organism exists in three morphological forms: trypomastigotes, amastigotes, and epimastigotes. The mechanism of transformation and differentiation is currently being explored, and signal transduction pathways of the parasites may be involved in this process. Parasite adherence to and invasion of host cells is a complex process involving complement, phospholipase, penetrin, neuraminidase, and hemolysin. Two clinical forms of the disease are recognized, acute and chronic. During the acute stage pathological damage is related to the presence of the parasite, whereas in the chronic stage few parasites are found. In recent years the roles of tumor necrosis factor, gamma interferon, and the interleukins in the pathogenesis of this infection have been reported. The common manifestations of chronic cardiomyopathy are arrhythmias and thromboembolic events. Autoimmune, neurogenic, and microvascular factors may be important in the pathogenesis of the cardiomyopathy. The gastrointestinal tract is another important target, and "mega syndromes" are common manifestations. The diagnosis and treatment of this infection are active areas of investigation. New serological and molecular biological techniques have improved the diagnosis of chronic infection. Exacerbations of T. cruzi infection have been reported for patients receiving immuno-suppressive therapy and for those with AIDS. Images PMID:1423218
Langner, Cord; Denk, Helmut
Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. Since daily copper intake exceeds the body's requirements, effective means of excreting excess copper are essential. These are accomplished by ATP7B, a new member of the cation-transporting p-type ATPase family, which is mainly expressed in the liver and mediates both copper secretion into plasma (coupled with ceruloplasmin synthesis) and its excretion into bile. Thus far, more than 200 mutations of the WD gene have been detected, causing impairment of ATP7B function and, ultimately, copper accumulation. Excess copper, however, induces free-radical reactions and lipid peroxidation. Resultant liver damage leads to steatosis, inflammation, cirrhosis, and, occasionally, fulminant liver failure. The diagnosis of WD is commonly made on the basis of typical clinical and laboratory findings, including low serum ceruloplasmin, increased urinary copper excretion, and increased hepatic copper content. Since liver morphology is non-specific, and copper histochemistry may lead to both false-negative and false-positive results, the pathologist usually only suspects the disease or assists in its confirmation. Although the value of molecular genetic testing is limited due to the high number of possible gene mutations, polymerase chain reaction may be useful for the evaluation of family members of homozygous index patients. PMID:15205951
Zautner, Andreas E
Adenotonsillar disease (adenoiditis and recurrent tonsillitis) is a prevalent otolaryngologic disorder aetiologically based on chronic inflammation triggered by a persistent bacterial infection. These bacteria, mostly Staphylococcus aureus, Haemophilus sp., and Streptococcus sp., persist predominantly intracellular and within mucosal biofilms. The recurrent or chronic inflammation of the adenoids and faucial tonsils leads to chronic activation of the cell-mediated and humoral immune response, resulting in hypertrophy of the lymphoid tonsillar tissue. This hypertrophic tissue is the cause for the prominent clinical symptoms: obstruction of the upper airways, snoring, and sleep apnea for adenoiditis or sore throat, dysphagia and halitosis for recurrent tonsillitis. Treatment strategies should target the persisting bacteria within their biofilm or intracellular shelter. Macrolide antibiotics like clarithromycin are able to modulate the immune system and to interfere in bacterial signaling within biofilms. Clindamycin, quinupristin-dalfopristin, and oritavancin are intracellular high active compounds. Surgical removal of the hypertrophic tissue by modern procedures like laser tonsil ablation, eliminates not only a mechanical obstacle of the airways, it removes also the basis for the aetiologic cause, the "biofilm carrier". This review summarizes the role of bacterial persistence in mucosal biofilms for the aetiology, diagnosis and treatment of adenotonsillar disease and relevant patents. PMID:22452646
Zuccato, Chiara; Cattaneo, Elena
Changes in the level and activity of brain-derived neurotrophic factor (BDNF) have been described in a number of neurodegenerative disorders since early 1990s. However, only in Huntington disease (HD) gain- and loss-of-function experiments have mechanistically linked these abnormalities with the genetic defect.In this chapter we will describe how huntingtin protein, whose mutation causes HD, is involved in the physiological control of BDNF synthesis and transport in neurons and how both processes are simultaneously disrupted in HD. We will describe the underlying molecular mechanisms and discuss pre-clinical data concerning the impact of the experimental manipulation of BDNF levels on HD progression. These studies have revealed that a major loss of BDNF protein in the brain of HD patients may contribute to the clinical manifestations of the disease. The experimental strategies under investigation to increase brain BDNF levels in animal models of HD will also be described, with a view to ultimately improving the clinical treatment of this condition. PMID:24668480
Chediak-Higashi Syndrome; Graft Versus Host Disease; X-Linked Lymphoproliferative Syndrome; Familial Erythrophagocytic Lymphohistiocytosis; Hemophagocytic Lymphohistiocytosis; Virus-Associated Hemophagocytic Syndrome
Myelodysplastic and Myeloproliferative Disorders; Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Chronic Myelogenous Leukemia; Multiple Myeloma; Plasma Cell Dyscrasia; Lymphoproliferative Disorders; Hematologic Diseases
... disease dementia is an impairment in thinking and reasoning that eventually affects many people with Parkinson's disease. ... disease dementia is a decline in thinking and reasoning that develops in someone diagnosed with Parkinson's disease ...
... Disease Children and Kidney Disease Additional Kidney Information Kidney Disease Basics Your kidneys filter extra water and ... blood pressure are the most common causes of kidney disease. These conditions can slowly damage the kidneys ...
... of Biological Chemistry , June 9, 2011 Learning About Parkinson's Disease What do we know about heredity and Parkinson's ... Disease What do we know about heredity and Parkinson's disease? Parkinson's disease (PD) is a neurological condition that ...
... your disease Email this page Print this page Learning about your disease Learn more about common diseases ... may be a treatment option for you. Tweet Learning about your disease Acute Lymphoblastic Leukemia (ALL) Acute ...
NINDS Motor Neuron Diseases Information Page Condensed from Motor Neuron Diseases Fact Sheet Table of Contents (click to jump ... is being done? Clinical Trials Organizations What are Motor Neuron Diseases? The motor neuron diseases (MNDs) are ...
... cholesterol metabolism or halt progression of the disease. Fabry disease , also known as alpha-galactosidase-A deficiency, causes ... autonomic nervous system, eyes, kidneys, and cardiovascular system. Fabry disease is the only X-linked lipid storage disease. ...
... 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 ...
... www.kidneyfund.org > Kidney Disease > Chronic Kidney Disease Chronic Kidney Disease (CKD) An estimated 31 million people in the United States are living with chronic kidney disease (CKD). What is CKD? The term “chronic kidney ...
... Of Huntington's Disease 1998 News Release Learning About Huntington's Disease What do we know about heredity and Hungtington's ... Information What do we know about heredity and Huntington's disease? Huntington's disease (HD) is an inherited neurological illness ...
... see the NIMH booklet on Depression . What is heart disease? Heart disease refers to a number of ... and save your life. How are depression and heart disease linked? People with heart disease are more ...
Disease http://www.ncbi.nlm.nih.gov/books/NBK22226/ #12;© Doug Brutlag 2015 Genetics Home Reference http://ghr.nlm.nih.gov/ #12;© Doug Brutlag 2015 Huntington Disease in Genetics Home Reference http://ghr.nlm.nih.gov/condition/huntington-disease and the · National Center for Biotechnology Information Genes and Diseases Genetics Home Reference Medline Plus
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
Berentsen, Sigbjørn; Randen, Ulla; Vågan, Anne Marita; Hjorth-Hansen, Henrik; Vik, Anders; Dalgaard, Jakob; Jacobsen, Eva-Marie; Thoresen, Aud S; Beiske, Klaus; Tjønnfjord, Geir E
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
Tavora, Fabio; Drachenberg, Cinthia; Iacono, Aldo; Burke, Allen P
The diagnostic role of immunohistochemical staining for T lymphocytes in grading acute airway rejection has not been fully explored. We examined 136 transbronchial biopsies from 52 lung transplant patients and 9 nontransplant controls. Transplant rejection was based on histologic assessment of perivascular (A) and bronchiolar (B) infiltrates. The clinical indication for the 136 allograft biopsies was routine surveillance (n = 72), decreased pulmonary function, rule out rejection (n = 36), suspect infection (n = 16), rule out obliterative bronchiolitis (n = 6), and persistent postoperative graft failure (n = 6). T lymphocytes were counted in bronchial mucosa per 100 bronchial epithelial cells, and in alveolar walls per square millimeters, after immunohistochemical staining with anti-CD3, CD4, and CD8. In controls, the mean alveolar wall CD3 cell count was 45 per square millimeter (95% confidence intervals, 30-52 per square millimeter) and the mean CD8 count was 15 per square millimeter (2-20 per square millimeter). In surveillance and negative patient biopsies, alveolar wall CD8 counts were significantly greater than controls (P = .03 and .02, respectively). Mean alveolar wall CD3 counts were significantly higher in type A rejection (88.7 +/- 12.9) than controls and negative biopsies (42 +/- 5.3, P < .001), but there was no difference compared to infections (119.7 +/- 22, P > .5). Mucosal CD3 cell counts were significantly higher in type B rejection (16.1 +/- 2.5) than controls and negative biopsies (1.5 +/- 0.4, P < .001), and also higher than infections (3.9 +/- 1.1, P < .001). In 7% of biopsies, T-cell staining identified perivascular circumferential infiltrates that were difficult to identify on routine stains, and in an additional 9% minor changes in grading were made after reviewing T-cell markers. Immunohistochemical staining may help in identifying perivascular infiltrates and demonstrates increased intraepithelial T-cells even in low-grade type B rejection. Type B rejection as assessed quantitatively is more specific than type A rejection in comparison to infection. PMID:19121842
Colombat, Magali; Mal, Hervé; Copie-Bergman, Christiane; Diebold, Jacques; Damotte, Diane; Callard, Patrice; Fournier, Michel; Farcet, Jean-Pierre; Stern, Marc; Delfau-Larue, Marie-Hélène
We have recently described a new form of light chain deposition disease (LCDD) presenting as a severe cystic lung disorder requiring lung transplantation. There was no bone marrow plasma cell proliferation. Because of the absence of disease recurrence after bilateral lung transplantation and of serum-free light chain ratio normalization after the procedure, we hypothesized that monoclonal light chain synthesis occurred within the lung. The aim of this study was to look for the monoclonal B-cell component in 3 patients with cystic lung LCDD. Histologic examination of the explanted lungs showed diffuse nonamyloid kappa light chain deposits associated with a mild lymphoid infiltrate composed of aggregates of small CD20(+), CD5(-), CD10(-) B lymphocytes reminiscent of bronchus-associated lymphoid tissue. Using polymerase chain reaction (PCR), we identified a dominant B-cell clone in the lung in the 3 studied patients. The clonal expansion of each patient shared an unmutated antigen receptor variable region sequence characterized by the use of IGHV4-34 and IGKV1 subgroups with heavy and light chain CDR3 sequences of more than 80% amino acid identity, a feature evocative of an antigen-driven process. Combined with clinical and biologic data, our results strongly argue for a new antigen-driven primary pulmonary lymphoproliferative disorder. PMID:18483396
Cross, G M
Since 1926, there have been three epizootics of ND. The latter two have been directly linked with psittacine species and Racing Pigeons. The modern poultry industry is extremely vulnerable to the effects of NDV, once it gains entry to any facet of the industry. Consequently considerable expense and effort are expended to keep the virus at bay. The main threat continues to come from psittacine species and racing pigeons. The considerable international trade in these birds, together with rapid air transport, can allow virulent NDV to gain entry to a country while exotic birds are incubating the disease. It is hoped that quarantine barriers and requirements will prevent the virus from entering a country, but smuggling continues and constitutes the biggest risk. Domestic avian pets are also vulnerable to the virus. It is hoped that new in vitro testing procedures, such as monoclonal antibody and oligonucleotide fingerprinting techniques, may be used to identify rapidly and characterize emergent virulent strains, so that appropriate measures may be taken to prevent infection of commercial poultry and domestic pets. PMID:1767471
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
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
Peccatori, J; Forcina, A; Clerici, D; Crocchiolo, R; Vago, L; Stanghellini, M T L; Noviello, M; Messina, C; Crotta, A; Assanelli, A; Marktel, S; Olek, S; Mastaglio, S; Giglio, F; Crucitti, L; Lorusso, A; Guggiari, E; Lunghi, F; Carrabba, M; Tassara, M; Battaglia, M; Ferraro, A; Carbone, M R; Oliveira, G; Roncarolo, M G; Rossini, S; Bernardi, M; Corti, C; Marcatti, M; Patriarca, F; Zecca, M; Locatelli, F; Bordignon, C; Fleischhauer, K; Bondanza, A; Bonini, C; Ciceri, F
Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients' bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II-IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus-mycophenolate-ATG-F-rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts. PMID:24897508
Lian, Ling; Zhang, Daixi; Wang, Qiong; Yang, Ning; Qu, Lujiang
Marek's disease (MD) is lymphoproliferative neoplastic disease in chickens, which is caused by Marek's disease virus (MDV). Our previous study profiled microRNA (miRNA) transcriptome in MD lymphoma, and found that gga-miR-199-3p, gga-miR-140-3p, and gga-miR-221-5p were down-regulated in MD lymphoma. In this study, we further investigated their differential expression between MDV-infected spleens and noninfected spleens at 4, 7, 14, 21, and 28 d postinfection (dpi) to elucidate whether deregulation of them was specific to late tumor transformation phase or not. The results showed that gga-miR-199-3p was down-regulated at 14 and 28 dpi, and the expression of gga-miR-140-3p was decreased at 14 dpi, which indicated that deregulation of these miRNAs appeared since early stage of MD tumor transformation. Additionally, the inhibitory effects of gga-miR-199-3p, gga-miR-140-3p, and gga-miR-221-5p on MDV-transformed lymphoid cell line (MSB1) cells proliferation were observed, which suggested that these miRNAs acted as MD tumor suppressors. Their aberrant expression at early tumor transformation phase and suppressive role in cell proliferation indicated that they were involved in MD lymphoma transformation, and might play crucial roles in MD tumorigenesis. PMID:26112035
. Meningococcal disease is a serious disease, caused by bacteria. Meningococcal disease is a contagious the risk of contracting the disease. Meningococcal vaccine can prevent four types of meningococcal disease; these include two of the three most common in the United States. Meningococcal vaccine cannot prevent all types
DANIEL L. DEPIETROPAOLO; Delaware JOHN H. POWERS; JAMES M. GILL; ANDREW J. FOY
The use of serologic testing and its value in the diagnosis of Lyme disease remain confusing and controversial for physi- cians, especially concerning persons who are at low risk for the disease. The approach to diagnosing Lyme disease varies depending on the probability of disease (based on endemicity and clinical findings) and the stage at which the disease may be.
Cohen, Jeffrey I
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
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
... increase the risk of heart and blood vessel (cardiovascular) disease. Contributing risk factors are associated with increased risk of cardiovascular disease, but their significance and prevalence haven't yet ...
McBroom, Lynn W.
Alzheimer's disease, a form of dementia in middle-age and older adults is becoming more evident because of growing numbers of older people and better diagnosis and detection methods. Describes the behavioral and physical symptoms of the disease as well as specific suggestions for care of patients with Alzheimer's disease, including dealing with…
anti-in? ammatory drugs in patients with Alzheimer’s diseaseAlzheimer’s disease show some evidence of success Review DrugAlzheimer’s disease. 203 Clinical trials and epidemiological ? ndings Anti-in? ammatory drugs
Resources - heart disease ... The following organizations are good resources for information on heart disease: American Heart Association -- www.heart.org Centers for Disease Control and Prevention -- www.cdc.gov/heartdisease/
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... PDF, 345 KB)????? Alternate Language URL Acquired Cystic Kidney Disease Page Content On this page: What is ... For More Information Acknowledgments What is acquired cystic kidney disease? Acquired cystic kidney disease happens when a ...
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... PDF, 269 KB). Alternate Language URL Pregnancy and Thyroid Disease Page Content On this page: What is ... through Research For More Information Acknowledgments What is thyroid disease? Thyroid disease is a disorder that affects ...