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Sample records for allogeneic hct recipients

  1. RECIPIENT PRETRANSPLANT INOSINE MONOPHOSPHATE DEHYDROGENASE ACTIVITY IN NONMYELOABLATIVE HCT

    PubMed Central

    Bemer, Meagan J.; Risler, Linda J.; Phillips, Brian R.; Wang, Joanne; Storer, Barry E.; Sandmaier, Brenda M.; Duan, Haichuan; Raccor, Brianne S.; Boeckh, Michael J.; McCune, Jeannine S.

    2014-01-01

    Mycophenolic acid, the active metabolite of mycophenolate mofetil (MMF), inhibits inosine monophosphate dehydrogenase (IMPDH) activity. IMPDH is the rate-limiting enzyme involved in de novo synthesis of guanosine nucleotides and catalyzes the oxidation of inosine 5’- monophosphate (IMP) to xanthosine 5’-monophosphate (XMP). We developed a highly sensitive liquid chromatography–mass spectrometry method to quantitate XMP concentrations in peripheral blood mononuclear cells (PMNC) isolated from the recipient pretransplant and used this method to determine IMPDH activity in 86 nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) patients. The incubation procedure and analytical method yielded acceptable within-sample and within-individual variability. Considerable between-individual variability was observed (12.2-fold). Low recipient pretransplant IMPDH activity was associated with increased day +28 donor T-cell chimerism, more acute graft-versus-host disease (GVHD), lower neutrophil nadirs, and more cytomegalovirus reactivation, but not with chronic GVHD, relapse, non-relapse mortality, or overall mortality. We conclude that quantitation of the recipient’s pretransplant IMPDH activity in PMNC lysate could provide a useful biomarker to evaluate a recipient’s sensitivity to MMF, but confirmatory studies are needed. Further trials should be conducted to confirm our findings and to optimize postgrafting immunosuppression in nonmyeloablative HCT recipients. PMID:24923537

  2. Financial burden in recipients of allogeneic hematopoietic cell transplantation.

    PubMed

    Khera, Nandita; Chang, Yu-hui; Hashmi, Shahrukh; Slack, James; Beebe, Timothy; Roy, Vivek; Noel, Pierre; Fauble, Veena; Sproat, Lisa; Tilburt, Jon; Leis, Jose F; Mikhael, Joseph

    2014-09-01

    Although allogeneic hematopoietic cell transplantation (HCT) is an expensive treatment for hematological disorders, little is known about the financial consequences for the patients who undergo this procedure. We analyzed factors associated with its financial burden and its impact on health behaviors of allogeneic HCT recipients. A questionnaire was retrospectively mailed to 482 patients who underwent allogeneic HCT from January 2006 to June 2012 at the Mayo Clinic, to collect information regarding current financial concerns, household income, employment, insurance, out-of-pocket expenses, and health and functional status. A multivariable logistic regression analysis identified factors associated with financial burden and treatment nonadherence. Of the 268 respondents (56% response rate), 73% reported that their sickness had hurt them financially. All patients for whom the insurance information was available (missing, n = 13) were insured. Forty-seven percent of respondents experienced financial burden, such as household income decreased by >50%, selling/mortgaging home, or withdrawing money from retirement accounts. Three percent declared bankruptcy. Younger age and poor current mental and physical functioning increased the likelihood of financial burden. Thirty-five percent of patients reported deleterious health behaviors because of financial constraints. These patients were likely to be younger, have lower education, and with a longer time since HCT. Being employed decreased the likelihood of experiencing financial burden and treatment nonadherence due to concern about costs. A significant proportion of allogeneic HCT survivors experience financial hardship despite insurance coverage. Future research should investigate potential interventions to help at-risk patients and prevent adverse financial outcomes after this life-saving procedure. PMID:24867778

  3. Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil

    PubMed Central

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2012-01-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. 4,496 MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance and volume of the central compartment were 24.2 L/hr and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA clearance by 33.8%. The optimal LSS was immediately before and at 0.25, 1.25, 2, and 4hr after oral MMF administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

  4. Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

    PubMed

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2013-04-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

  5. Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation

    PubMed Central

    Hashimoto, Daigo; Chow, Andrew; Greter, Melanie; Saenger, Yvonne; Kwan, Wing-Hong; Leboeuf, Marylene; Ginhoux, Florent; Ochando, Jordi C.; Kunisaki, Yuya; van Rooijen, Nico; Liu, Chen; Teshima, Takanori; Heeger, Peter S.; Stanley, E. Richard; Frenette, Paul S.

    2011-01-01

    Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic. PMID:21536742

  6. Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD.

    PubMed

    Matta, Benjamin M; Reichenbach, Dawn K; Zhang, Xiaoli; Mathews, Lisa; Koehn, Brent H; Dwyer, Gaelen K; Lott, Jeremy M; Uhl, Franziska M; Pfeifer, Dietmar; Feser, Colby J; Smith, Michelle J; Liu, Quan; Zeiser, Robert; Blazar, Bruce R; Turnquist, Hēth R

    2016-07-21

    During allogeneic hematopoietic cell transplantation (alloHCT), nonhematopoietic cell interleukin-33 (IL-33) is augmented and released by recipient conditioning to promote type 1 alloimmunity and lethal acute graft-versus-host disease (GVHD). Yet, IL-33 is highly pleiotropic and exhibits potent immunoregulatory properties in the absence of coincident proinflammatory stimuli. We tested whether peri-alloHCT IL-33 delivery can protect against development of GVHD by augmenting IL-33-associated regulatory mechanisms. IL-33 administration augmented the frequency of regulatory T cells (Tregs) expressing the IL-33 receptor, suppression of tumorigenicity-2 (ST2), which persist following total body irradiation. ST2 expression is not exclusive to Tregs and IL-33 expands innate immune cells with regulatory or reparative properties. However, selective depletion of recipient Foxp3(+) cells concurrent with peri-alloHCT IL-33 administration accelerated acute GVHD lethality. IL-33-expanded Tregs protected recipients from GVHD by controlling macrophage activation and preventing accumulation of effector T cells in GVHD-target tissue. IL-33 stimulation of ST2 on Tregs activates p38 MAPK, which drives expansion of the ST2(+) Treg subset. Associated mechanistic studies revealed that proliferating Tregs exhibit IL-33-independent upregulation of ST2 and the adoptive transfer of st2(+) but not st2(-) Tregs mediated GVHD protection. In total, these data demonstrate the protective capacity of peri-alloHCT administration of IL-33 and IL-33-responsive Tregs in mouse models of acute GVHD. These findings provide strong support that the immunoregulatory relationship between IL-33 and Tregs can be harnessed therapeutically to prevent GVHD after alloHCT for treatment of malignancy or as a means for tolerance induction in solid organ transplantation. PMID:27222477

  7. Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients

    PubMed Central

    McCune, Jeannine S.; Mager, Donald E.; Bemer, Meagan J.; Sandmaier, Brenda M.; Storer, Barry E.; Heimfeld, Shelly

    2015-01-01

    Purpose Fludarabine monophosphate (fludarabine) is an integral component of many reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Fludarabine’s metabolite, 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), undergoes cellular uptake and activation to form the active cytotoxic metabolite fludarabine triphosphate (F-ara-ATP), which inhibits cellular DNA synthesis in CD4+ and CD8+ cells. In this study, we evaluated whether fludarabine-based pharmacologic biomarkers were associated with clinical outcomes in HCT recipients. Methods Participants with hematologic diseases were conditioned with fludarabine and low-dose total body irradiation (TBI) followed by allogeneic HCT and post-grafting immunosuppression. After fludarabine administration, we evaluated pharmacological biomarkers for fludarabine – F-ara-A area under the curve (AUC) and the ratio of circulating CD4+ and CD8+ cells (CD4+/CD8+ ratio) after fludarabine administration – in 102 patients; F-ara-ATP accumulation rate in enriched CD4+ and CD8+ cells was evaluated in 34 and 36 patients, respectively. Results Interpatient variability in the pharmacological biomarkers was high, ranging from 3.7-fold (F-ara-A AUC) to 39-fold (F-ara-ATP in CD8+ cells). Circulating CD8+ cells were more sensitive to fludarabine administration. A population pharmacokinetic-based sampling schedule successfully allowed for estimation of F-ara-A AUC in this outpatient population. There was poor correlation between the F-ara-AUC and the F-ara-ATP accumulation rate in CD4+ (R2=0.01) and CD8+ cells (R2=0.00). No associations were seen between the four biomarkers and clinical outcomes (day +28 donor T-cell chimerism, acute graft-versus-host disease (GVHD), neutrophil nadirs, cytomegalovirus reactivation, chronic GVHD, relapse, non-relapse mortality, or overall mortality). Conclusions Considerable interpatient variability exists in pharmacokinetic and fludarabine-based biomarkers, but these biomarkers

  8. Correlation and Agreement of Handheld Spirometry with Laboratory Spirometry in Allogeneic Hematopoietic Cell Transplant Recipients.

    PubMed

    Cheng, Guang-Shing; Campbell, Angela P; Xie, Hu; Stednick, Zach; Callais, Cheryl; Leisenring, Wendy M; Englund, Janet A; Chien, Jason W; Boeckh, Michael

    2016-05-01

    Early detection of subclinical lung function decline may help identify allogeneic hematopoietic cell transplant (HCT) recipients who are at increased risk for late noninfectious pulmonary complications, including bronchiolitis obliterans syndrome. We evaluated the use of handheld spirometry in this population. Allogeneic HCT recipients enrolled in a single-center observational trial performed weekly spirometry with a handheld spirometer for 1 year after transplantation. Participants performed pulmonary function tests in an outpatient laboratory setting at 3 time points: before transplantation, at day 80 after transplantation, and at 1 year after transplantation. Correlation between the 2 methods was assessed by Pearson and Spearman correlations; agreement was assessed using Bland-Altman plots. A total of 437 subjects had evaluable pulmonary function tests. Correlation for forced expiratory volume in 1 second (FEV1) was r = .954 (P < .0001) at day 80 and r = .931 (P < .0001) at 1 year when the handheld and laboratory tests were performed within 1 day of each other. Correlation for handheld forced expiratory volume in 6 seconds (FEV6) with laboratory forced vital capacity was r = .914 (P < .0001) at day 80 and r = .826 (P < .0001) at 1 year. The bias, or the mean difference (handheld minus laboratory), for FEV1 at day 80 and 1 year was -.13 L (limits of agreement, -.63 to .37) and -.10 L (limits of agreement, -.77 to .56), respectively. FEV6 showed greater bias at day 80 (-.51 L [limits of agreement, -1.44 to .42]) and 1 year (-.40 L [limits of agreement, -1.81 to 1.01]). Handheld spirometry correlated well with laboratory spirometry after allogeneic HCT and may be useful for self-monitoring of patients for early identification of airflow obstruction. PMID:26748162

  9. PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF INOSINE MONOPHOSPHATE DEHYDROGENASE (IMPDH) ACTIVITY IN MMF-TREATED HCT RECIPIENTS

    PubMed Central

    Li, Hong; Mager, Donald E.; Sandmaier, Brenda M.; Storer, Barry E.; Boeckh, Michael J.; Bemer, Meagan J.; Phillips, Brian R.; Risler, Linda J.; McCune, Jeannine S.

    2014-01-01

    A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplant (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNC) at five time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in the pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic/dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory Emax model with an IC50 = 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, non-relapse mortality, and overall mortality. In conclusion, a pharmacokinetic/dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker. PMID:24727337

  10. Risk Factors and Impact of non-Aspergillus mold infections (NAMI) following Allogeneic HCT: A CIBMTR Infection & Immune Reconstitution analysis

    PubMed Central

    Riches, Marcie L.; Trifilio, Steven; Chen, Min; Ahn, Kwang Woo; Langston, Amelia; Lazarus, Hillard M.; Marks, David I.; Martino, Rodrigo; Maziarz, Richard T.; Papinicolou, Genofeva A.; Wingard, John R.; Young, Jo-Anne H.; Bennett, Charles L.

    2015-01-01

    Risk factors for non-Aspergillus mold infection (NAMI) and the impact on transplant outcome are poorly assessed in the current era of antifungal agents. Outcomes of 124 patients receiving allogeneic HCT diagnosed with either mucormycosis [n=72] or fusariosis [n=52] between days 0-365 after HCT are described and compared to a control cohort (n=11856). Patients with NAMI had more advanced disease [mucormycois 25%, fusariosis 23%, controls 18%; p = 0.004] and were more likely to have a KPS<90% at HCT [mucormycosis 42%, fusariosis 38%, controls 28%; p=0.048]. The 1-year survival after HCT was 22% (15–29%) for cases and was significantly inferior compared to controls [65%(64–65%); p < 0.001]. Survival from infection was similarly dismal regardless of mucormycosis [15% (8-25%)] and fusariosis [21% (11-33%)]. In multivariable analysis, NAMI was associated with a 6-fold higher risk of death (p<0.0001) regardless of the site or timing of infection. Risk factors for mucormycosis include preceding acute GVHD, prior aspergillus infection, and older age. For fusariosis, increased risks including receipt of cord blood, prior CMV infection, and transplant prior to May 2002. In conclusion, NAMI occurs infrequently, is associated with high mortality, and appears with similar frequency in the current antifungal era. PMID:26524262

  11. Challenges in Determining Genotypes for Pharmacogenetics in Allogeneic Hematopoietic Cell Transplant Recipients.

    PubMed

    Langman, Loralie J; Nesher, Lior; Shah, Dimpy P; Azzi, Jacques M; Shpall, Elizabeth J; Rezvani, Katy; Black, John L; Chemaly, Roy F

    2016-09-01

    As part of a pharmacogenetic study, paired blood and oral fluid samples were tested for the IL28B polymorphism (rs12979860) before and after hematopoietic cell transplantation (HCT) to evaluate changes in the genotype and investigate the utility of genotyping in oral fluid in HCT recipients. In 54 patients with leukemia >18 years of age, samples were collected approximately 7 days before HCT and 60 days after HCT. IL28B polymorphism testing was performed using real-time PCR with allele-specific probes. Twenty-four patients had the same genotype as their donors. In 30 patients, the genotype was different from that of the donor. In the oral fluid samples, 4 retained the recipient's genotype, and 18 had a genotype that matched that of the donor. In the remaining 8 patients, the results could not be characterized and appeared to be a combination of both, suggesting mixed proportions of donor and recipient cells. The assumption was that the sloughed epithelial cells of the mouth are of recipient origin. However, oral fluid is a mixture that contains varying numbers of cells of the recipient and immunomodulatory cells from the donor. Therefore, the use of oral fluid after HCT for clinical pharmacogenetics purposes needs further investigation. PMID:27371869

  12. Systematic Nutritional Support in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

    PubMed

    Fuji, Shigeo; Einsele, Hermann; Savani, Bipin N; Kapp, Markus

    2015-10-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) has become an established treatment modality for various hematological diseases. However, in allogeneic HSCT, patients often suffer from severe gastrointestinal complications caused by the conditioning regimen and acute/chronic graft-versus-host disease, which requires support by multidisciplinary nutritional support teams (NST). In addition, pretransplantation nutritional status can affect the clinical outcome after allogeneic HSCT. Therefore, it is important to refer the patient to a NST when becoming aware of nutritional problems before allogeneic HSCT. It is also important to follow nutritional status over the long term, as patients often suffer from various nutritional problems, such as malnutrition and metabolic syndrome, even late after allogeneic HSCT. In summary, NST can contribute to the improvement of nutritional status and possibly prognosis at every stage before and after allogeneic HSCT. Here, we aim to give a comprehensive overview of current understanding about nutritional support in allogeneic HSCT and try to provoke a constructive discussion to stimulate further investigation. PMID:26172477

  13. OUTCOMES FOLLOWING HCT USING FLUDARABINE, BUSULFAN AND THYMOGLOBULIN: A MATCHED COMPARISON TO ALLOGENEIC TRANSPLANTS CONDITIONED WITH BUSULFAN AND CYCLOPHOSPHAMIDE

    PubMed Central

    Bredeson, Christopher N.; Zhang, Mei-Jie; Agovi, Manza-A.; Bacigalupo, Andrea; Bahlis, Nizar J.; Ballen, Karen; Brown, Christopher; Chaudhry, M. Ahsan; Horowitz, Mary M.; Kurian, Seira; Quinlan, Diana; Muehlenbien, Catherine E.; Russell, James A.; Savoie, Lynn; Rizzo, J. Douglas; Stewart, Douglas A.

    2012-01-01

    We have reported a lower incidence of acute graft versus host disease (aGVHD) with a novel conditioning regimen using low dose rabbit anti-thymocyte globulin (TG, Thymoglobulin) with fludarabine and intravenous busulfan (FluBuTG). To assess further this single center experience, we performed a retrospective matched pair analysis comparing outcomes of adult patients transplanted using the FluBuTG conditioning regimen with matched controls from patients reported to the CIBMTR receiving a first allogeneic hematopoietic stem cell transplant (HCT) after standard oral busulfan and cyclophosphamide (BuCy). 120 cases and 215 matched controls were available for comparison. Patients receiving FluBuTG had significantly less treatment related mortality (12% vs 34%, p<0.001) and grades II–IV aGVHD (15% vs 34% p<0.001) compared to BuCy patients. The risk of relapse was higher in the FluBuTG patients (42% vs 20%, p<0.001). The risks of chronic GVHD (cGVHD) and disease free survival (DFS) were similar in the cases and controls. These results suggest that the novel regimen FluBuTG decreases the risk of aGVHD and transplant mortality after HLA-identical sibling HCT, but is associated with an increased risk of relapse, resulting in similar DFS. Whether these conditioning regimens may be more suitable for specific patient populations based on relapse risk requires testing in prospective randomized trials. PMID:18721762

  14. DAS181 Treatment of Severe Parainfluenza Virus 3 Pneumonia in Allogeneic Hematopoietic Stem Cell Transplant Recipients Requiring Mechanical Ventilation

    PubMed Central

    Dhakal, B.; D'Souza, A.; Pasquini, M.; Saber, W.; Fenske, T. S.; Moss, R. B.; Drobyski, W. R.; Hari, P.; Abidi, M. Z.

    2016-01-01

    Parainfluenza virus (PIV) may cause life-threatening pneumonia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Currently, there are no proven effective therapies. We report the use of inhaled DAS181, a novel sialidase fusion protein, for treatment of PIV type 3 pneumonia in two allogeneic hematopoietic SCT recipients with respiratory failure. PMID:26941799

  15. No evidence of plasticity in hair follicles of recipients after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Rovó, Alicia; Meyer-Monard, Sandrine; Heim, Dominik; Arber, Caroline; Passweg, Jakob R; Gratwohl, Alois; Tichelli, André

    2005-08-01

    Here we show in a prospective quantitative study of 115 patients after allogeneic hematopoietic stem cell transplantation that hair follicles remain exclusively of recipient type despite full whole blood donor-type chimerism. Our data indicate that unmanipulated hematopoietic donor stem cells do not contribute directly to reconstitution even in an organ at highest need for repair. PMID:16038783

  16. Donor-derived DNA in hair follicles of recipients after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Jacewicz, R; Lewandowski, K; Rupa-Matysek, J; Jedrzejczyk, M; Brzezinski, P M; Dobosz, T; Jonkisz, A; Szram, S; Komarnicki, M; Berent, J

    2010-11-01

    The hair follicles of recipients of allogeneic hematopoietic SCT (HSCT) constitute the tissue with the greatest need for regeneration after high-dose chemotherapy. Previous studies have shown a lack of donor-derived DNA in the hair follicles of recipients. Therefore, we carried out a study to determine whether male donor-derived genetic material can be found in female recipients' hair follicles after HSCT. Fluorescent-based PCR with analyses of Y-chromosome STR (Y-STR) and RQ-PCR with the sex-determining region Y (SRY) were used independently to evaluate chimerism status. Our results proved the existence of donor-derived stem DNA in the recipients' hair follicle cells. This report undermines the validity of data indicating that hair follicle cells maintain 100% of recipient origin. PMID:20173789

  17. Geriatric assessment to predict survival in older allogeneic hematopoietic cell transplantation recipients

    PubMed Central

    Muffly, Lori S.; Kocherginsky, Masha; Stock, Wendy; Chu, Quynh; Bishop, Michael R.; Godley, Lucy A.; Kline, Justin; Liu, Hongtao; Odenike, Olatoyosi M.; Larson, Richard A.; van Besien, Koen; Artz, Andrew S.

    2014-01-01

    Allogeneic hematopoietic cell transplantation is increasingly utilized in older adults. This study prospectively evaluated the prognostic utility of geriatric assessment domains prior to allogeneic transplantation in recipients aged 50 years and over. Geriatric assessment was performed prior to transplant, and included validated measures across domains of function and disability, comorbidity, frailty, mental health, nutritional status, and systemic inflammation. A total of 203 patients completed geriatric assessment and underwent transplant. Median age was 58 years (range 50–73). After adjusting for established prognostic factors, limitations in instrumental activities of daily living (HR 2.38, 95%CI: 1.59–3.56; P<0.001), slow walk speed (HR 1.80, 95%CI: 1.14–2.83; P=0.01), high comorbidity by hematopoietic cell transplantation-specific comorbidity index (HR 1.56, 95%CI: 1.07–2.28; P=0.02), low mental health by short-form-36 mental component summary (HR 1.67, 95%CI: 1.13–2.48; P=0.01), and elevated serum C-reactive protein (HR 2.51, 95%CI: 1.54–4.09; P<0.001) were significantly associated with inferior overall survival. These associations were more pronounced in the cohort 60 years and over. Geriatric assessment measures confer independent prognostic utility in older allogeneic transplant recipients. Implementation of geriatric assessment prior to allogeneic transplantation may aid appropriate selection of older adults. PMID:24816237

  18. Hair follicle: a reliable source of recipient origin after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Hong, Y C; Liu, H M; Chen, P S; Chen, Y J; Lyou, J Y; Hu, H Y; Yi, M F; Lin, J S; Tzeng, C-H

    2007-11-01

    Blood, buccal swab and hair follicles are among the most commonly used sources for forensic science, parentage testing and personal identification. A total of 29 patients who have had a sustained engraftment from 15 months to 21.5 years after allogeneic hematopoietic stem cell transplantation (HSCT) without rejection, relapse or chronic GVHD involving oral mucosa were enrolled for a chimerism study. PCR-amplified short tandem repeat analyses were conducted per patient every 3 months for at least three consecutive times. The results for blood were all donor type except one who had a mixed chimerism, 14.5 years after receiving a transplant for lymphoma. As for buccal swab, mixed chimerism ranging from 10 to 96% donor origin was noted for 28 recipients except the one who had mixed chimerism of blood and retained total recipient type. In contrast, hair follicles were 100% recipient type for the entire group. It is concluded that the hair follicle is devoid of adult stem cell plasticity and may serve as a reliable source of recipient's origin when pre-transplant DNA fingerprinting or reference DNA is not available for people who have successfully received allogeneic HSCT while in need of a personal identification. PMID:17704789

  19. Hematopoietic stem cells from NOD mice exhibit autonomous behavior and a competitive advantage in allogeneic recipients.

    PubMed

    Chilton, Paula M; Rezzoug, Francine; Ratajczak, Mariusz Z; Fugier-Vivier, Isabelle; Ratajczak, Janina; Kucia, Magda; Huang, Yiming; Tanner, Michael K; Ildstad, Suzanne T

    2005-03-01

    Type 1 diabetes is a systemic autoimmune disease that can be cured by transplantation of hematopoietic stem cells (HSCs) from disease-resistant donors. Nonobese diabetic (NOD) mice have a number of features that distinguish them as bone marrow transplant recipients that must be understood prior to the clinical application of chimerism to induce tolerance. In the present studies, we characterized NOD HSCs, comparing their engraftment characteristics to HSCs from disease-resistant strains. Strikingly, NOD HSCs are significantly enhanced in engraftment potential compared with HSCs from disease-resistant donors. Unlike HSCs from disease-resistant strains, they do not require graft-facilitating cells to engraft in allogeneic recipients. Additionally, they exhibit a competitive advantage when coadministered with increasing numbers of syngeneic HSCs, produce significantly more spleen colony-forming units (CFU-Ss) in vivo in allogeneic recipients, and more granulocyte macrophage-colony-forming units (CFU-GMs) in vitro compared with HSCs from disease-resistant controls. NOD HSCs also exhibit significantly enhanced chemotaxis to a stromal cell-derived factor 1 (SDF-1) gradient and adhere significantly better on primary stroma. This enhanced engraftment potential maps to the insulin-dependent diabetes locus 9 (Idd9) locus, and as such the tumor necrosis factor (TNF) receptor family as well as ski/sno genes may be involved in the mechanism underlying the autonomy of NOD HSCs. These findings may have important implications to understand the evolution of autoimmune disease and impact on potential strategies for cure. PMID:15522953

  20. Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT.

    PubMed

    Crivello, Pietro; Heinold, Andreas; Rebmann, Vera; Ottinger, Hellmut D; Horn, Peter A; Beelen, Dietrich W; Fleischhauer, Katharina

    2016-07-01

    The role of HLA amino acid (AA) polymorphism for the outcome of hematopoietic cell transplantation (HCT) is controversial, in particular for HLA class II. Here, we investigated this question in nonpermissive HLA-DPB1 T-cell epitope (TCE) mismatches reflected by numerical functional distance (FD) scores, assignable to all HLA-DPB1 alleles based on the combined impact of 12 polymorphic AAs. We calculated the difference in FD scores (ΔFD) of mismatched HLA-DPB1 alleles in patients and their 10/10 HLA-matched unrelated donors of 379 HCTs performed at our center for acute leukemia or myelodysplastic syndrome. Receiver-operator curve-based stratification into 2 ΔFD subgroups showed a significantly higher percentage of nonpermissive TCE mismatches for ΔFD >2.665, compared with ΔFD ≤2.665 (88% vs 25%, P < .0001). In multivariate analysis, ΔFD >2.665 was significantly associated with overall survival (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.05-1.87; P < .021) and event-free survival (HR, 1.39; 95% CI, 1.05-1.82; P < .021), compared with ΔFD ≤2.665. These associations were stronger than those observed for TCE mismatches. There was a marked but not statistically significant increase in the hazards of relapse and nonrelapse mortality in the high ΔFD subgroup, whereas no differences were observed for acute and chronic graft-versus-host disease. Seven nonconservative AA substitutions in peptide-binding positions had a significantly stronger impact on ΔFD compared with 5 others (P = .0025), demonstrating qualitative differences in the relative impact of AA polymorphism in HLA-DPB1. The novel concept of ΔFD sheds new light onto nonpermissive HLA-DPB1 mismatches in unrelated HCT. PMID:27162243

  1. Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT

    PubMed Central

    Cooley, Sarah; Parham, Peter; Farag, Sherif S.; Verneris, Michael R.; McQueen, Karina L.; Guethlein, Lisbeth A.; Trachtenberg, Elizabeth A.; Haagenson, Michael; Horowitz, Mary M.; Klein, John P.; Weisdorf, Daniel J.

    2007-01-01

    Natural killer (NK) cells can alter the outcome of hematopoietic cell transplantation (HCT) if donor alloreactivity targets the recipient. Since most NK cells express inhibitory killer-immunoglobulin receptors (KIRs), we hypothesized that the susceptibility of recipient cells to donor NK cell–mediated lysis is genetically predetermined by the absence of known KIR ligands. We analyzed data from 2062 patients undergoing unrelated donor HCT for acute myeloid leukemia (AML; n = 556), chronic myeloid leukemia (CML; n = 1224), and myelodysplastic syndrome (MDS; n = 282). Missing 1 or more KIR ligands versus the presence of all ligands protected against relapse in patients with early myeloid leukemia (relative risk [RR] = 0.54; n = 536, 95% confidence interval [CI] 0.30-0.95, P = .03). In the subset of CML patients that received a transplant beyond 1 year from diagnosis (n = 479), missing a KIR ligand independently predicted a greater risk of developing grade 3-4 acute graft-versus-host disease (GVHD; RR = 1.58, 95% CI 1.13-2.22; P = .008). These data support a genetically determined role for NK cells following unrelated HCT in myeloid leukemia. PMID:17317850

  2. Allogeneic and Xenogeneic Transplantation of Adipose-Derived Stem Cells in Immunocompetent Recipients Without Immunosuppressants

    PubMed Central

    Lin, Guiting; Lue, Tom F.

    2012-01-01

    Mesenchymal stem cells (MSCs) are well known for their immunomodulatory capabilities. In particular, their immunosuppressive property is believed to permit their allogeneic or even xenogeneic transplantation into immunocompetent recipients without the use of immunosuppressants. Adipose-derived stem cell (ADSC), owing to its ease of isolation from an abundant tissue source, is a promising MSC for the treatment of a wide range of diseases. ADSC has been shown to lack major histocompatibility complex-II expression, and its immunosuppressive effects mediated by prostaglandin E2. Both preclinical and clinical studies have shown that allogeneic transplantation of ADSCs was able to control graft-versus-host disease. In regard to xenotransplantation a total of 27 preclinical studies have been published, with 20 of them performed with the investigators' intent. All 27 studies used ADSCs isolated from humans, possibly due to the wide availability of lipoaspirates. On the other hand, the recipients were mouse in 13 studies, rat in 11, rabbit in 2, and dog in 1. The targeted diseases varied greatly but all showed significant improvements after ADSC xenotransplantation. For clinical application in human medicine, ADSC xenotransplantation offers no obvious advantage over autotransplantation. But in veterinary medicine, xenotransplantation with porcine ADSC is a practical alternative to the costly and inconvenient autotransplantation. PMID:22621212

  3. Immune transfer studies in canine allogeneic marrow graft donor-recipient pairs

    SciTech Connect

    Grosse-Wilde, H.; Krumbacher, K.; Schuening, F.D.; Doxiadis, I.; Mahmoud, H.K.; Emde, C.; Schmidt-Weinmar, A.; Schaefer, U.W.

    1986-07-01

    Transfer of immunity occurring with bone marrow grafting was studied using the dog as a preclinical model. Allogeneic bone marrow transplantation (BMT) was performed between DLA-identical beagle litter-mates. The donors were immunized with tetanus toxoid (TT) or sheep red blood cells (SRBC), and their humoral response was monitored by hemagglutination. The recipients of bone marrow from TT-immunized donors showed a marked increase of antibody titer one week posttransplantation, while in the recipients of marrow from SRBC immunized donors the antibody titers were considerably lower. Within the following 60 days the antibody titers in both groups diminished gradually to pregrafting levels. Control experiments in which cell-free plasma from donors immunized with TT and SRBC respectively was transfused indicated that the initial rise of specific antibody titers after marrow grafting is likely to be due to a passive transfer of humoral immunity. A single challenge of these marrow graft recipients with the respective antigen 15-18 weeks posttransplantation led to a secondary type of humoral immune response. It could be demonstrated that transfer of memory against TT or SRBC was independent from the actual antibody titer and the time of vaccination of the donor. One dog was immunized with TT after serving as marrow donor. When the donor had shown an antibody response, a peripheral blood leukocytes (PBL) transfusion was given to his chimera. Subsequent challenge of the latter resulted in a secondary type of specific antibody response. This indicates that specific cellular-bound immunological memory can be transferred after BMT from the donor to his allogeneic bone marrow chimera by transfusion of peripheral blood leukocytes. The data may be of importance in clinical BMT to protect patients during the phase of reduced immune reactivity by transfer of memory cells.

  4. Radiologically guided fine needle lung biopsies in the evaluation of focal pulmonary lesions in allogeneic stem cell transplant recipients.

    PubMed

    Jantunen, E; Piilonen, A; Volin, L; Ruutu, P; Parkkali, T; Koukila-Kähkölä, P; Ruutu, T

    2002-02-01

    Lung problems are common in allogeneic stem cell transplant (SCT) recipients. To evaluate the feasibility and diagnostic yield of radiologically guided fine needle lung biopsy (FNLB) in allogeneic SCT recipients with focal pulmonary lesions, a retrospective analysis was carried out. Between 1989 and 1998, radiologists performed a total of 30 FNLBs in 21 allogeneic SCT recipients, guided either by ultrasound (n = 17) or computed tomography (n = 13). The median time from SCT to the first FNLB was 131 days (20-343 days). Prophylactic platelet transfusions were given in 19 procedures (66%). The complications of FNLB included clinically insignificant pneumothorax in four procedures (13%) and self-limiting haemoptysis in one case (3%). The first FNLB was suggestive of invasive pulmonary aspergillosis (IPA) in five patients (24%). Additional clinically useful findings of FNLB included Pseudomonas (two patients) and Nocardia (one patient). The final diagnosis of pulmonary lesions was IPA in 14 patients, immunological lung problems in four patients and other in three patients. Radiologically guided FNLB is feasible in allogeneic SCT recipients and has a low complication rate. The diagnostic yield is high especially for IPA. PMID:11896433

  5. Pneumonia in allogeneic stem cell transplantation recipients: a multicenter prospective study.

    PubMed

    Aguilar-Guisado, Manuela; Jiménez-Jambrina, Margarita; Espigado, Ildefonso; Rovira, Montserrat; Martino, Rodrigo; Oriol, Albert; Borrell, Nuria; Ruiz, Isabel; Martín-Dávila, Pilar; de la Cámara, Rafael; Salavert, Miquel; de la Torre, Julián; Cisneros, José Miguel

    2011-01-01

    Pneumonia is a common cause of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) but updated and prospective information is partial. The aim of this nationwide prospective study is to determine the current epidemiology, etiology, and outcome of pneumonia in allo-HSCT recipients. From September-2003 to November-2005, 112 episodes in 427 consecutive allo-HSCT recipients were included (incidence 52.2 per 100 allo-HSCT/yr), and 72 of them (64.3%) were microbiologically defined pneumonia. Bacterial pneumonia (44.4%) was more frequent than fungal (29.2%) and viral pneumonia (19.4%). The most frequent microorganisms in each group were: Escherichia coli (n = 7, 8.9%), Streptococcus pneumoniae (n = 4, 5.0%), cytomegalovirus (n = 12, 15.4%), and Aspergillus spp. (n = 12, 15.4%). The development of pneumonia and chronic graft-versus-host disease (GVHD) was associated with increased mortality after allo-HSCT, and the probability of survival was significantly lower in patients that had at least one pneumonia episode (p < 0.01). Pneumonia development in the first 100 d after transplantation, fungal etiology, GVHD, acute respiratory failure, and septic shock were associated with increased mortality after pneumonia. Our results show that pneumonia remains a frequent infectious complication after allo-HSCT, contributing to significant mortality, and provide a large current experience with the incidence, etiology and outcome of pneumonia in these patients. PMID:22150886

  6. Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection.

    PubMed

    Avery, R K; Bolwell, B J; Yen-Lieberman, B; Lurain, N; Waldman, W J; Longworth, D L; Taege, A J; Mossad, S B; Kohn, D; Long, J R; Curtis, J; Kalaycio, M; Pohlman, B; Williams, J W

    2004-12-01

    Ganciclovir-resistant cytomegalovirus (CMV) infection is an emerging problem in transplant recipients. Foscarnet resistance and cidofovir resistance have also been described, but no previous reports have suggested treatment regimens for patients with CMV refractory to all three of these drugs. Leflunomide, an immunosuppressive drug used in rheumatoid arthritis and in rejection in solid-organ transplantation, has been reported to have novel anti-CMV activity. However, its clinical utility in CMV treatment has not been described previously. We report an allogeneic bone marrow transplant recipient who developed CMV infection refractory to sequential therapy with ganciclovir, foscarnet, and cidofovir. The patient was ultimately treated with a combination of leflunomide and foscarnet. Both phenotypic and genotypic virologic analysis was performed on sequential CMV isolates. The patient's high CMV-DNA viral load became undetectable on leflunomide and foscarnet, but the patient, who had severe graft-versus-host disease (GVHD) of the liver, expired with progressive liver failure and other complications. We concluded that leflunomide is a new immunosuppressive agent with anti-CMV activity, which may be useful in the treatment of multiresistant CMV. However, the toxicity profile of leflunomide in patients with underlying GVHD remains to be defined. PMID:15489872

  7. Risk factors for recurrent Clostridium difficile infection in allogeneic hematopoietic cell transplant recipients.

    PubMed

    Mani, S; Rybicki, L; Jagadeesh, D; Mossad, S B

    2016-05-01

    Clostridium difficile infection (CDI) is one of the leading causes of hospital-acquired infections in recent times. Hematopoietic stem cell transplantation (HSCT) confers increased risk for CDI because of prolonged hospital stay, immunosuppression, the need to use broad-spectrum antibiotics and a complex interplay of preparative regimen and GvHD-induced gut mucosal damage. Our study evaluated risk factors (RF) for recurrent CDI in HSCT recipients given the ubiquity of traditional RF for CDI in this population. Of the 499 allogeneic HSCT recipients transplanted between 2005 and 2012, 61 (12%) developed CDI within 6 months before transplant or 2 years after transplant and were included in the analysis. Recurrent CDI occurred in 20 (33%) patients. One year incidence of CDI recurrence was 31%. Multivariable analyses identified the number of antecedent antibiotics other than those used to treat CDI as the only significant RF for recurrence (hazard ratio 1.96, 95% confidence interval 1.09-3.52, P=0.025). Most recurrences occurred within 6 months of the first CDI, and the recurrence of CDI was associated with a trend for increased risk of mortality. This prompts the need for further investigation into secondary prophylaxis to prevent recurrent CDI. PMID:26726944

  8. Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning

    PubMed Central

    Brazauskas, Ruta; Rizzo, J. Douglas; Sobecks, Ronald M.; Wang, Zhiwei; Horowitz, Mary M.; Bolwell, Brian; Wingard, John R.; Socie, Gerard

    2011-01-01

    Risks of secondary solid cancers among allogeneic hematopoietic cell transplant (HCT) recipients who receive conditioning without total body irradiation are not well known. We evaluated the incidence and risk factors for solid cancers after HCT using high-dose busulfan-cyclophosphamide conditioning in 4318 recipients of first allogeneic HCT for acute myeloid leukemia in first complete remission (N = 1742) and chronic myeloid leukemia in first chronic phase (N = 2576). Our cohort represented 22 041 person-years at risk. Sixty-six solid cancers were reported at a median of 6 years after HCT. The cumulative-incidence of solid cancers at 5 and 10 years after HCT was 0.6% and 1.2% among acute myeloid leukemia and 0.9% and 2.4% among chronic myeloid leukemia patients. In comparison to general population incidence rates, HCT recipients had 1.4× higher than expected rate of invasive solid cancers (95% confidence interval, 1.08-1.79, P = .01). Significantly elevated risks were observed for tumors of the oral cavity, esophagus, lung, soft tissue, and brain. Chronic graft-versus-host disease was an independent risk factor for all solid cancers, and especially cancers of the oral cavity. Recipients of allogeneic HCT using busulfan-cyclophosphamide conditioning are at risk for developing solid cancers. Their incidence continues to increase with time, and lifelong cancer surveillance is warranted in this population. PMID:20926773

  9. Correlation of Pain and Fluoride Concentration in Allogeneic Hematopoietic Stem Cell Transplant Recipients on Voriconazole.

    PubMed

    Barajas, Megan R; McCullough, Kristen B; Merten, Julianna A; Dierkhising, Ross A; Bartoo, Gabriel T; Hashmi, Shahrukh K; Hogan, William J; Litzow, Mark R; Patnaik, Mrinal M; Wilson, John W; Wolf, Robert C; Wermers, Robert A

    2016-03-01

    Supportive care guidelines recommend antimold prophylaxis in hematopoietic stem cell transplant (HSCT) recipients deemed to have high risk for invasive fungal infection, leading to long-term use of voriconazole after allogeneic HSCT in patients who remain immunocompromised. Voriconazole has been associated with periostitis, exostoses, and fluoride excess in patients after solid organ transplantation, HSCT, and leukemia therapy. The aims of this study were to describe the frequency and clinical presentation of patients presenting with pain and fluoride excess among allogeneic HSCT patients taking voriconazole, to identify when a plasma fluoride concentration was measured with respect to voriconazole initiation and onset of pain, and to describe the outcomes of patients with fluoride excess in the setting of HSCT. A retrospective review was conducted of all adult allogeneic HSCT patients receiving voriconazole at Mayo Clinic in Rochester, Minnesota, between January 1, 2009 and July 31, 2012. Of 242 patients included, 32 had plasma fluoride measured to explore the etiology of musculoskeletal pain. In 31 patients with fluoride measurement while on voriconazole, 29 (93.5%) had elevated levels. The median plasma fluoride was 11.1 μmol/L (range, 2.4 to 24.7). The median duration of voriconazole was 163 days (range, 2 to 1327). The median time to fluoride measurement was 128 days after voriconazole initiation (range, 28 to 692). At 1 year after the start of voriconazole after HSCT, 15.3% of patients had developed pain associated with voriconazole use and 35.7% developed pain while on voriconazole after 2 years. Of the patients with an elevated fluoride level, 22 discontinued voriconazole; pain resolved or improved in 15, stabilized in 3, and worsened in 4 patients. Ten patients continued voriconazole; pain resolved or improved in 7, was attributable to alternative causes in 2, and undefined in 1. Serum creatinine, estimated glomerular filtration rate, alkaline phosphatase

  10. Morphological and immunohistological changes in the skin in allogeneic bone marrow recipients.

    PubMed Central

    Sloane, J P; Thomas, J A; Imrie, S F; Easton, D F; Powles, R L

    1984-01-01

    Skin biopsies from leukaemic patients undergoing allogeneic bone marrow transplantations and treated prophylactically with cyclosporin A were analysed using histological, morphometric, and immunohistological techniques. Samples from donors were used to establish normal values. Biopsies taken from recipients two days before grafting were all histologically normal, but on immunohistological staining half of them showed a reduction in the number of epidermal Langerhans' cells and 29% a reduction in T inducer lymphocytes. Thirty two biopsies were taken from patients with rashes at various times after transplantation: 14 showed lichenoid changes consistent with graft versus host disease, three eczematous tissue reactions, two vesicular lesions, and 12 no histological abnormality. One sample showed changes intermediate between the lichenoid and eczematous forms. The numbers of epidermal Langerhans' cells were low during the first few weeks after transplantation and were normal or raised later regardless of histological appearances. Unlike epidermal Langerhans' cells, significant reductions in the numbers of lymphocytes were not seen. Lesions of all histological types contained mixtures of T inducer and T suppressor/cytotoxic cells, although the eczematous and vesicular lesions contained higher proportions of T inducer cells. Epidermal infiltrates invariably contained T suppressor/cytotoxic cells but infiltration of epidermis by T inducer cells occurred only in the presence of normal numbers of epidermal Langerhans' cells. Natural killer cells were not identified. The immunological appearances of the various histological subgroups thus change with time after transplantation. Images PMID:6381547

  11. A 16 Month Survey of Cyclosporine Utilization Evaluation in Allogeneic Hematopoietic Stem Cell Transplant Recipients

    PubMed Central

    Tavakoli Ardakani, Maria; Tafazoli, Ali; Mehdizadeh, Mahshid; Hajifathali, Abbas; Dadashzadeh, Simin

    2016-01-01

    Objectives: Graft versus host disease (GVHD) is a life threatening reaction in the stem cell transplantation process. Nowadays Cyclosporine is the most commonly utilized agent for GVHD prophylaxis and it has a major role in successful transplantation. Cyclosporine has been applied for many years in this field but it could be stated that currently no general consensus is available for its optimal method of administration. Conditions related to cyclosporine administration and possible related adverse reactions observed closely in our patients with the aim of constructing a comprehensive practice guideline in the future. Patients and Methods: Allogeneic stem cell transplant recipients who have been taking cyclosporine were monitored during and after their hospitalization while recording all observations on predefined questionnaires on the basis of periodic clinical and laboratory examinations for a 16 month period. Results: Mean recorded duration of infusions was 1.44 ± 0.68 h and by twice daily administration, means intravenous and oral dose was 101.85 ± 22.03 mg and 219.28 ± 63.9 mg, respectively. A mean CsA trough level after about 12 h of specified unique doses was 223 ± 65 ng/mL. We found hypertension, nephrotoxicity, neurotoxicity, hypertension, and dyslipidemia in about 14, 20, 48, and 94 percent of patients. Conclusions: This study proposed that permanent guidance of healthcare team according to a fixed and standard method of cyclosporine administration routine with using efficient facilities and protocols would be helpful considerably for an optimal pharmacotherapy. PMID:27610174

  12. Risk Factors and Utility of a Risk-Based Algorithm for Monitoring Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections in Pediatric Recipients after Allogeneic Hematopoietic Cell Transplantation.

    PubMed

    Rustia, Evelyn; Violago, Leah; Jin, Zhezhen; Foca, Marc D; Kahn, Justine M; Arnold, Staci; Sosna, Jean; Bhatia, Monica; Kung, Andrew L; George, Diane; Garvin, James H; Satwani, Prakash

    2016-09-01

    Infectious complications, particularly viral infections, remain a significant cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT). Only a handful of studies in children have analyzed the risks for and impact of viremia on alloHCT-related outcomes. We conducted a retrospective study of 140 pediatric patients undergoing alloHCT to investigate the incidence of and risk factors for cytomegalovirus (CMV), adenovirus (ADV), and Epstein-Barr virus (EBV) viremia and viral disease after alloHCT. Furthermore, we assessed the impact of viremia on days of hospitalization and develop an algorithm for routine monitoring of viremia. Patients were monitored before alloHCT and then weekly for 180 days after alloHCT. Patients were considered to have viremia if CMV were > 600 copies/mL, EBV were > 1000 copies/mL, or ADV were > 1000 copies/mL on 2 consecutive PCRs. The overall incidences of viremia and viral disease in all patients from day 0 to +180 after alloHCT were 41.4% (n = 58) and 17% (n = 24), respectively. The overall survival for patients with viremia and viral disease was significantly lower compared with those without viremia (58% versus 74.2%, P = .03) and viral disease (48.2% versus 71.2%, P = .024). We identified that pretransplantation CMV risk status, pre-alloHCT viremia, and use of alemtuzumab were associated with the risk of post-alloHCT viremia. The average hospitalization days in patients with CMV risk (P = .011), viremia (P = .024), and viral disease (P = .002) were significantly higher. The algorithm developed from our data can potentially reduce viral PCR testing by 50% and is being studied prospectively at our center. Improved preventative treatment strategies for children at risk of viremia after alloHCT are needed. PMID:27252110

  13. The Biology of Allogeneic Hematopoietic Cell Resistance

    PubMed Central

    Shizuru, Judith A.; Bhattacharya, Deepta; Cavazzana-Calvo, Marina

    2016-01-01

    At the most basic level, success of an allogeneic hematopoietic cell transplantation (HCT) procedure relies upon the engraftment of recipients with donor hematopoietic stem cells (HSCs) that will generate blood formation for the life of that individual. The formula to achieve durable HSC engraftment involves multiple factors including the recipient conditioning regimen, the nature of the genetic disparity between donor and recipient, and the content of the hematopoietic graft. Animal and clinical studies have shown that the biology of host resistance is complex, involving both immune and nonimmune elements. In this article, we review the factors that contribute to host resistance, describe emerging concepts on the basic biology of resistance, and discuss hematopoietic resistance as it relates specifically to patients with severe combined immunodeficiencies (SCID)— disorders that bring unique insights into the dynamics of cell replacement by allogeneic HSCs and progenitor cells. PMID:19913629

  14. A comparison of HLA-identical sibling allogeneic versus autologous transplantation for diffuse large B cell lymphoma: a report from the CIBMTR.

    PubMed

    Lazarus, Hillard M; Zhang, Mei-Jie; Carreras, Jeanette; Hayes-Lattin, Brandon M; Ataergin, Asli Selmin; Bitran, Jacob D; Bolwell, Brian J; Freytes, César O; Gale, Robert Peter; Goldstein, Steven C; Hale, Gregory A; Inwards, David J; Klumpp, Thomas R; Marks, David I; Maziarz, Richard T; McCarthy, Philip L; Pavlovsky, Santiago; Rizzo, J Douglas; Shea, Thomas C; Schouten, Harry C; Slavin, Shimon; Winter, Jane N; van Besien, Koen; Vose, Julie M; Hari, Parameswaran N

    2010-01-01

    We compared outcomes of 916 diffuse large B cell lymphoma (DLBCL) patients aged >or=18 years undergoing first autologous (n = 837) or myeloablative (MA) allogeneic hematopoietic cell transplant (HCT) (n = 79) between 1995 and 2003 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Median follow-up was 81 months for allogeneic HCT versus 60 months for autologous HCT. Allogeneic HCT recipients were more likely to have high-risk disease features including higher stage, more prior chemotherapy regimens, and resistant disease. Allogeneic HCT was associated with a higher 1 year treatment-related mortality (TRM) (relative risk [RR] 4.88, 95% confidence interval [CI], 3.21-7.40, P < .001), treatment failure (RR 2.06, 95% CI, 1.54-2.75, P < .001), and mortality (RR 2.75, 95% CI, 2.03-3.72, P < .001). Risk of disease progression was similar in the 2 groups (RR 1.12, 95% CI, 0.73-1.72, P = .59). In fact, for 1-year survivors, no significant differences were observed for TRM, progression, progression-free (PFS) or overall survival (OS). Increased risks of TRM and mortality were associated with older age (>50 years), lower performance score, chemoresistance, and earlier year of transplant. In a cohort of mainly high-risk DLBCL patients, upfront MA allogeneic HCT, although associated with increased early mortality, was associated with a similar risk of disease progression compared to lower risk patients receiving autologous HCT. PMID:20053330

  15. Fungemia Caused by Zygoascus hellenicus in an Allogeneic Stem Cell Transplant Recipient

    PubMed Central

    Brandt, Mary E.; Kauffman, Carol A.; Pappas, Peter G.; Iqbal, Naureen; Arthington-Skaggs, Beth A.; Lee-Yang, Wendy; Smith, Maudy T.

    2004-01-01

    Zygoascus hellenicus (Candida hellenica) was isolated from a blood culture from a patient who had received an allogeneic stem cell transplant. The isolate displayed an antifungal susceptibility pattern of decreased susceptibility to fluconazole and itraconazole, high susceptibility to voriconazole, and low susceptibility to caspofungin. The organism was misidentified by a commercial yeast identification system. This is the first reported case of human infection with this rare ascomycetous yeast. PMID:15243118

  16. Fungemia caused by Zygoascus hellenicus in an allogeneic stem cell transplant recipient.

    PubMed

    Brandt, Mary E; Kauffman, Carol A; Pappas, Peter G; Iqbal, Naureen; Arthington-Skaggs, Beth A; Lee-Yang, Wendy; Smith, Maudy T

    2004-07-01

    Zygoascus hellenicus (Candida hellenica) was isolated from a blood culture from a patient who had received an allogeneic stem cell transplant. The isolate displayed an antifungal susceptibility pattern of decreased susceptibility to fluconazole and itraconazole, high susceptibility to voriconazole, and low susceptibility to caspofungin. The organism was misidentified by a commercial yeast identification system. This is the first reported case of human infection with this rare ascomycetous yeast. PMID:15243118

  17. No increased mortality from donor or recipient hepatitis B- and/or hepatitis C-positive serostatus after related-donor allogeneic hematopoietic cell transplantation

    PubMed Central

    Tomblyn, M.; Chen, M.; Kukreja, M.; Aljurf, M.D.; Al Mohareb, F.; Bolwell, B.J.; Cahn, J.-Y.; Carabasi, M.H.; Gale, R.P.; Gress, R.E.; Gupta, V.; Hale, G.A.; Ljungman, P.; Maziarz, R.T.; Storek, J.; Wingard, J.R.; Young, J.-A.H.; Horowitz, M.M.; Ballen, K.K.

    2012-01-01

    Limited data exist on allogeneic transplant outcomes in recipients receiving hematopoietic cells from donors with prior or current hepatitis B (HBV) or C (HCV) infection (seropositive donors) or for recipients with prior or current HBV or HCV infection (seropositive recipients). Transplant outcomes are reported for 416 recipients from 121 centers who received a human leukocyte antigen-identical related-donor allogeneic transplant for hematologic malignancies between 1995 and 2003. Of these, 33 seronegative recipients received grafts from seropositive donors and 128 recipients were seropositive. The remaining 256 patients served as controls. With comparable median follow-up (cases, 5.9 years; controls, 6.7 years), the incidence of treatment-related mortality, survival, graft-versus-host disease, and hepatic toxicity appears similar in all cohorts. The frequencies of hepatic toxicities as well as causes of death between cases and controls were similar. Prior exposure to HBV or HCV in either the donor or the recipient should not be considered an absolute contraindication to transplant. PMID:22548788

  18. Absence of P-selectin in Recipients of Allogeneic Bone Marrow Transplantation Ameliorates Experimental Graft-versus-Host-Disease

    PubMed Central

    Lu, Sydney X.; Holland, Amanda M.; Na, Il-Kang; Terwey, Theis H.; Alpdogan, Onder; Bautista, Jhoanne L.; Smith, Odette M.; Suh, David; King, Christopher; Kochman, Adam; Hubbard, Vanessa M.; Rao, Uttam K.; Yim, Nury; Liu, Chen; Laga, Alvaro C.; Murphy, George; Jenq, Robert; Zakrzewski, Johannes L.; Penack, Olaf; Dykstra, Lindsay; Bampoe, Kevin; Perez, Lia; Furie, Bruce; Furie, Barbara; van den Brink, Marcel R.M.

    2013-01-01

    Alloreactive T cells are crucial for graft-versus-host-disease (GVHD) pathophysiology, and modulating their trafficking patterns has been efficacious in ameliorating experimental disease. We report here that P-selectin, a glycoprotein found on resting and inflamed endothelium, is important for donor alloreactive T cells trafficking into GVHD target organs such as the intestines and skin. Compared with wildtype recipients of allogeneic bone marrow transplantation (allo-BMT), P-selectin−/− recipients exhibit decreased GVHD mortality and decreased GVHD of the skin, liver and small bowels. This was associated with diminished infiltration of alloactivated T cells into the Peyer's Patches and small bowels, coupled with increased numbers of donor T cells in the spleen and secondary lymphoid organs (SLO). Surprisingly however, donor T cells deficient for PSGL1, the most well-described P-selectin ligand, mediated similar GVHD as WT T cells, and accumulated in SLO and target organs in similar numbers as WT T cells. This suggests that P-selectin may be required for trafficking into inflamed tissues but not SLO, and that donor T cells may utilize multiple P-selectin ligands apart from PSGL1 to interact with P-selectin and traffic into inflamed tissues during GVHD. We conclude that targeting P-selectin may be a viable target for GVHD prophylaxis or treatment. PMID:20622117

  19. A COMPARISON OF HLA-IDENTICAL SIBLING ALLOGENEIC VERSUS AUTOLOGOUS TRANSPLANTATION FOR DIFFUSE LARGE B-CELL LYMPHOMA: A REPORT FROM THE CIBMTR

    PubMed Central

    Lazarus, Hillard M.; Zhang, Mei-Jie; Carreras, Jeanette; Hayes-Lattin, Brandon M.; Ataergin, Asli Selmin; Bitran, Jacob D.; Bolwell, Brian J.; Freytes, César O.; Gale, Robert Peter; Goldstein, Steven C.; Hale, Gregory A.; Inwards, David J.; Klumpp, Thomas R.; Marks, David I.; Maziarz, Richard T.; McCarthy, Philip L.; Pavlovsky, Santiago; Rizzo, J Douglas; Shea, Thomas C.; Schouten, Harry C.; Slavin, Shimon; Winter, Jane N.; van Besien, Koen; Vose, Julie M.; Hari, Parameswaran N.

    2010-01-01

    We compared outcomes of 916 diffuse large B cell lymphoma (DLBCL) patients age ≥ 18 years undergoing first autologous (n=837) or myeloablative allogeneic hematopoietic cell transplant (HCT) (n=79) between 1995–2003 reported to the CIBMTR. Median follow-up was 81 months for allogeneic HCT vs. 60 months for autologous. Allogeneic HCT recipients were more likely to have high risk disease features including higher stage, more prior chemotherapy regimens and resistant disease. Allogeneic HCT was associated with a higher 1 year treatment-related mortality (TRM) (RR 4.88, 95% CI, 3.21–7.40, p<0.001), treatment failure (RR 2.06, 95% CI, 1.54–2.75, p<0.001) and mortality (RR 2.75, 95% CI, 2.03–3.72, p<0.001). Risk of disease progression was similar in the 2 groups (RR 1.12, 95% CI, 0.73–1.72, p=0.59). In fact, for 1 year survivors, no significant differences were observed for TRM, progression, progression-free or overall survival. Increased risks of TRM and mortality were associated with older age (>50 years), lower performance score, chemoresistance and earlier year of transplant. In a cohort of mainly high risk DLBCL patients, upfront myeloablative allogeneic HCT while associated with increased early mortality was associated with a similar risk of disease progression compared to lower risk patients receiving autologous HCT. PMID:20053330

  20. Survival in a recent cohort of mechanically ventilated pediatric allogeneic hematopoietic stem cell transplantation recipients.

    PubMed

    van Gestel, Josephus P J; Bollen, Casper W; Bierings, Marc B; Boelens, Jaap Jan; Wulffraat, Nico M; van Vught, Adrianus J

    2008-12-01

    There is ongoing discussion whether survival improved for children requiring mechanical ventilation after hematopoietic stem cell transplantation (HSCT). We reviewed the outcomes of 150 children who received an allogeneic HSCT between January 1999 and April 2007, in a pediatric university hospital in The Netherlands. Thirty-five of the 150 patients received mechanical ventilation on 38 occasions. None of the recorded risk factors was significantly associated with the requirement of mechanical ventilation. Sixteen admissions resulted in death in the intensive care unit (ICU), giving a case fatality rate of 42% (95% confidence interval 26%-58%). ICU mortality was associated with multiorgan failure on the second day of admission and with the use of high frequency oscillatory ventilation. Patients had higher pediatric risk of mortality scores than in previous studies, reflecting higher acuity of illness on admission to the ICU. Six-month survival in patients discharged from the ICU was 82%. Compared to previous studies, we found an improvement in ICU survival and survival 6 months after ICU discharge in a recent cohort of ventilated children after allogeneic HSCT, even though our patients were more severely ill. Our results are promising, but they need to be confirmed in larger, preferably multicenter, studies. PMID:19041061

  1. Predictors of invasive fungal infection in pediatric allogeneic hematopoietic SCT recipients.

    PubMed

    Hol, J A; Wolfs, T F W; Bierings, M B; Lindemans, C A; Versluys, A B J; Wildt de, A; Gerhardt, C E; Boelens, J J

    2014-01-01

    This study was aimed at finding predictors of invasive fungal infection (IFI) after pediatric allogeneic hematopoietic SCT (HSCT). All children who received allogeneic HSCT in the Wilhelmina Children's Hospital Utrecht between 2004 and 2012 were included. HSCT data were prospectively collected. Patients were retrospectively classified into high- or low-risk groups for developing IFI using criteria based on available literature. Predictors for the occurrence of IFI were analyzed using Cox regression models. We used logistic regression models to analyze the association between other HSCT-related complications and IFI. Secondary outcomes were overall survival and treatment-related mortality (TRM). Two-hundred nine patients were included in the analysis; median age was 6.6 years. The cumulative incidence of IFI was 12%. In patients classified as 'low risk' (n=75), only 5.3% developed IFI (odds ratio (OR): 0.325; P=0.047). In multivariate analysis, a predictor for the occurrence of IFI was an a priori determined HSCT TRM risk >20% (based on EBMT-risk score). Post-HSCT, the administration of high-dose steroids was associated with IFI (OR: 4.458; P=0.010). Patients who developed IFI showed an increased risk of TRM (OR: 3.773; P=0.004). These results confirm that risk group stratification should guide intensity of monitoring for IFI and use of antifungal prophylaxis. PMID:24121212

  2. Rhodococcus equi pneumonia and sepsis in an allogeneic haematopoietic stem cell transplant recipient

    PubMed Central

    Shahani, Lokesh

    2014-01-01

    Rhodococcus equi is an aerobic facultative intracellular organism that is known to infect cells of the macrophage–monocyte lineage. It is a common veterinary pathogen; however, the incidence of this infection in humans has risen and it has been recognised as an emerging opportunistic pathogen among the immunocompromised patients. We present the case of a patient with chronic myeloid leukaemia who had received allogenic stem cell transplant and presented to the hospital with clinical picture of pneumonia. Her condition worsened on initial broad spectrum antimicrobials and 3 weeks into her hospitalisation, R. equi was isolated from her broncheoalveolar lavage and blood cultures. Based on the susceptibility, therapy was changed to four active antimicrobials; however, the patient failed to improve and eventually died. This case highlights the importance of considering the diagnosis of R. equi among immunosuppressed patients early in the right clinical setting due to the high virulence associated with this organism. PMID:24943142

  3. WU and KI Polyomaviruses in Respiratory Samples from Allogeneic Hematopoietic Cell Transplant Recipients

    PubMed Central

    Campbell, Angela P.; Guthrie, Katherine A.; Wright, Nancy L.; Englund, Janet A.; Corey, Lawrence; Boeckh, Michael

    2012-01-01

    Data are limited regarding 2 new human polyomaviruses, KI polyomavirus (KIPyV) and WU polyomavirus (WUPyV), in immunocompromised patients. We used real-time PCR to test for these and 12 respiratory viruses in 2,732 nasal wash samples collected during the first year after allogeneic hematopoietic cell transplantation from 222 patients. Specimens were collected weekly until day 100; then at least every 3 months. One year after hematopoietic cell transplantation, the cumulative incidence estimate was 26% for KIPyV and 8% for WUPyV. Age <20 years predicted detection of KIPyV (hazard ratio [HR] 4.6) and WUPyV (HR 4.4), and detection of a respiratory virus in the previous 2 weeks predicted KIPyV detection (HR 3.4). Sputum production and wheezing were associated with detection of KIPyV in the past week and WUPyV in the past month. There were no associations with polyomavirus detection and acute graft versus host disease, cytomegalovirus reactivation, neutropenia, lymphopenia, hospitalization, or death. PMID:23017213

  4. Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients.

    PubMed

    Yew, P Y; Alachkar, H; Yamaguchi, R; Kiyotani, K; Fang, H; Yap, K L; Liu, H T; Wickrema, A; Artz, A; van Besien, K; Imoto, S; Miyano, S; Bishop, M R; Stock, W; Nakamura, Y

    2015-09-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is one of curative treatment options for patients with hematologic malignancies. Although GVHD mediated by the donor's T lymphocytes remains the most challenging toxicity of allo-HSCT, graft-versus-leukemia (GVL) effect targeting leukemic cells, has an important role in affecting the overall outcome of patients with AML. Here we comprehensively characterized the TCR repertoire in patients who underwent matched donor or haplo-cord HSCT using next-generation sequencing approach. Our study defines the functional kinetics of each TCRA and TCRB clone, and changes in T-cell diversity (with identification of CDR3 sequences) and the extent of clonal expansion of certain T-cells. Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery. Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones. Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation. PMID:26052909

  5. Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients

    PubMed Central

    Yew, P Y; Alachkar, H; Yamaguchi, R; Kiyotani, K; Fang, H; Yap, K L; Liu, H T; Wickrema, A; Artz, A; van Besien, K; Imoto, S; Miyano, S; Bishop, M R; Stock, W; Nakamura, Y

    2015-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is one of curative treatment options for patients with hematologic malignancies. Although GVHD mediated by the donor's T lymphocytes remains the most challenging toxicity of allo-HSCT, graft-versus-leukemia (GVL) effect targeting leukemic cells, has an important role in affecting the overall outcome of patients with AML. Here we comprehensively characterized the TCR repertoire in patients who underwent matched donor or haplo-cord HSCT using next-generation sequencing approach. Our study defines the functional kinetics of each TCRA and TCRB clone, and changes in T-cell diversity (with identification of CDR3 sequences) and the extent of clonal expansion of certain T-cells. Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery. Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones. Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation. PMID:26052909

  6. Induction of Cytomegalovirus-Specific T Cell Responses in Healthy Volunteers and Allogeneic Stem Cell Recipients Using Vaccination With Messenger RNA–Transfected Dendritic Cells

    PubMed Central

    Van Craenenbroeck, Amaryllis H.; Smits, Evelien L.J.; Anguille, Sébastien; Van de Velde, Ann; Stein, Barbara; Braeckman, Tessa; Van Camp, Kirsten; Nijs, Griet; Ieven, Margareta; Goossens, Herman; Berneman, Zwi N.; Van Tendeloo, Viggo F.I.; Verpooten, Gert A.; Van Damme, Pierre; Cools, Nathalie

    2015-01-01

    Background Infection with human cytomegalovirus (CMV) is a significant cause of morbidity and mortality in solid organ and hematopoietic stem cell transplant (HSCT) recipients. Methods The present study explored the safety, feasibility, and immunogenicity of CMV pp65 messenger RNA–loaded autologous monocyte-derived dendritic cells (DC) as a cellular vaccine for active immunization in healthy volunteers and allogeneic HSCT recipients. Four CMV-seronegative healthy volunteers and three allogeneic HSCT recipients were included in the study. Four clinical-grade autologous monocyte-derived DC vaccines were prepared after a single leukapheresis procedure and administered intradermally at a weekly interval. Results De novo induction of CMV-specific T-cell responses was detected in three of four healthy volunteers without serious adverse events. Of the HSCT recipients, none developed CMV disease and one of two patients displayed a remarkable threefold increase in CMV pp65-specific T cells on completion of the DC vaccination trial. Conclusion In conclusion, our DC vaccination strategy induced or expanded a CMV-specific cellular response in four of six efficacy-evaluable study subjects, providing a base for its further exploration in larger cohorts. PMID:25050468

  7. Analysis of incidence, risk factors and clinical outcome of thromboembolic and bleeding events in 431 allogeneic hematopoietic stem cell transplantation recipients

    PubMed Central

    Labrador, Jorge; Lopez-Anglada, Lucia; Perez-Lopez, Estefania; Lozano, Francisco S.; Lopez-Corral, Lucia; Sanchez-Guijo, Fermin M.; Vazquez, Lourdes; Perez Rivera, Jose Angel; Martin-Herrero, Francisco; Sanchez-Barba, Mercedes; Guerrero, Carmen; del Cañizo, Maria Consuelo; Caballero, Maria Dolores; San Miguel, Jesus Fernando; Alberca, Ignacio; Gonzalez-Porras, Jose Ramon

    2013-01-01

    Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III-IV graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P<0.001). In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival. PMID:22899581

  8. Donor and Recipient CMV Serostatus and Outcome of Pediatric Allogeneic HSCT for Acute Leukemia in the Era of CMV-Preemptive Therapy

    PubMed Central

    Behrendt, Carolyn E.; Rosenthal, Joseph; Bolotin, Ellen; Nakamura, Ryotaro; Zaia, John; Forman, Stephen J.

    2009-01-01

    In the era of cytomegalovirus(CMV)-preemptive therapy, it is unclear whether CMV serostatus of donor or recipient affects outcome of allogeneic hematopoietic stem cell transplantation (HSCT) among children with leukemia. To investigate, consecutive patients age 0–8 who underwent primary HSCT for acute leukemia in 1997–007 (HLA-matched sibling or unrelated donor, myeloablative conditioning, unmanipulated bone marrow or peripheral blood, preemptive therapy, no CMV prophylaxis) were followed retrospectively through January 2008. Treatment failure (relapse or death) was analyzed using survival-based proportional hazards regression. Competing risks (relapse and non-relapse mortality, NRM) were analyzed using generalized linear models of cumulative incidence-based proportional hazards. Excluding 4 (2.8%) patients lacking serostatus of donor or recipient, there were 140 subjects, of whom 50 relapsed and 24 died in remission. Pretransplant CMV seroprevalence was 55.7% in recipients, 57.1% in donors. Thirty-five (25.0%) grafts were from seronegative donor to seronegative recipient (D−/R−). On univariate analysis, D−/R− grafts were associated with shorter relapse-free survival (RFS) than other grafts (median 1.06 versus 3.15 years, p<0.05). Adjusted for donor type, diagnosis, disease stage, recipient and donor age, female-to-male graft, graft source, and year, D−/R− graft was associated with relapse (hazards ratio 3.15, 95% confidence interval 1.46–6.76) and treatment failure (2.45, 1.46–4.12) but not significantly with NRM (2.00, 0.44–9.09). In the current era, children who undergo allogeneic HSCT for acute leukemia have reduced risk of relapse and superior RFS when recipient and/or donor is CMV-seropositive before transplantation. However, no net improvement in RFS would be gained from substituting seropositive unrelated for seronegative sibling donors. PMID:19135943

  9. Late Mortality and Causes of Death among Long-Term Survivors after Allogeneic Stem Cell Transplantation.

    PubMed

    Atsuta, Yoshiko; Hirakawa, Akihiro; Nakasone, Hideki; Kurosawa, Saiko; Oshima, Kumi; Sakai, Rika; Ohashi, Kazuteru; Takahashi, Satoshi; Mori, Takehiko; Ozawa, Yukiyasu; Fukuda, Takahiro; Kanamori, Heiwa; Morishima, Yasuo; Kato, Koji; Yabe, Hiromasa; Sakamaki, Hisashi; Taniguchi, Shuichi; Yamashita, Takuya

    2016-09-01

    We sought to assess the late mortality risks and causes of death among long-term survivors of allogeneic hematopoietic stem cell transplantation (HCT). The cases of 11,047 relapse-free survivors of a first HCT at least 2 years after HCT were analyzed. Standardized mortality ratios (SMR) were calculated and specific causes of death were compared with those of the Japanese population. Among relapse-free survivors at 2 years, overall survival percentages at 10 and 15 years were 87% and 83%, respectively. The overall risk of mortality was significantly higher compared with that of the general population. The risk of mortality was significantly higher from infection (SMR = 57.0), new hematologic malignancies (SMR = 2.2), other new malignancies (SMR = 3.0), respiratory causes (SMR = 109.3), gastrointestinal causes (SMR = 3.8), liver dysfunction (SMR = 6.1), genitourinary dysfunction (SMR = 17.6), and external or accidental causes (SMR = 2.3). The overall annual mortality rate showed a steep decrease from 2 to 5 years after HCT; however, the decrease rate slowed after 10 years but was still higher than that of the general population at 20 years after HCT. SMRs in the earlier period of 2 to 4 years after HCT and 5 years or longer after HCT were 16.1 and 7.4, respectively. Long-term survivors after allogeneic HCT are at higher risk of mortality from various causes other than the underlying disease that led to HCT. Screening and preventive measures should be given a central role in reducing the morbidity and mortality of HCT recipients on long-term follow-up. PMID:27246369

  10. Alterations in Memory and Impact on Academic Outcomes in Children Following Allogeneic Hematopoietic Cell Transplantation.

    PubMed

    Lajiness-O'Neill, R; Hoodin, F; Kentor, R; Heinrich, K; Colbert, A; Connelly, J A

    2015-11-01

    The prevalence of late effects following allogeneic hematopoietic cell transplantation (HCT), a curative treatment for pediatric leukemia, is high: 79% of HCT recipients experience chronic medical conditions. The few extant studies of cognitive late effects have focused on intelligence and are equivocal about HCT neurotoxicity. In an archival study of 30 children (mean transplant age = 6 years), we characterize neuropsychological predictors of academic outcomes. Mean intellectual and academic abilities were average, but evidenced extreme variability, particularly on measures of attention and memory: ∼25% of the sample exhibited borderline performance or lower. Medical predictors of outcome revealed paradoxically better memory associated with more severe acute graft-versus-host disease (GVHD) and associated with steroid treatment. Processing speed and memory accounted for 69% and 61% of variance in mathematics and reading outcomes, respectively. Thus, our findings revealed neurocognitive areas of vulnerability in processing speed and memory following HCT that contribute to subsequent academic difficulties. PMID:26319492

  11. Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis.

    PubMed

    Abdul Wahid, S Fadilah; Ismail, Nor-Azimah; Mohd-Idris, Mohd-Razif; Jamaluddin, Fariza Wan; Tumian, NorRafeah; Sze-Wei, Ernie Yap; Muhammad, Norasiah; Nai, Ming Lai

    2014-11-01

    Currently, the indications to perform reduced-intensity conditioning allogeneic hematopoietic stem cell transplant (RIC-HCT) are based on data derived mainly from large registry and single-centre retrospective studies. Thus, at the present time, there is limited direct evidence supporting the current practice in selecting patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) for RIC versus myeloablative conditioning (MAC) transplants. To determine the relationship between dose intensity of conditioning regimen and survival outcomes after allografting in AML/ALL patients, we performed a meta-analysis of 23 clinical trials reported between 1990 and 2013 involving 15,258 adult patients that compare survival outcomes after RIC-HCT versus MAC-HCT. RIC-HCT resulted in comparable <2-year and 2-6 year overall survival (OS) rates post-transplantation even though the RIC-HCT recipients were older and had more active disease than MAC-HCT recipients. The 2-6 year progression-free survival (PFS), nonrelapse mortality, acute graft-versus-host disease (GvHD) and chronic GvHD rates were reduced after RIC-HCT, but relapse rate was increased. Similar outcomes were observed regardless of disease type and status at transplantation. Odds ratio for all outcomes remained comparable with or without performing separate analyses for the year of HCT and for retrospective versus prospective studies. Among RIC-HCT recipients, survival rates were superior if patients were in CR at transplantation. Significant inter-study heterogeneity for aGvHD data and publication bias for PFS data were observed. This meta-analysis showed no OS benefit of MAC-HCT over RIC-HCT across the entire cohort of patients suggesting that RIC-HCT could be an effective therapeutic option for AML/ALL patients who are ineligible for MAC-HCT and CR status is preferred before RIC-HCT. PMID:25072307

  12. Comparison of Reduced-Intensity and Myeloablative Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia: A Meta-Analysis

    PubMed Central

    Ismail, Nor-Azimah; Mohd-Idris, Mohd-Razif; Jamaluddin, Fariza Wan; Tumian, NorRafeah; Sze-Wei, Ernie Yap; Muhammad, Norasiah; Nai, Ming Lai

    2014-01-01

    Currently, the indications to perform reduced-intensity conditioning allogeneic hematopoietic stem cell transplant (RIC-HCT) are based on data derived mainly from large registry and single-centre retrospective studies. Thus, at the present time, there is limited direct evidence supporting the current practice in selecting patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) for RIC versus myeloablative conditioning (MAC) transplants. To determine the relationship between dose intensity of conditioning regimen and survival outcomes after allografting in AML/ALL patients, we performed a meta-analysis of 23 clinical trials reported between 1990 and 2013 involving 15,258 adult patients that compare survival outcomes after RIC-HCT versus MAC-HCT. RIC-HCT resulted in comparable <2-year and 2–6 year overall survival (OS) rates post-transplantation even though the RIC-HCT recipients were older and had more active disease than MAC-HCT recipients. The 2–6 year progression-free survival (PFS), nonrelapse mortality, acute graft-versus-host disease (GvHD) and chronic GvHD rates were reduced after RIC-HCT, but relapse rate was increased. Similar outcomes were observed regardless of disease type and status at transplantation. Odds ratio for all outcomes remained comparable with or without performing separate analyses for the year of HCT and for retrospective versus prospective studies. Among RIC-HCT recipients, survival rates were superior if patients were in CR at transplantation. Significant inter-study heterogeneity for aGvHD data and publication bias for PFS data were observed. This meta-analysis showed no OS benefit of MAC-HCT over RIC-HCT across the entire cohort of patients suggesting that RIC-HCT could be an effective therapeutic option for AML/ALL patients who are ineligible for MAC-HCT and CR status is preferred before RIC-HCT. PMID:25072307

  13. Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma.

    PubMed

    Klyuchnikov, E; Bacher, U; Woo Ahn, K; Carreras, J; Kröger, N M; Hari, P N; Ku, G H; Ayala, E; Chen, A I; Chen, Y-B; Cohen, J B; Freytes, C O; Gale, R P; Kamble, R T; Kharfan-Dabaja, M A; Lazarus, H M; Martino, R; Mussetti, A; Savani, B N; Schouten, H C; Usmani, S Z; Wiernik, P H; Wirk, B; Smith, S M; Sureda, A; Hamadani, M

    2016-01-01

    Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors. PMID:26437062

  14. Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma

    PubMed Central

    Klyuchnikov, Evgeny; Bacher, Ulrike; Ahn, Kwang Woo; Carreras, Jeanette; Kröger, Nicolaus M.; Hari, Parameswaran N.; Ku, Grace H.; Ayala, Ernesto; Chen, Andy I.; Chen, Yi-Bin; Cohen, Jonathon B.; Freytes, César O.; Gale, Robert Peter; Kamble, Rammurti T.; Kharfan-Dabaja, Mohamed A.; Lazarus, Hillard M.; Martino, Rodrigo; Mussetti, Alberto; Savani, Bipin N.; Schouten, Harry C.; Usmani, Saad Z.; Wiernik, Peter H.; Wirk, Baldeep; Smith, Sonali M.; Sureda, Anna; Hamadani, Mehdi

    2015-01-01

    Grade-3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade-3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs. autologous hematopoietic cell transplantation (auto-HCT) in the rituximab-era. A total of 197 patients undergoing first RIC allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naïve patients were excluded. Allo-HCT recipients were younger; more heavily pretreated, and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, progression-free survival (PFS) and overall survival (OS) for auto-HCT vs. allo-HCT groups were 4% vs. 27% (p<0.001); 61% vs. 20% (p<0.001); 36% vs. 51% (p=0.07) and 59% vs. 54% (p=0.7), respectively. On multivariate analysis auto-HCT was associated with reduced risk of NRM (RR=0.20; p=0.001). Within the first 11months post-HCT auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; p=0.003) and inferior PFS (RR=3.2; p=0.005). In the first 24 months post-HCT, auto-HCT was associated with improved OS (RR=0.42; p=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; p=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors. PMID:26437062

  15. Relapse and Late Mortality in 5-Year Survivors of Myeloablative Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase

    PubMed Central

    Goldman, John M.; Majhail, Navneet S.; Klein, John P.; Wang, Zhiwei; Sobocinski, Kathleen A.; Arora, Mukta; Horowitz, Mary M.; Rizzo, J. Douglas

    2010-01-01

    Purpose Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes are not well described. We studied the long-term outcomes of CML patients in first chronic phase who receive an allogeneic HCT. Patients and Methods Our study included 2,444 patients who received myeloablative HCT for CML in first chronic phase between 1978 and 1998 and survived in continuous complete remission for at least 5 years (median follow-up, 11 years; range, 5 to 25 years). Donor sources were human leukocyte antigen–matched siblings in 1,692 patients, unrelated donors in 639 patients, and other related donors in 113 patients. Results Overall survival rates at 15 years were 88% (95% CI, 86% to 90%) for sibling HCT and 87% (95% CI, 83% to 90%) for unrelated donor HCT. Corresponding cumulative incidences of relapse were 8% (95% CI, 7% to 10%) and 2% (95% CI, 1% to 4%), respectively. The latest relapse was reported 18 years post-HCT. In multivariable analyses, history of chronic graft-versus-host disease increased risks of late overall mortality and nonrelapse mortality but reduced risks of relapse. In comparison with age-, race-, and sex-adjusted normal populations, the mortality of HCT recipients was significantly higher until 14 years post-HCT; thereafter, mortality rates were similar to those of the general population (relative mortality ratio at 15 years, 2.3; 95% CI, 0 to 4.9). Conclusion Recipients of allogeneic HCT for CML in first chronic phase who remain in remission for at least 5 years have favorable subsequent long-term survival, and their mortality rates eventually approach those of the general population. PMID:20212247

  16. Autologous is Superior to Allogeneic Hematopoietic Cell Transplantation for Acute Promyelocytic Leukemia in Second Complete Remission

    PubMed Central

    Chakrabarty, Jennifer L. Holter; Rubinger, Morel; Le-Rademacher, Jennifer; Wang, Hai-Lin; Grigg, Andrew; Selby, George B.; Szer, Jeffrey; Rowe, Jacob M.; Weisdorf, Daniel J.; Tallman, Martin S.

    2014-01-01

    PURPOSE To identify favored choice of transplantation in patients with acute promyelocytic leukemia in second complete remission. PATIENTS We studied 294 acute promyelocytic leukemia (APL) patients receiving allogeneic (n=232) or autologous (62) hematopoietic cell transplantation (HCT) in second complete remission (CR2) reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR) from 1995 to 2006 including pre-HCT PML/RAR∝ status in 155 (49% of allogeneic and 66% of autologous). METHODS Patient characteristics and transplant characteristics including treatment related mortality, overall survival, and disease free survival were collected and analyzed for both univariate and multivariate outcomes. RESULTS With median follow-up of 115 (allogeneic) and 72 months (autologous), 5-year disease-free survival (DFS) favored autologous 63% (49-75%) compared to allogeneic 50% (44-57%) (p=0.10) and overall survival (OS) 75% (63-85%) vs. 54% (48-61%) (p=.002) Multivariate analysis showed significantly worse DFS after allogeneic HCT (HR=1.88, 95% CI=1.16-3.06, p=0.011) and age >40 years (HR=2.30, 95% CI 1.44-3.67, p=0.0005). OS was significantly worse after allogeneic HCT (HR=2.66, 95%CI 1.52-4.65, p=0.0006; age >40 (HR=3.29, 95% CI 1.95-5.54, p<0.001) and CR1<12 months (HR=1.56 95% CI 1.07-2.26, p=0.021). Positive pre-HCT PML-RAR∝ status in 17/114 allogeneic and 6/41 autologous transplants did not influence relapse, treatment failure or survival in either group. The survival advantage for autografting was attributable to increased 3 years TRM: allogeneic 30%; autologous 2%, and GVHD. CONCLUSION We conclude that autologous HCT yields superior overall survival for APL in CR2. Long term DFS in autologous recipients, even with MRD+ grafts remains an important subject for further study. PMID:24691221

  17. High prevalence of potential drug interactions affecting mycophenolic acid pharmacokinetics in nonmyeloablative hematopoietic stem cell transplant recipients

    PubMed Central

    Jaklič, Alenka; Collins, Carol J.; Mrhar, Aleš; Sorror, Mohamed L.; Sandmaier, Brenda M.; Bemer, Meagan J.; Locatelli, Igor; McCune, Jeannine S.

    2013-01-01

    Objective: Mycophenolic acid (MPA) exposure is associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients. Various drug interaction studies, predominantly in healthy volunteers or solid organ transplant recipients, have identified medications which impact MPA pharmacokinetics. Recipients of nonmyeloablative HCT, however, have an increased burden of comorbidities, potentially increasing the number of concomitant medications and potential drug interactions (PDI) affecting MPA exposure. Thus, we sought to be the first to characterize these PDI in nonmyeloablative HCT recipients. Materials and methods: We compiled PDI affecting MPA pharmacokinetics and characterized the prevalence of PDI in nonmyeloablative HCT recipients. A comprehensive literature evaluation of four databases and PubMed was conducted to identify medications with PDI affecting MPA pharmacokinetics. Subsequently, a retrospective medication review was conducted to characterize the cumulative PDI burden, defined as the number of PDI for an individual patient over the first 21 days after allogeneic graft infusion, in 84 nonmyeloablative HCT recipients. Results: Of the 187 concomitant medications, 11 (5.9%) had a PDI affecting MPA pharmacokinetics. 87% of 84 patients had one PDI, with a median cumulative PDI burden of 2 (range 0 – 4). The most common PDI, in descending order, were cyclosporine, omeprazole and pantoprazole. Conclusion: Only a minority of medications (5.9%) have a PDI affecting MPA pharmacokinetics. However, the majority of nonmyeloablative HCT recipients had a PDI, with cyclosporine and the proton pump inhibitors being the most common. A better understanding of PDI and their management should lead to safer medication regimens for nonmyeloablative HCT recipients. PMID:23782584

  18. CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT.

    PubMed

    Cichocki, F; Cooley, S; Davis, Z; DeFor, T E; Schlums, H; Zhang, B; Brunstein, C G; Blazar, B R; Wagner, J; Diamond, D J; Verneris, M R; Bryceson, Y T; Weisdorf, D J; Miller, J S

    2016-02-01

    We have recently described a specialized subset of human natural killer (NK) cells with a CD56(dim)CD57(+)NKG2C(+) phenotype that expand specifically in response to cytomegalovirus (CMV) reactivation in hematopoietic cell transplant (HCT) recipients and exhibit properties characteristic of adaptive immunity. We hypothesize that these cells mediate relapse protection and improve post-HCT outcomes. In 674 allogeneic HCT recipients, we found that those who reactivated CMV had lower leukemia relapse (26% (17-35%), P=0.05) and superior disease-free survival (DFS) (55% (45-65%) P=0.04) 1 year after reduced intensity conditioning (RIC) compared with CMV seronegative recipients who experienced higher relapse rates (35% (27-43%)) and lower DFS (46% (38-54%)). This protective effect was independent of age and graft-vs-host disease and was not observed in recipients who received myeloablative regimens. Analysis of the reconstituting NK cells demonstrated that CMV reactivation is associated with both higher frequencies and greater absolute numbers of CD56(dim)CD57(+)NKG2C(+) NK cells, particularly after RIC HCT. Furthermore, expansion of these cells at 6 months posttransplant independently trended toward a lower 2-year relapse risk. Together, our data suggest that the protective effect of CMV reactivation on posttransplant relapse is in part driven by adaptive NK cell responses. PMID:26416461

  19. CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT

    PubMed Central

    Cichocki, Frank; Cooley, Sarah; Davis, Zachary; DeFor, Todd E.; Schlums, Heinrich; Zhang, Bin; Brunstein, Claudio G.; Blazar, Bruce R.; Wagner, John; Diamond, Don J.; Verneris, Michael R.; Bryceson, Yenan T.; Weisdorf, Daniel J.; Miller, Jeffrey S.

    2015-01-01

    We have recently described a specialized subset of human natural killer (NK) cells with a CD56dimCD57+NKG2C+ phenotype that expand specifically in response to cytomegalovirus (CMV) reactivation in hematopoietic cell transplant (HCT) recipients and exhibit properties characteristic of adaptive immunity. We hypothesize that these cells mediate relapse protection and improve post-HCT outcomes. In 674 allogeneic HCT recipients, we found that those who reactivated CMV had lower leukemia relapse (26% [17–35%], p=0.05) and superior disease-free survival (DFS) (55% [45–65%] p=0.04) 1 year after reduced intensity conditioning (RIC) compared to CMV seronegative recipients who experienced higher relapse rates (35% [27–43%]) and lower DFS (46% [38–54%]). This protective effect was independent of age and graft-versus-host disease (GvHD) and was not observed in recipients who received myeloablative (MA) regimens. Analysis of the reconstituting NK cells demonstrated that CMV reactivation is associated with both higher frequencies and greater absolute numbers of CD56dimCD57+NKG2C+ NK cells, particularly after RIC HCT. Furthermore, expansion of these cells at 6 months post-transplant independently trended toward a lower 2-year relapse risk. Together, our data suggest that the protective effect of CMV reactivation on post-transplant relapse is in part driven by adaptive NK cell responses. PMID:26416461

  20. Tolerance Associated Gene Expression following Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Pidala, Joseph; Bloom, Gregory C.; Eschrich, Steven; Sarwal, Minnie; Enkemann, Steve; Betts, Brian C.; Beato, Francisca; Yoder, Sean; Anasetti, Claudio

    2015-01-01

    Biologic markers of immune tolerance may facilitate tailoring of immune suppression duration after allogeneic hematopoietic cell transplantation (HCT). In a cross-sectional study, peripheral blood samples were obtained from tolerant (n = 15, median 38.5 months post-HCT) and non-tolerant (n = 17, median 39.5 post-HCT) HCT recipients and healthy control subjects (n = 10) for analysis of immune cell subsets and differential gene expression. There were no significant differences in immune subsets across groups. We identified 281 probe sets unique to the tolerant (TOL) group and 122 for non-tolerant (non-TOL). These were enriched for process networks including NK cell cytotoxicity, antigen presentation, lymphocyte proliferation, and cell cycle and apoptosis. Differential gene expression was enriched for CD56, CD66, and CD14 human lineage-specific gene expression. Differential expression of 20 probe sets between groups was sufficient to develop a classifier with > 90% accuracy, correctly classifying 14/15 TOL cases and 15/17 non-TOL cases. These data suggest that differential gene expression can be utilized to accurately classify tolerant patients following HCT. Prospective investigation of immune tolerance biologic markers is warranted. PMID:25774806

  1. Can a Female Donor for a Male Recipient Decrease Relapse Rate for Patients with AML Treated with Allogeneic Hematopoietic Stem Cell Transplantation?

    PubMed Central

    Kongtim, Piyanuch; Di Stasi, Antonio; Rondon, Gabriela; Chen, Julianne; Adekola, Kehinde; Popat, Uday; Oran, Betul; Kebriaei, Partow; Andersson, Borje S.; Champlin, Richard E.; Ciurea, Stefan O.

    2015-01-01

    The mismatched minor histocompatibility antigens present on Y chromosome (H-Y) in male recipients receiving stem cells from female donors may contribute to graft-versus-leukemia effect (GVL) and results in reduce relapse rate especially in patients with high-risk disease. We retrospectively compared the outcomes of male AML patients who received an allogeneic hematopoietic stem cell transplant (HSCT) from female donors (F-M) (174 patients) versus other gender combinations (667 patients). Median age was 50 years (range 18–74 years). For the whole group, the one-year cumulative incidence of relapse was significantly lower in F-M group (34.1% versus 41.3%, p=0.044) while non-relapse mortality (NRM) was higher (23.2% versus 15.7%, p=0.004). For patients younger than 50 years beyond first complete remission, the F-M group was associated with lower relapse rate (42.5% versus 55.2%, p=0.045) whereas NRM was not significantly different (35.8% versus 25.5%, p=0.141). Although survival was not significantly improved, transplantation from a female donor for male recipient was associated with a lower relapse rate. When relapse is most common concern for treatment failure, especially for younger patients, a female donor for a male recipient might be beneficial to decrease relapse rate post-transplant. Future studies are needed to explore how H-Y mismatch may improve survival post-transplant. PMID:25540936

  2. Estimating Demand and Unmet Need for Allogeneic Hematopoietic Cell Transplantation in the United States Using Geographic Information Systems

    PubMed Central

    Besse, Kelsey L.; Preussler, Jaime M.; Murphy, Elizabeth A.; Denzen, Ellen M.; Lill, Michael C.; Chell, Jeffrey W.; Senneka, Mary K.; Majhail, Navneet S.; Williams, Eric P.

    2015-01-01

    Purpose: Allogeneic hematopoietic cell transplantation (HCT) is an increasingly used therapy for many patients with hematologic malignancies and other marrow failure or immune system disorders. The purpose of this study was to quantify and visualize both the demand and unmet need for HCT. Methods: HCT use for 2012 was described using the Center for International Blood and Marrow Transplant Research registry. Potential demand for HCT was calculated using 2012 SEER data and published literature for HCT-treatable conditions. Point locations of transplant centers were geocoded using geographic information system (GIS) software; Thiessen polygons were created to establish adult (age 20 to 74 years) and pediatric (age 0 to 19 years) market areas. Market-area population estimates were calculated using 2012 population estimates by age aggregated by census block. Results: US market areas for HCTs were identified separately for transplant centers treating adult (n = 62) and pediatric patients (n = 52). Overall HCT demand among adults was 16,096, with an unmet need for HCTs of 10,276 patients. For pediatric patients, the total demand was 4,561, with an unmet need of 3,213 potential recipients. Evaluation of adult and pediatric market areas indicated that the largest unmet needs tended to be in areas with large populations. Conclusion: Market-area maps and statistics developed using GIS will help communicate the unmet need for HCT, inform policy, and assist transplant centers in planning for the anticipated growth in HCT use. PMID:25784576

  3. Effect of Posaconazole on Cyclosporine Blood Levels and Dose Adjustment in Allogeneic Blood and Marrow Transplant Recipients

    PubMed Central

    Sánchez-Ortega, Isabel; Vázquez, Lourdes; Montes, Carmen; Patiño, Beatriz; Arnan, Montserrat; Bermúdez, Arancha; Yáñez, Lucrecia; Caballero, Teresa

    2012-01-01

    The posaconazole prescribing information recommends an upfront cyclosporine dose reduction upon initiation of posaconazole prophylaxis. We examined this recommendation in the early phase of allogeneic transplantation, where cyclosporine levels potentially becoming subtherapeutic following upfront dose reduction would be deleterious to transplant outcome. Our data show that while posaconazole leads to an increase in cyclosporine levels, subsequent cyclosporine dose reduction can be safely guided by therapeutic drug monitoring and is not required upfront. Therefore, the current recommendation may be modified. PMID:23027192

  4. Allogeneic hematopoietic cell transplantation for mycosis fungoides and Sezary syndrome.

    PubMed

    Lechowicz, M J; Lazarus, H M; Carreras, J; Laport, G G; Cutler, C S; Wiernik, P H; Hale, G A; Maharaj, D; Gale, R P; Rowlings, P A; Freytes, C O; Miller, A M; Vose, J M; Maziarz, R T; Montoto, S; Maloney, D G; Hari, P N

    2014-11-01

    We describe outcomes after allogeneic hematopoietic cell transplantation (HCT) for mycosis fungoides and Sezary syndrome (MF/SS). Outcomes of 129 subjects with MF/SS reported to the Center for the International Blood and Marrow Transplant from 2000-2009. Median time from diagnosis to transplant was 30 (4-206) months and most subjects were with multiply relapsed/ refractory disease. The majority (64%) received non-myeloablative conditioning (NST) or reduced intensity conditioning (RIC). NST/RIC recipients were older in age compared with myeloablative recipients (median age 51 vs 44 years, P=0.005) and transplanted in recent years. Non-relapse mortality (NRM) at 1 and 5 years was 19% (95% confidence interval (CI) 12-27%) and 22% (95% CI 15-31%), respectively. Risk of disease progression was 50% (95% CI 41-60%) at 1 year and 61% (95% CI 50-71%) at 5 years. PFS at 1 and 5 years was 31% (95% CI 22-40%) and 17% (95% CI 9-26%), respectively. OS at 1 and 5 years was 54% (95% CI 45-63%) and 32% (95% CI 22-44%), respectively. Allogeneic HCT in MF/SS results in 5-year survival in approximately one-third of patients and of those, half remain disease-free. PMID:25068422

  5. ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR MYCOSIS FUNGOIDES AND SEZARY SYNDROME

    PubMed Central

    Lechowicz, Mary Jo; Lazarus, Hillard M.; Carreras, Jeanette; Laport, Ginna G.; Cutler, Corey S.; Wiernik, Peter H.; Hale, Gregory A.; Maharaj, Dipnarine; Gale, Robert Peter; Rowlings, Phillip A.; Freytes, César O; Miller, Alan M.; Vose, Julie M.; Maziarz, Richard T.; Montoto, Silvia; Maloney, David G.; Hari, Parameswaran N.

    2014-01-01

    We describe outcomes after allogeneic hematopoietic cell transplantation (HCT) for mycosis fungoides and sezary syndrome (MF/SS). Outcomes of 129 subjects with MF/SS reported to the Center for the International Blood and Marrow Transplant (CIBMTR) from 2000–2009. Median time from diagnosis to transplant was 30 (4–206) months and most subjects were with multiply relapsed/refractory disease. Majority (64%) received non-myeloablative conditioning (NST) or reduced intensity conditioning (RIC). NST/RIC recipients were older in age compared to myeloablative recipients (median age 51 vs. 44 y p= 0.005) and transplanted in recent years. Non-relapse mortality (NRM) at 1 and 5 years was 19% (95 % CI 12–27%) and 22% (95 % CI 15–31%) respectively. Risk of disease progression was 50% (95% CI 41–60%) at 1 year and 61% (95% CI 50–71%) at 5 years. Progression free survival (PFS) at 1 and 5 years was 31% (95% CI 22–40%) and 17% (95% CI 9–26%) respectively. Overall survival at 1 and 5 years was 54% (95% CI 45–63%) and 32% (95% CI 22–44%) respectively. Allogeneic HCT in MF/SS results in 5 year survival in approximately one-third of patients and of those, half of them remain disease-free. PMID:25068422

  6. Impact of donor age on outcome after allogeneic hematopoietic cell transplantation.

    PubMed

    Rezvani, Andrew R; Storer, Barry E; Guthrie, Katherine A; Schoch, H Gary; Maloney, David G; Sandmaier, Brenda M; Storb, Rainer

    2015-01-01

    As older patients are eligible for allogeneic hematopoietic cell transplantation (HCT), older siblings are increasingly proposed as donors. We studied the impact of donor age on the tempo of hematopoietic engraftment and donor chimerism, acute and chronic graft-versus-host disease (GVHD), and nonrelapse mortality (NRM) among 1174 consecutive patients undergoing myeloablative and 367 patients undergoing nonmyeloablative HCT from HLA-matched related or unrelated donors with granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell allografts. Sustained engraftment rates were 97% and 98% in patients undergoing myeloablative and nonmyeloablative conditioning, respectively, for grafts from donors < 60 years old (younger; n = 1416) and 98% and 100%, respectively, for those from donors ≥ 60 years old (older; n = 125). No significant differences were seen in the tempo of neutrophil and platelet recoveries and donor chimerism except for an average 1.3-day delay in neutrophil recovery among myeloablative patients with older donors (P = .04). CD34(+) cell dose had an independent effect on the tempo of engraftment. Aged stem cells did not convey an increased risk of donor-derived clonal disorders after HCT. Myeloablative and nonmyeloablative recipients with older sibling donors had significantly less grade II to IV acute GVHD than recipients with grafts from younger unrelated donors. Rates of grade III and IV acute GVHD, chronic GVHD, and NRM for recipients with older donors were not significantly different from recipients with younger donors. In conclusion, grafts from donors ≥ 60 years old do not adversely affect outcomes of allogeneic HCT compared with grafts from younger donors. PMID:25278458

  7. Patient education in allogeneic hematopoietic cell transplant: What patients wish they had known about quality of life

    PubMed Central

    Jim, Heather S.L.; Quinn, Gwendolyn P.; Gwede, Clement K.; Cases, Mallory G.; Barata, Anna; Cessna, Julie; Christie, Juliette; Gonzalez, Luis; Koskan, Alexis; Pidala, Joseph

    2013-01-01

    Quality of life (QOL) is increasingly recognized as an important clinical outcome of hematopoietic cell transplantation (HCT), but patient education is often overlooked. The goal of the current qualitative study was to examine education regarding post-HCT QOL from the patient’s perspective. Allogeneic HCT recipients participated in one of four focus groups. Participants were asked to recall what they had been told about post-HCT QOL as they were preparing for transplant, how their QOL differed from what they expected, and how to educate future patients about post-HCT QOL. Verbatim transcripts were coded for both a priori and emergent themes using content analysis. A total of 24 patients participated (54% female, mean age 51, range 23-73). Participants frequently expressed the desire for additional education regarding post-HCT QOL, particularly late complications. They noted that late complications were often unexpected, had a profound impact on their QOL, and threatened their ongoing sense of recovery. They emphasized that the timing, content, and format of education regarding QOL should be flexible to meet their diverse needs. Findings from the current study draw attention to the importance of patient education regarding post-HCT QOL as well as additional QOL research designed with patient education in mind. PMID:24121210

  8. Blood stream infections in allogeneic hematopoietic stem cell transplant recipients: reemergence of Gram-negative rods and increasing antibiotic resistance.

    PubMed

    Mikulska, Malgorzata; Del Bono, Valerio; Raiola, Anna Maria; Bruno, Barbara; Gualandi, Francesca; Occhini, Domenico; di Grazia, Carmen; Frassoni, Francesco; Bacigalupo, Andrea; Viscoli, Claudio

    2009-01-01

    Blood stream infections (BSI) are a well-known cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) patients. The aim of this study was to analyze etiology and microbial resistance of BSI in patients undergoing allogeneic HSCT in a single center over a 4-year period (2004-2007). There were 168 episodes of BSI in 132 patients (median 10 days after HSCT) and 182 pathogens were isolated. Gram-positive bacteria (GPB) accounted for 57% of 182 isolates. Gram-negative rods (GNR) for 37% and fungi for 6%. All patients received routine fluoroquinolone prophylaxis. There was a significant decrease in GPB/GNR ratio over time, from 2.4 in 2004 to 1 in 2007 (P = .043). Among GPB, staphylococci decreased from 37 of 68 (64%) in 2004-2005 to 8 of 35 (23%) in 2006-2007 (P < .002). The Enterococcus faecalis/E. faecium ratio decreased from 4.5 in 2004 to 0.33 in 2007 (P = .006), whereas the total number of enterococcal strains per year did not change. The incidence of Escherichia coli among GNR increased from 3 of 15 (20%) in 2004 to 13 of 21 (62%) in 2007 (P = .003). Fluoroquinolone-resistance was common, both among GPB and GNR (81% and 74%, respectively). Mortality rate at 7 days after BSI was 11% (19 of 168), reaching 39% for Pseudomonas aeruginosa BSI (7 of 18). BSI remains a frequent and potentially life-threatening complication of allogeneic HSCT, the causative organism influencing 7- and 30-day mortality rate. BSI etiology may change rapidly, requiring implementation of new empirical-therapy schemes. PMID:19135942

  9. Efficacy and Safety of a Preemptive Antiviral Therapy Strategy Based on Combined Virological and Immunological Monitoring for Active Cytomegalovirus Infection in Allogeneic Stem Cell Transplant Recipients

    PubMed Central

    Navarro, David; Amat, Paula; de la Cámara, Rafael; López, Javier; Vázquez, Lourdes; Serrano, David; Nieto, José; Rovira, Monserrat; Piñana, José Luis; Giménez, Estela; Solano, Carlos

    2016-01-01

    Background. Preemptive antiviral therapy for active cytomegalovirus (CMV) infection in allogeneic stem cell transplant recipients (Allo-SCT) results in overtreatment and a high rate of recurrences. Monitoring of CMV-specific T-cell immunity may help to individualize treatments and minimize these problems. Methods. We conducted a prospective, multicenter, matched comparison-group study to evaluate the efficacy and safety of a novel strategy that consisted of interrupting anti-CMV therapy upon CMV DNAemia clearance and concurrent detection of phosphoprotein 65/immediate-early-1-specific interferon-γ-producing CD8+ T cells at levels of >1 cell/µL (within 30 days after the initiation of therapy). Immunological monitoring was performed on days +7, +14, +21, and +28 after treatment initiation. The primary endpoint was the cumulative incidence of recurrent DNAemia within 2 months after treatment cessation. Secondary endpoints were the length of antiviral treatment courses and the incidence of hematological toxicity. Results. Sixty-one patients were enrolled in the study group. Fifty-six patients were included in the matched-control group. Eleven patients (18%) fulfilled the criteria for antiviral treatment interruption. The cumulative incidence of recurrent CMV DNAemia was significantly lower (P = .02) in these patients than in patients in the comparative groups. Likewise, the length of antiviral treatment courses was significantly shorter in these patients than that in patients in the matched-control group (P = .003). No significant differences in the incidence of hematological toxicity was observed between the comparative groups. Conclusions. Our data support the clinical utility of combining immunological and virological monitoring for the management of CMV infection in a subset of Allo-SCT recipients. PMID:27419179

  10. Greatly reduced risk of EBV reactivation in rituximab-experienced recipients of alemtuzumab-conditioned allogeneic HSCT.

    PubMed

    Burns, D M; Rana, S; Martin, E; Nagra, S; Ward, J; Osman, H; Bell, A I; Moss, P; Russell, N H; Craddock, C F; Fox, C P; Chaganti, S

    2016-06-01

    EBV-associated post-transplant lymphoproliferative disease (PTLD) remains an important complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). We retrospectively analysed the incidence and risk factors for EBV reactivation in 186 adult patients undergoing consecutive allo-HSCT with alemtuzumab T-cell depletion at a single centre. The cumulative incidence of EBV reactivation was 48% (confidence interval (CI) 41-55%) by 1 year, with an incidence of high-level EBV reactivation of 18% (CI 13-24%); 8 patients were concurrently diagnosed with PTLD. Amongst patients with high-level reactivation 31/38 (82%) developed this within only 2 weeks of first EBV qPCR positivity. In univariate analysis age⩾50 years was associated with significantly increased risk of EBV reactivation (hazard ratio (HR) 1.54, CI 1.02-2.31; P=0.039). Furthermore, a diagnosis of non-Hodgkin lymphoma (NHL) was associated with greatly reduced risk of reactivation (HR 0.10, CI 0.03-0.33; P=0.0001) and this was confirmed in multivariate testing. Importantly, rituximab therapy within 6 months prior to allo-HSCT was also highly predictive for lack of EBV reactivation (HR 0.18, CI 0.07-0.48; P=0.001) although confounding with NHL was apparent. Our data emphasise the risk of PTLD associated with alemtuzumab. Furthermore, we report the clinically important observation that rituximab, administered in the peri-transplant period, may provide effective prophylaxis for PTLD. PMID:26901708

  11. Fatal B-cell lymphoproliferative syndrome in allogeneic marrow graft recipients. A clinical, immunobiological and pathological study.

    PubMed

    Simon, M; Bartram, C R; Friedrich, W; Arnold, R; Schmeiser, T; Hampl, W; Müller-Hermelink, H K; Heymer, B

    1991-01-01

    We have studied four cases of fatal B-cell lymphoproliferative syndrome (LPS) developing among 333 patients (incidence 1.2%) treated with allogeneic bone marrow transplantation (BMT). All four patients had received a T-cell depleted graft. Onset of the first clinical symptoms (palpable lymph node enlargement in three and IgA-lambda paraproteinemia in two patients) occurred between 41 and 188 days post-BMT (median 76 days). The course of the LPS was rapidly progressive in all cases, leading to death in 2-5 weeks. The peripheral blood showed progressive pancytopenia with disproportionally high numbers of activated NK cells, apparently compensating for the T-cell deficiency. Post-mortem histological studies disclosed polymorphic B-cell proliferations, most pronounced in the lymph nodes, spleen, liver, lungs and kidneys. Lymphohemopoietic cells were of donor origin in three patients. In the fourth patient, graft failure suggested a host origin for the proliferating cells. Immunophenotyping and gene rearrangement analysis revealed polyclonal proliferation in one patient, monoclonal proliferation in another patient, and an oligoclonal pattern in the other two patients. The clinical behavior of the LPS was independent of clonality. Immunohistologically, the proliferating cells showed characteristics of relatively mature B-cells in three cases, and pre-B-cell features in one case. Epstein Barr virus (EBV) serology indicated seroconversion (primary infection) in one child, and chronic active EBV infection in both adults. EBV DNA as well as EBV nuclear antigen (EBNA) were detected in infiltrated tissues of all four patients. The labeling pattern on in situ hybridization suggested a replicative EBV infection comparable to that in lymphoblastoid cell lines. We conclude that EBV-associated LPS developing as a result of post-transplant immunodeficiency is a distinct clinicopathologic entity, differing from non-Hodgkin's lymphoma (including Burkitt's lymphoma) and infectious

  12. Allogeneic unrelated bone marrow transplantation from older donors results in worse prognosis in recipients with aplastic anemia.

    PubMed

    Arai, Yasuyuki; Kondo, Tadakazu; Yamazaki, Hirohito; Takenaka, Katsuto; Sugita, Junichi; Kobayashi, Takeshi; Ozawa, Yukiyasu; Uchida, Naoyuki; Iwato, Koji; Kobayashi, Naoki; Takahashi, Yoshiyuki; Ishiyama, Ken; Fukuda, Takahiro; Ichinohe, Tatsuo; Atsuta, Yoshiko; Mori, Takehiko; Teshima, Takanori

    2016-05-01

    Allogeneic bone marrow transplantation is an essential therapy for acquired aplastic anemia and prognosis has recently improved. However, engraftment failure and graft-versus-host disease are potential fatal complications. Various risk factors for poor prognosis have been identified, such as patient age and human-leukocyte antigen disparity, but the relationship between donor age and prognosis is still unknown. Therefore, we performed a cohort study to compare the prognosis of unrelated bone marrow transplantation from younger and older donors using the registry database in Japan. We evaluated 427 patients (age 16-72 years) with aplastic anemia who underwent bone marrow transplantation from younger (≤39 years, n=281) or older (≥40 years, n=146) unrelated donors. Overall survival of the older donor group was significantly inferior to that of the younger donor group (adjusted hazard ratio 1.64; 95% confidence interval 1.15-2.35; P<0.01). The incidence of fatal infection was significantly higher in the older donor group (13.7% vs. 7.5%; P=0.03). Primary engraftment failure and acute graft-versus-host disease were significantly more frequent in the older donor group (9.7% vs. 5.0%; adjusted hazard ratio 1.30; P=0.01, and 27.1% vs. 19.7%; adjusted hazard ratio 1.56; P=0.03, respectively). Acute graft-versus-host disease was related to a worse prognosis in the whole cohort. This study showed the inferiority of older donors in aplastic anemia; thus, donor age should be considered when multiple donors are available. A large-scale prospective study is warranted to establish a better donor selection algorithm for bone marrow transplantation in aplastic anemia. PMID:26858357

  13. Allogeneic unrelated bone marrow transplantation from older donors results in worse prognosis in recipients with aplastic anemia

    PubMed Central

    Arai, Yasuyuki; Kondo, Tadakazu; Yamazaki, Hirohito; Takenaka, Katsuto; Sugita, Junichi; Kobayashi, Takeshi; Ozawa, Yukiyasu; Uchida, Naoyuki; Iwato, Koji; Kobayashi, Naoki; Takahashi, Yoshiyuki; Ishiyama, Ken; Fukuda, Takahiro; Ichinohe, Tatsuo; Atsuta, Yoshiko; Mori, Takehiko; Teshima, Takanori

    2016-01-01

    Allogeneic bone marrow transplantation is an essential therapy for acquired aplastic anemia and prognosis has recently improved. However, engraftment failure and graft-versus-host disease are potential fatal complications. Various risk factors for poor prognosis have been identified, such as patient age and human-leukocyte antigen disparity, but the relationship between donor age and prognosis is still unknown. Therefore, we performed a cohort study to compare the prognosis of unrelated bone marrow transplantation from younger and older donors using the registry database in Japan. We evaluated 427 patients (age 16–72 years) with aplastic anemia who underwent bone marrow transplantation from younger (≤39 years, n=281) or older (≥40 years, n=146) unrelated donors. Overall survival of the older donor group was significantly inferior to that of the younger donor group (adjusted hazard ratio 1.64; 95% confidence interval 1.15–2.35; P<0.01). The incidence of fatal infection was significantly higher in the older donor group (13.7% vs. 7.5%; P=0.03). Primary engraftment failure and acute graft-versus-host disease were significantly more frequent in the older donor group (9.7% vs. 5.0%; adjusted hazard ratio 1.30; P=0.01, and 27.1% vs. 19.7%; adjusted hazard ratio 1.56; P=0.03, respectively). Acute graft-versus-host disease was related to a worse prognosis in the whole cohort. This study showed the inferiority of older donors in aplastic anemia; thus, donor age should be considered when multiple donors are available. A large-scale prospective study is warranted to establish a better donor selection algorithm for bone marrow transplantation in aplastic anemia. PMID:26858357

  14. Anti-thymocyte globulin for conditioning in matched unrelated donor hematopoietic cell transplantation provides comparable outcomes to matched related donor recipients

    PubMed Central

    Portier, DA; Sabo, RT; Roberts, CH; Fletcher, DS; Meier, J; Clark, WB; Neale, MC; Manjili, MH; McCarty, JM; Chung, HM; Toor, AA

    2016-01-01

    Rabbit anti-thymocyte globulin (ATG) is used as prophylaxis against GVHD following allogeneic hematopoietic cell transplantation (HCT). At our institution, ATG is exclusively used in the conditioning of matched unrelated donor (URD) transplant recipients. A total of 50 URD HCT recipients who received ATG (ATG group) were retrospectively compared with 48 matched related donor (MRD) HCT recipients who did not receive ATG (no ATG group). There were no significant differences between the groups in rates of day 100 mortality, acute GVHD or relapse. Chronic GVHD incidence was significantly lower in the ATG group (P = 0.007). At a median follow-up of 36 months in the entire cohort, 50% patients are alive in the ATG group and 63% of the patients are alive in the no ATG group (P = 0.13). We conclude that the administration of ATG to patients undergoing URD HCT preserves the anti-leukemia benefit of the transplant, while reducing the risk of developing GVHD, resulting in OS rates that are comparable to MRD HCT recipients. PMID:22580767

  15. Reducing the Risk for Transplantation-Related Mortality After Allogeneic Hematopoietic Cell Transplantation: How Much Progress Has Been Made?

    PubMed Central

    Horan, John T.; Logan, Brent R.; Agovi-Johnson, Manza-A.; Lazarus, Hillard M.; Bacigalupo, Andrea A.; Ballen, Karen K.; Bredeson, Christopher N.; Carabasi, Matthew H.; Gupta, Vikas; Hale, Gregory A.; Khoury, Hanna Jean; Juckett, Mark B.; Litzow, Mark R.; Martino, Rodrigo; McCarthy, Philip L.; Smith, Franklin O.; Rizzo, J. Douglas; Pasquini, Marcelo C.

    2011-01-01

    Purpose Transplantation-related mortality (TRM) is a major barrier to the success of allogeneic hematopoietic cell transplantation (HCT). Patients and Methods We assessed changes in the incidence of TRM and overall survival from 1985 through 2004 in 5,972 patients younger than age 50 years who received myeloablative conditioning and HCT for acute myeloid leukemia (AML) in first complete remission (CR1) or second complete remission (CR2). Results Among HLA-matched sibling donor transplantation recipients, the relative risks (RRs) for TRM were 0.5 and 0.3 for 2000 to 2004 compared with those for 1985 to 1989 in patients in CR1 and CR2, respectively (P < .001). The RRs for all causes of mortality in the latter period were 0.73 (P = .001) and 0.60 (P = .005) for the CR1 and CR2 groups, respectively. Among unrelated donor transplantation recipients, the RRs for TRM were 0.73 (P = .095) and 0.58 (P < .001) for 2000 to 2004 compared with those in 1990 to 1994 in the CR1 and CR2 groups, respectively. Reductions in mortality were observed in the CR2 group (RR, 0.74; P = .03) but not in the CR1 group. Conclusion Our results suggest that innovations in transplantation care since the 1980s and 1990s have reduced the risk of TRM in patients undergoing allogeneic HCT for AML and that this reduction has been accompanied by improvements in overall survival. PMID:21220593

  16. Incidence and risk of postherpetic neuralgia after varicella zoster virus infection in hematopoietic cell transplantation recipients: Hokkaido Hematology Study Group.

    PubMed

    Onozawa, Masahiro; Hashino, Satoshi; Haseyama, Yoshifumi; Hirayama, Yasuo; Iizuka, Susumu; Ishida, Tadao; Kaneda, Makoto; Kobayashi, Hajime; Kobayashi, Ryoji; Koda, Kyuhei; Kurosawa, Mitsutoshi; Masauji, Nobuo; Matsunaga, Takuya; Mori, Akio; Mukai, Masaya; Nishio, Mitsufumi; Noto, Satoshi; Ota, Shuichi; Sakai, Hajime; Suzuki, Nobuhiro; Takahashi, Tohru; Tanaka, Junji; Torimoto, Yoshihiro; Yoshida, Makoto; Fukuhara, Takashi

    2009-06-01

    To assess the incidence of and risk factors associated with postherpetic neuralgia (PHN) after hematopoietic cell transplantation (HCT) varicella zoster virus (VZV) infection, we conducted a retrospective chart review of 418 consecutive patients who underwent HCT between April 2005 and March 2007. The male/female ratio was 221/197, median age at HCT was 47 years (range: 0-69 years), and autologous/allogeneic/syngeneic HCT ratio was 154/263/1. Seventy-eight patients developed VZV infection after HCT. Sixty-two patients had localized zoster, 11 patients had disseminated zoster (rash like chicken pox), and 4 patients had visceral zoster. All cases were treated with acyclovir (ACV) or valacyclovir (VACV), and there was no VZV infection-related death. Twenty-seven (35%) of the 78 patients with VZV infection suffered PHN after resolution of VZV infection. Multivariate analysis showed that advanced age is the only risk factor in autologous HCT (P = .0075; odds ratio [OR] = 1.14; 95% confidence interval [CI], 0.97-1.33). On the other hand, advanced age (P = .0097; OR = 1.06; 95% CI, 1.01-1.12), male gender (P = .0055; OR = 12.7; 95% CI, 1.61-100.1), and graft-versus-host disease (GVHD) prophylaxis with a tacrolimus-based regimen (P = .0092; OR = 9.56; 95% CI, 1.44-63.3) were associated with increased risk of PHN in allogeneic HCT. This study for the first time clarified the risk of PHN in HCT recipients. PMID:19450757

  17. Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients

    PubMed Central

    Zhou, Wendi; Longmate, Jeff; Lacey, Simon F.; Palmer, Joycelynne M.; Gallez-Hawkins, Ghislaine; Thao, Lia; Spielberger, Ricardo; Nakamura, Ryotaro; Forman, Stephen J.; Zaia, John A.

    2009-01-01

    Reconstitution of cytomegalovirus (CMV)–specific CD8+ T cells is essential to the control of CMV infection in CMV-positive recipients (R+) after allogeneic hematopoietic stem cell transplantation (HCT). Six-color flow cytometry was used to assess the functional profile of CMV-specific CD8+ T cells in 62 of 178 R+ HCT recipients followed virologically for CMV reactivation. R+ recipients receiving grafts from CMV-negative donors (D−; D−/R+) reconstituted fewer multifunctional CD8+ T cells expressing tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-1β (MIP-1β), and CD107 in addition to interferon-γ (IFN-γ), compared with D+/R+ recipients. Unlike monofunctional CD8+ T cells secreting IFN-γ, which were abundantly generated during CMV reactivation in D−/R+ recipients, the relative lack of multifunctional CD8+ T cells persisted until at least 1 year post-HCT. D−/R+ recipients were more likely to require recurrent and prolonged use of antivirals. These findings were robust to statistical adjustment for pretransplant factors, as well as for posttransplant factors including graft-versus-host disease (GVHD) and its treatment by steroids. These analyses suggest that D+/R+ transplants, on average, generate higher levels of multifunctional CMV-specific T cells and require less antiviral therapy compared with D−/R+ HCT recipients. These results highlight the benefit of D+ donors in improving outcomes of R+ HCT recipients by reducing the duration and recurrent need of antiviral treatment, aided by increased levels of multifunctional CMV-specific T cells. PMID:19369230

  18. Lenalidomide maintenance for high-risk multiple myeloma after allogeneic hematopoietic cell transplantation.

    PubMed

    Alsina, Melissa; Becker, Pamela S; Zhong, Xiaobo; Adams, Alexia; Hari, Parameswaran; Rowley, Scott; Stadtmauer, Edward A; Vesole, David H; Logan, Brent; Weisdorf, Daniel; Qazilbash, Muzaffar; Popplewell, Leslie L; McClune, Brian; Bensinger, William; Riches, Marcie; Giralt, Sergio A; Pasquini, Marcelo C

    2014-08-01

    Allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning is an appealing option for patients with high-risk multiple myeloma (MM). However, progression after alloHCT remains a challenge. Maintenance therapy after alloHCT may offer additional disease control and allow time for a graft-versus-myeloma effect. The primary objective of this clinical trial was to determine the tolerability and safety profile of maintenance lenalidomide (LEN) given on days 1 to 21 of 28 days cycles, with intrapatient dose escalation during 12 months/cycles after alloHCT. Thirty alloHCT recipients (median age, 54 years) with high-risk MM were enrolled at 8 centers between 2009 and 2012. The median time from alloHCT to LEN initiation was 96 days (range, 66 to 171 days). Eleven patients (37%) completed maintenance and 10 mg daily was the most commonly delivered dose (44%). Most common reasons for discontinuation were acute graft-versus-host disease (GVHD) (37%) and disease progression (37%). Cumulative incidence of grades III to IV acute GVHD from time of initiation of LEN was 17%. Outcomes at 18 months after initiation of maintenance were MM progression, 28%; transplantation-related mortality, 11%; and progression-free and overall survival, 63% and 78%, respectively. The use of LEN after alloHCT is feasible at lower doses, although it is associated with a 38% incidence of acute GVHD. Survival outcomes observed in this high-risk MM population warrant further study of this approach. PMID:24769014

  19. Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Zinöcker, Severin; Dressel, Ralf; Wang, Xiao-Nong; Dickinson, Anne M.; Rolstad, Bent

    2012-01-01

    Allogeneic hematopoietic cell transplantation (alloHCT) extends the lives of thousands of patients who would otherwise succumb to hematopoietic malignancies such as leukemias and lymphomas, aplastic anemia, and disorders of the immune system. In alloHCT, different immune cell types mediate beneficial graft-versus-tumor (GvT) effects, regulate detrimental graft-versus-host disease (GvHD), and are required for protection against infections. Today, the “good” (GvT effector cells and memory cells conferring protection) cannot be easily separated from the “bad” (GvHD-causing cells), and alloHCT remains a hazardous medical modality. The transplantation of hematopoietic stem cells into an immunosuppressed patient creates a delicate environment for the reconstitution of donor blood and immune cells in co-existence with host cells. Immunological reconstitution determines to a large extent the immune status of the allo-transplanted host against infections and the recurrence of cancer, and is critical for long-term protection and survival after clinical alloHCT. Animal models continue to be extremely valuable experimental tools that widen our understanding of, for example, the dynamics of post-transplant hematopoiesis and the complexity of immune reconstitution with multiple ways of interaction between host and donor cells. In this review, we discuss the rat as an experimental model of HCT between allogeneic individuals. We summarize our findings on lymphocyte reconstitution in transplanted rats and illustrate the disease pathology of this particular model. We also introduce the rat skin explant assay, a feasible alternative to in vivo transplantation studies. The skin explant assay can be used to elucidate the biology of graft-versus-host reactions, which are known to have a major impact on immune reconstitution, and to perform genome-wide gene expression studies using controlled combinations of minor and major histocompatibility between the donor and the recipient

  20. Adaptive Natural Killer Cell and Killer Cell Immunoglobulin-Like Receptor-Expressing T Cell Responses are Induced by Cytomegalovirus and Are Associated with Protection against Cytomegalovirus Reactivation after Allogeneic Donor Hematopoietic Cell Transplantation.

    PubMed

    Davis, Zachary B; Cooley, Sarah A; Cichocki, Frank; Felices, Martin; Wangen, Rose; Luo, Xianghua; DeFor, Todd E; Bryceson, Yenan T; Diamond, Don J; Brunstein, Claudio; Blazar, Bruce R; Wagner, John E; Weisdorf, Daniel J; Horowitz, Amir; Guethlein, Lisbeth A; Parham, Peter; Verneris, Michael R; Miller, Jeffrey S

    2015-09-01

    Cytomegalovirus (CMV) reactivates in >30% of CMV-seropositive patients after allogeneic hematopoietic cell transplantation (HCT). Previously, we reported an increase of natural killer (NK) cells expressing NKG2C, CD57, and inhibitory killer cell immunoglobulin-like receptors (KIRs) in response to CMV reactivation after HCT. These NK cells persist after the resolution of infection and display "adaptive" or memory properties. Despite these findings, the differential impact of persistent/inactive versus reactivated CMV on NK versus T cell maturation after HCT from different graft sources has not been defined. We compared the phenotype of NK and T cells from 292 recipients of allogeneic sibling (n = 118) or umbilical cord blood (UCB; n = 174) grafts based on recipient pretransplantation CMV serostatus and post-HCT CMV reactivation. This cohort was utilized to evaluate CMV-dependent increases in KIR-expressing NK cells exhibiting an adaptive phenotype (NKG2C(+)CD57(+)). Compared with CMV-seronegative recipients, those who reactivated CMV had the highest adaptive cell frequencies, whereas intermediate frequencies were observed in CMV-seropositive recipients harboring persistent/nonreplicating CMV. The same effect was observed in T cells and CD56(+) T cells. These adaptive lymphocyte subsets were increased in CMV-seropositive recipients of sibling but not UCB grafts and were correlated with lower rates of CMV reactivation (sibling 33% versus UCB 51%; P < .01). These data suggest that persistent/nonreplicating recipient CMV induces rapid production of adaptive NK and T cells from mature cells from sibling but not UCB grafts. These adaptive lymphocytes are associated with protection from CMV reactivation. PMID:26055301

  1. Observational prospective study of viral infections in children undergoing allogeneic hematopoietic cell transplantation: a 3-year GETMON experience.

    PubMed

    Verdeguer, A; de Heredia, C D; González, M; Martínez, A M; Fernández-Navarro, J M; Pérez-Hurtado, J M; Badell, I; Gómez, P; González, M E; Muñoz, A; Díaz, M A

    2011-01-01

    We studied surveillance, incidence and outcome of viral infections in children undergoing allogeneic hematopoietic cell transplantation (HCT) in the main pediatric transplant units in Spain. We prospectively collected data from first year post-HCT in every consecutive allogeneic HCT performed during 3 years (N = 215): first HCT = 188 and second HCT = 27; median age = 6.6 years (0.1-20.7). Most patients had acute leukemia (N = 137) and 135 recipients (63%) were CMV seropositive. A total of 46 patients underwent cord blood transplant, 133 patients underwent HCT from alternative donors (62%) and 101 patients received anti-thymocyte globulin. Observational time was completed in 137 patients, whereas the remaining 78 died after a median survival time of 99 days (3-352). CMV was monitored in all patients; adenovirus (ADV) and human herpesvirus 6 (HHV-6) were monitored in 101 and 33 patients, respectively. We found 145 viral infections in 103 patients: CMV (n = 42), ADV (n = 32), HHV-6 (n = 7), polyomavirus (n = 20), EBV (n = 6), VZV (n=17) and others (n = 8). CMV infection was significantly higher in seropositive patients (25 vs 7%) (P = 0.02). Extensive chronic GVHD (cGVHD) was significantly associated with an increased rate of viral infections (12 of 16 patients with cGVHD had infections vs 91 of 199 without GVHD) (P = 0.035). In total, 10 patients (4.6%) died of viral infections (CMV = 5, ADV = 3, respiratory = 2). We found a high incidence of viral infection, but mortality was low. PMID:20228849

  2. Incidence and dynamics of active cytomegalovirus infection in allogeneic stem cell transplant patients according to single nucleotide polymorphisms in donor and recipient CCR5, MCP-1, IL-10, and TLR9 genes.

    PubMed

    Corrales, Isabel; Giménez, Estela; Solano, Carlos; Amat, Paula; de la Cámara, Rafael; Nieto, José; Garcia-Noblejas, Ana; Navarro, David

    2015-02-01

    Single nucleotide polymorphisms (SNPs) in genes involved in the activation or regulation of innate and adaptive immune responses may modulate the susceptibility to and the natural history of certain chronic viral infections. The current study aimed to investigate whether donor and recipient SNPs in the chemokine receptor 5 (rs1800023), monocyte chemoattractant protein 1 (rs13900), interleukin-10 (rs1878672), and Toll-like receptor 9 (rs352140) genes would exert any influence on the rate of incidence and features of CMV DNAemia in the allogeneic stem cell transplantation setting. This was a retrospective observational multicenter study. The cohort consisted of 102 non-consecutive allogeneic stem cell transplant recipients. SNP genotyping was performed by allele-specific real-time PCR. CMV surveillance was performed by the pp65 antigenemia assay/and or by real-time PCR. Seventy-three patients developed CMV DNAemia within the first 100 days after transplantation (71.5%). Neither donor nor recipient SNPs were associated significantly with the rate of incidence of active CMV infection, nor with the need for pre-emptive antiviral therapy. Both the duration of CMV DNAemia and the plasma CMV DNA peak load during episodes were significantly higher in patients harboring the donor (but not the recipient) chemokine receptor 5 A/A genotype, than in their A/G and G/G counterparts (P = 0.022 and P = 0.045, respectively). The data reported suggest that SNPs in chemokine receptor 5 may influence the dynamics of CMV infection in the Allo-SCT setting. PMID:25132583

  3. Effects of T cell depletion in radiation bone marrow chimeras. III. Characterization of allogeneic bone marrow cell populations that increase allogeneic chimerism independently of graft-vs-host disease in mixed marrow recipients

    SciTech Connect

    Sykes, M.; Chester, C.H.; Sundt, T.M.; Romick, M.L.; Hoyles, K.A.; Sachs, D.H. )

    1989-12-01

    The opposing problems of graft-vs-host disease vs failure of alloengraftment severely limit the success of allogeneic bone marrow transplantation as a therapeutic modality. We have recently used a murine bone marrow transplantation model involving reconstitution of lethally irradiated mice with mixtures of allogeneic and syngeneic marrow to demonstrate that an allogeneic bone marrow subpopulation, removed by T cell depletion with rabbit anti-mouse brain serum and complement (RAMB/C), is capable of increasing levels of allogeneic chimerism. This effect was observed in an F1 into parent genetic combination lacking the potential for graft-vs-host disease, and radiation protection studies suggested that it was not due to depletion of stem cells by RAMB/C. We have now attempted to characterize the cell population responsible for increasing allogeneic chimerism in this model. The results indicate that neither mature T cells nor NK cells are responsible for this activity. However, an assay involving mixed marrow reconstitution in an Ly-5 congenic strain combination was found to be more sensitive to small degrees of stem cell depletion than radiation protection assays using three-fold titrations of bone marrow cells. Using this assay, we were able to detect some degree of stem cell depletion by treatment with RAMB/C, but not with anti-T cell mAb. Nevertheless, if the effects of alloresistance observed in this model are considered, the degree of stem cell depletion detected by such mixing studies in insufficient to account for the effects of RAMB/C depletion on levels of allogeneic chimerism, suggesting that another cell population with this property remains to be identified.

  4. ALTERNATE DONOR HEMATOPOIETIC CELL TRANSPLANTATION (HCT) IN NON-HODGKIN LYMPHOMA USING LOWER INTENSITY CONDITIONING: A REPORT FROM THE CIBMTR

    PubMed Central

    Hale, Gregory A.; Shrestha, Smriti; Le-Rademacher, Jennifer; Burns, Linda J.; Gibson, John; Inwards, David J.; Freytes, Cesar O.; Bolwell, Brian J.; Hsu, Jack W.; Slavin, Shimon; Isola, Luis; Rizzieri, David A.; Gale, Robert Peter; Laport, Ginna G.; Montoto, Silvia; Lazarus, Hillard M.; Hari, Parameswaran N.

    2013-01-01

    We analyzed the outcomes of 248 (61% male) adult recipients of HLA-matched unrelated and HLA-mismatched related donor hematopoietic cell transplantation (HCT) for non-Hodgkin lymphoma (NHL) after reduced or lower intensity conditioning (RIC), reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1997 to 2004. Median age was 52 (range, 18–72 yrs); 31% had a Karnofsky performance score <90. Follicular NHL (43%) was the major histology. Incidence of grades II–IV acute graft-versus-host disease (GVHD) was 43% at 100 days; and chronic GVHD was 44% at three years. Treatment-related mortality (TRM) at 100 days was 24%. Three-year overall survival (OS) and progression-free survival (PFS) were 41% and 32%, respectively. In multivariate analysis, use of anti-thymocyte globulin (ATG) and HLA mismatch were associated with increased TRM. High-grade histology, ATG use and chemotherapy resistance were associated with lower progression-free survival (PFS). Older age, shorter interval from diagnosis to HCT, non-TBI conditioning regimens, ex vivo T-cell depletion and HLA-mismatched unrelated donors were associated with mortality. GVHD did not influence relapse or PFS. Older age, aggressive histology and chemotherapy resistance correlated with poorer survival. For selected patients with NHL, lack of an available sibling donor should not be a barrier to allogeneic HCT. PMID:22155506

  5. Design and Validation of an Augmented Hematopoietic Cell Transplantation-Comorbidity Index Comprising Pretransplant Ferritin, Albumin, and Platelet Count for Prediction of Outcomes after Allogeneic Transplantation.

    PubMed

    Vaughn, Jennifer E; Storer, Barry E; Armand, Philippe; Raimondi, Roberto; Gibson, Christopher; Rambaldi, Alessandro; Ciceri, Fabio; Oneto, Rosi; Bruno, Benedetto; Martin, Paul J; Sandmaier, Brenda M; Storb, Rainer; Sorror, Mohamed L

    2015-08-01

    Pretransplant values of serum ferritin, albumin, and peripheral blood counts were previously suggested to provide prognostic information about hematopoietic cell transplantation (HCT) outcomes. Whether these "biomarkers" have prognostic value independent of each other and the HCT-comorbidity index (HCT-CI) is unknown. We analyzed data from 3917 allogeneic HCT recipients at multiple sites in the United States and Italy using multivariate models including each biomarker and the HCT-CI. Data from all sites were then randomly divided into a training set (n = 2352) to develop weights for the relevant biomarkers to be added to the HCT-CI scores and a validation set (n = 1407) to validate an augmented HCT-CI compared with the original index. Multivariate analysis with data from one site showed that ferritin, albumin, and platelets-not neutrophils or hemoglobin-were independently associated with increased nonrelapse mortality (NRM) and decreased overall survival. Findings were validated in data from the other sites. Subsequently, in a training set from all sites, ferritin >2500 mg/dL (hazard ratio [HR], 1.69); albumin 3 to 3.5 g/dL (HR, 1.61) and <3.0 g/dL (HR, 2.27); and platelets 50 to <100,000 (HR, 1.28), 20 to <50,000 (HR, 1.29), and <20,000 (HR, 1.55) were statistically significantly associated with NRM. Weights were assigned to these laboratory values following the same equation used to design the original index. In the validation set, the addition of the biomarkers to the original index to develop an augmented HCT-CI resulted in a statistically significant increase in a higher c-statistic estimate for prediction of NRM (P = .0007). Ferritin, albumin, and platelet counts are important prognostic markers that further refine the discriminative power of the HCT-CI for transplant outcomes. PMID:25862589

  6. NK cell education after allogeneic transplantation: dissociation between recovery of cytokine-producing and cytotoxic functions.

    PubMed

    Foley, Bree; Cooley, Sarah; Verneris, Michael R; Curtsinger, Julie; Luo, Xianghua; Waller, Edmund K; Weisdorf, Daniel J; Miller, Jeffrey S

    2011-09-01

    Natural killer (NK) cells mediate GVL effects after allogeneic hematopoietic cell transplantation (allo-HCT) by the production of inflammatory cytokines and by direct target lysis. The acquisition of both functions was presumed to be developmentally linked, but this linkage remained unstudied after allo-HCT. We tested the cytokine production and degranulation of reconstituting NK cells after adult unrelated donor or umbilical cord blood grafting. Recipients of T cell-depleted transplants, receiving no immune suppression, showed diminished NK cell degranulation. In contrast, degranulation was normal or increased after T-cell replete transplants given with immune suppression. Strikingly, target cell-induced IFNγ production was markedly diminished in all transplant settings, especially with T cell-depleted or naive T cell-containing umbilical cord blood grafts, suggesting a role for T cells in NK education. Although degranulation was similar in the KIR(+) and KIR(-) populations that coexpressed NKG2A, target cell-induced IFNγ production was limited to the subset of NK cells expressing KIR inhibited by self-ligands. Thus, cytokine production and cytotoxic function do not consistently coexist in NK cells reconstituting after allo-HCT. Exposure to IL-15 rapidly increased target-inducible IFNγ production, indicative of IL-15's potential as a therapeutic tool to enhance NK cell function to protect against infection and relapse after allo-HCT. PMID:21757615

  7. HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients

    PubMed Central

    Fann, Jesse R.; Breiger, David; Boeckh, Michael; Adler, Amanda L.; Xie, Hu; Delaney, Colleen; Huang, Meei-Li; Corey, Lawrence; Leisenring, Wendy M.

    2011-01-01

    Human herpesvirus 6 (HHV-6) is detected in the plasma of approximately 40% of patients undergoing hematopoietic cell transplantation (HCT) and sporadically causes encephalitis in this population. The effect of HHV-6 reactivation on central nervous system function has not been fully characterized. This prospective study aimed to evaluate associations between HHV-6 reactivation and central nervous system dysfunction after allogeneic HCT. Patients were enrolled before HCT. Plasma samples were tested for HHV-6 at baseline and twice weekly after transplantation until day 84. Delirium was assessed at baseline, 3 times weekly until day 56, and weekly on days 56 to 84 using a validated instrument. Neurocognitive testing was performed at baseline and at approximately day 84. HHV-6 was detected in 111 (35%) of the 315 included patients. Patients with HHV-6 were more likely to develop delirium (adjusted odds ratio = 2.5; 95% confidence interval, 1.2-5.3) and demonstrate neurocognitive decline (adjusted odds ratio = 2.6; 95% confidence interval, 1.1-6.2) in the first 84 days after HCT. Cord blood and unrelated transplantation increased risk of HHV-6 reactivation. These data provide the basis to conduct a randomized clinical trial to determine whether prevention of HHV-6 reactivation will reduce neurocognitive morbidity in HCT recipients. PMID:21389320

  8. Recipient pretransplant inosine monophosphate dehydrogenase activity in nonmyeloablative hematopoietic cell transplantation.

    PubMed

    Bemer, Meagan J; Risler, Linda J; Phillips, Brian R; Wang, Joanne; Storer, Barry E; Sandmaier, Brenda M; Duan, Haichuan; Raccor, Brianne S; Boeckh, Michael J; McCune, Jeannine S

    2014-10-01

    Mycophenolic acid, the active metabolite of mycophenolate mofetil (MMF), inhibits inosine monophosphate dehydrogenase (IMPDH) activity. IMPDH is the rate-limiting enzyme involved in de novo synthesis of guanosine nucleotides and catalyzes the oxidation of inosine 5'-monophosphate to xanthosine 5'-monophosphate (XMP). We developed a highly sensitive liquid chromatography-mass spectrometry method to quantitate XMP concentrations in peripheral blood mononuclear cells (PMNCs) isolated from the recipient pretransplant and used this method to determine IMPDH activity in 86 nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) patients. The incubation procedure and analytical method yielded acceptable within-sample and within-individual variability. Considerable between-individual variability was observed (12.2-fold). Low recipient pretransplant IMPDH activity was associated with increased day +28 donor T cell chimerism, more acute graft-versus-host disease (GVHD), lower neutrophil nadirs, and more cytomegalovirus reactivation but not with chronic GVHD, relapse, nonrelapse mortality, or overall mortality. We conclude that quantitation of the recipient's pretransplant IMPDH activity in PMNC lysate could provide a useful biomarker to evaluate a recipient's sensitivity to MMF. Further trials should be conducted to confirm our findings and to optimize postgrafting immunosuppression in nonmyeloablative HCT recipients. PMID:24923537

  9. MHC Class I Expression by Donor Hematopoietic Stem Cells Is Required to Prevent NK Cell Attack in Allogeneic, but Not Syngeneic Recipient Mice

    PubMed Central

    Hirata, Yuichi; Li, Hao-Wei; Takahashi, Kazuko; Ishii, Hiroshi; Sykes, Megan; Fujisaki, Joji

    2015-01-01

    NK cells resist engraftment of syngeneic and allogeneic bone marrow (BM) cells lacking major histocompatibility (MHC) class I molecules, suggesting a critical role for donor MHC class I molecules in preventing NK cell attack against donor hematopoietic stem and progenitor cells (HSPCs), and their derivatives. However, using high-resolution in vivo imaging, we demonstrated here that syngeneic MHC class I knockout (KO) donor HSPCs persist with the same survival frequencies as wild-type donor HSPCs. In contrast, syngeneic MHC class I KO differentiated hematopoietic cells and allogeneic MHC class I KO HSPCs were rejected in a manner that was significantly inhibited by NK cell depletion. In vivo time-lapse imaging demonstrated that mice receiving allogeneic MHC class I KO HSPCs showed a significant increase in NK cell motility and proliferation as well as frequencies of NK cell contact with and killing of HSPCs as compared to mice receiving wild-type HSPCs. The data indicate that donor MHC class I molecules are required to prevent NK cell-mediated rejection of syngeneic differentiated cells and allogeneic HSPCs, but not of syngeneic HSPCs. PMID:26544200

  10. A prognostic index for survival among mechanically ventilated hematopoietic cell transplant recipients.

    PubMed

    Solh, Melhem; Oommen, Sanjay; Vogel, Rachel Isaksson; Shanley, Ryan; Majhail, Navneet S; Burns, Linda J

    2012-09-01

    The prognosis of recipients of allogeneic hematopoietic cell transplantation (HCT) who require mechanical ventilation (MV) has historically been poor. Of 883 adults undergoing allogeneic HCT at the University of Minnesota between 1998 and 2009, 179 (20%) required MV before day 100 posttransplantation. We evaluated the outcomes of these patients to develop a prognostic index to predict the 100-day post-MV overall survival (OS) based on factors present at the time of MV. The 179 patients were divided at random into a training set (n = 119) and a validation set (n = 60). The 100-day postventilation OS was 17% for the total population. Multivariate Cox regression on the training set identified creatinine <2 mg/dL and platelet count >20 × 10(9)/L as significant predictors of better OS. Recursive partitioning classified patients with these good prognostic criteria into class A (n = 76); all other patients were classified as class B (n = 103). Among class A patients, 100-day OS was 29% in the training set and 30% in the validation set. Corresponding OS in class B patients was 5% and 15%, respectively. This prognostic index should help guide physicians in counseling HCT patients and their families regarding the use of MV and potential outcomes. PMID:22387348

  11. Proteomic Characterization Reveals That MMP-3 Correlates With Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Cell and Lung Transplantation.

    PubMed

    Liu, X; Yue, Z; Yu, J; Daguindau, E; Kushekhar, K; Zhang, Q; Ogata, Y; Gafken, P R; Inamoto, Y; Gracon, A; Wilkes, D S; Hansen, J A; Lee, S J; Chen, J Y; Paczesny, S

    2016-08-01

    Improved diagnostic methods are needed for bronchiolitis obliterans syndrome (BOS), a serious complication after allogeneic hematopoietic cell transplantation (HCT) and lung transplantation. For protein candidate discovery, we compared plasma pools from HCT transplantation recipients with BOS at onset (n = 12), pulmonary infection (n = 16), chronic graft-versus-host disease without pulmonary involvement (n = 15) and no chronic complications after HCT (n = 15). Pools were labeled with different tags (isobaric tags for relative and absolute quantification), and two software tools identified differentially expressed proteins (≥1.5-fold change). Candidate proteins were further selected using a six-step computational biology approach. The diagnostic value of the lead candidate, matrix metalloproteinase 3 (MMP3), was evaluated by enzyme-linked immunosorbent assay in plasma of a verification cohort (n = 112) with and without BOS following HCT (n = 76) or lung transplantation (n = 36). MMP3 plasma concentrations differed significantly between patients with and without BOS (area under the receiver operating characteristic curve 0.77). Consequently, MMP3 represents a potential noninvasive blood test for diagnosis of BOS. PMID:26887344

  12. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation

    PubMed Central

    Gilbert, Ethel S.; Rizzo, J. Douglas; Socié, Gérard; Banks, Peter M.; Sobocinski, Kathleen A.; Horowitz, Mary M.; Jaffe, Elaine S.; Kingma, Douglas W.; Travis, Lois B.; Flowers, Mary E.; Martin, Paul J.; Deeg, H. Joachim; Curtis, Rochelle E.

    2009-01-01

    We evaluated 26 901 patients who underwent allogeneic hematopoietic cell transplantation (HCT) at 271 centers worldwide to define patterns of posttransplantation lymphoproliferative disorders (PTLDs). PTLDs developed in 127 recipients, with 105 (83%) cases occurring within 1 year after transplantation. In multivariate analyses, we confirmed that PTLD risks were strongly associated (P < .001) with T-cell depletion of the donor marrow, antithymocyte globulin (ATG) use, and unrelated or HLA-mismatched grafts (URD/HLA mismatch). Significant associations were also confirmed for acute and chronic graft-versus-host disease. The increased risk associated with URD/HLA-mismatched donors (RR = 3.8) was limited to patients with T-cell depletion or ATG use (P = .004). New findings were elevated risks for age 50 years or older at transplantation (RR = 5.1; P < .001) and second transplantation (RR = 3.5; P < .001). Lower risks were found for T-cell depletion methods that remove both T and B cells (alemtuzumab and elutriation, RR = 3.1; P = .025) compared with other methods (RR = 9.4; P = .005 for difference). The cumulative incidence of PTLDs was low (0.2%) among 21 686 patients with no major risk factors, but increased to 1.1%, 3.6%, and 8.1% with 1, 2, and more than 3 major risk factors, respectively. Our findings identify subgroups of patients who underwent allogeneic HCT at elevated risk of PTLDs for whom prospective monitoring of Epstein-Barr virus activation and early treatment intervention may be particularly beneficial. PMID:19264919

  13. Impact of Donor and Recipient Cytomegalovirus Serostatus on Outcomes of Antithymocyte Globulin-Conditioned Hematopoietic Cell Transplantation.

    PubMed

    Kalra, Amit; Williamson, Tyler; Daly, Andrew; Savoie, M Lynn; Stewart, Douglas A; Khan, Faisal; Storek, Jan

    2016-09-01

    Although previous studies involving allogeneic hematopoietic cell transplantation (HCT) without in vivo T cell depletion by rabbit antithymocyte globulin (ATG) have reported a substantial survival difference between D-R- and D+R- patients, but little to no survival difference between D-R+ and D+R+ patients (D, donor; R, recipient; +, cytomegalovirus [CMV] seropositive; -, CMV seronegative), whether this applies to HCT using ATG is unknown. We studied 928 patients who underwent myeloablative HCT for hematologic malignancies in Alberta between 1999 and 2014 who received graft-versus-host disease (GVHD) prophylaxis using ATG (Thymoglobulin, 4.5 mg/kg) in addition to methotrexate and cyclosporine. D-R- and D+R- patients had similar survival (no significant difference). D-R+ patients had a substantially lower survival than D+R+ patients (41% versus 59% at 5 years; P = .001). This difference was attributed to higher nonrelapse mortality, apparently due to higher GVHD-associated mortality. Survival rates were also lower for D-R+ HLA-matched sibling transplant recipients compared with D+R+ HLA-matched unrelated donor transplant recipients (44% versus 66% at 5 years; P = .009). In conclusion, when using ATG, choosing a seronegative donor for a seronegative patient is relatively unimportant, whereas choosing a seropositive donor for a seropositive patient is important, even if this requires the use of a seropositive matched unrelated donor graft. PMID:27246372

  14. Cytogenetics Does Not Impact Outcomes in Adult Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation.

    PubMed

    Aldoss, Ibrahim; Tsai, Ni-Chun; Slovak, Marilyn L; Palmer, Joycelynne; Alvarnas, Joseph; Marcucci, Guido; Forman, Stephen J; Pullarkat, Vinod

    2016-07-01

    The prognostic relevance of cytogenetics at diagnosis on the outcome of allogeneic hematopoietic stem cell transplantation (alloHCT) for adult acute lymphoblastic leukemia (ALL) remains unclear. We retrospectively analyzed outcomes of 333 adult ALL patients who underwent alloHCT at our institution over a 10-year period. Patients were classified according to disease status at transplantation (complete response [CR] 1 [n = 202] or > CR1) and according to cytogenetic risk, defined as good (2%), intermediate (42%), poor (46%), or unknown (10%) based on available outcome data for each of the cytogenetic abnormalities. Three-year overall survival (OS), leukemia-free survival (LFS), and relapse incidence (RI) were 55.7%, 47.9% and 27.5%, respectively; 1-year nonrelapse mortality (NRM) was 17.3%. For patients undergoing alloHCT in CR1, 3-year OS, LFS, and RI were 69.8%, 62.3%, and 17.1%, respectively. In multivariable analysis, cytogenetic risk did not impact OS or LFS for the whole cohort or for patients who underwent transplantation in CR1. Disease status at alloHCT was an independent predictor for LFS (CR1 versus others: hazard ratio [HR], 3.17; P < .01) and OS (CR1 versus others: HR, 2.90; P < .01). Graft-versus-host disease prophylaxis with tacrolimus/sirolimus was associated with a low NRM of 11.5% in the alloHCT recipients in CR1. Our data indicate that cytogenetic risk is not an independent predictor of outcomes in alloHCT performed to treat adult ALL. PMID:27044907

  15. Successful management of EBV-PTLD in allogeneic bone marrow transplant recipient by virological-immunological monitoring of EBV infection, prompt diagnosis and early treatment.

    PubMed

    Chiereghin, Angela; Bertuzzi, Clara; Piccirilli, Giulia; Gabrielli, Liliana; Squarzoni, Diego; Turello, Gabriele; Ferioli, Martina; Sessa, Mariarosaria; Bonifazi, Francesca; Zanoni, Lucia; Sabattini, Elena; Lazzarotto, Tiziana

    2016-02-01

    Epstein-Barr virus-related post-transplant lymphoproliferative disorder (EBV-PTLD) is an uncommon, but frequently fatal, complication after allogeneic hematopoietic stem cell transplant. Prospective post-transplant virological and immunological monitoring allowed to successfully manage a patient who developed both polymorphic and monomorphic, "diffuse large B-cell lymphoma like", as an EBV-PTLD, 65days after allogeneic bone marrow transplant. Early detection of significant increase in EBV DNA level in patient's peripheral blood (peak of viral load equal to 119,039copies/mL whole blood, +56day after transplant) led to administration of pre-emptive anti-CD20 monoclonal antibody (rituximab) and close clinical monitoring. After one week, physical exam revealed laterocervical adenopathy. Histopathologic features, immunohistochemical characterization and in situ hybridization study allowed to establish a diagnosis of EBV-related PTLD. Immunological monitoring showed no EBV-specific T-cell responses during EBV replication, thus potentially explaining the occurrence of high EBV load with subsequent PTLD development. A total of four doses of anti-CD20 monoclonal antibody were administered and at the end of the treatment, EBV infection was cleared and imaging technique showed complete disease remission. In conclusion, the early use of anti-CD20 monoclonal antibody proved to be a safe and effective treatment strategy for EBV-PTLD. Moreover, combined virological-immunological monitoring of EBV infection may more accurately assess patients at higher risk for EBV-PTLD. PMID:26687013

  16. A Safety and Tolerability Study of CDX-301 With or Without Plerixafor for Stem Cell Mobilization in Matched Related Allogeneic Donor/Recipient Sibling Transplant Pairs

    ClinicalTrials.gov

    2016-05-23

    For Donors:; Related Donors Giving Peripheral Blood Stem Cells (PBSC) to a Sibling; For Recipients:; Acute Myelogenous Leukemia (AML); Acute Lymphoblastic Leukemia (ALL); Myelodysplastic Syndrome (MDS); Chronic Myelogenous Leukemia (CML); Non-Hodgkins Lymphoma (NHL); Hodgkins Disease (HD); Chronic Lymphocytic Leukemia (CLL)

  17. Kinetics of iron removal by phlebotomy in patients with iron overload after allogeneic hematopoietic cell transplantation

    PubMed Central

    Eisfeld, Ann-Kathrin; Krahl, Rainer; Jaekel, Nadja; Niederwieser, Dietger; Al-Ali, Haifa Kathrin

    2012-01-01

    Excess body iron could persist for years after allogeneic hematopoietic cell transplantation (HCT) with possible deleterious sequels. An iron depletive therapy with phlebotomy seems rational. Kinetics of iron removal by phlebotomy without erythropoietin support in non-thalassemic adult patients with iron overload after HCT and the impact of pre- and post-HCT hemochromatosis (HFE) genotype on iron mobilization were investigated. Patients and methods: Phlebotomy was initiated in 61 recipients of allografts due to hematologic malignancies (median age 48 years) after a median of 18 months. The prephlebotomy median serum ferritin (SF) was 1697ng/ml and the median number of blood transfusions 28 units. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST), alkaline phosphates (AP), and bilirubin were elevated in 55.7%, 64% and 11.5% patients respectively. HFE-genotype was elucidated by polymerase chain reaction using hybridization probes and melting curve analysis. Results: Phlebotomy was well-tolerated irrespective of age or conditioning. A negative iron balance in 80% of patients (median SF 1086 ng/ml) and a rise in hemoglobin were observed (p<0.0001). Higher transfusional burden and SF were associated with a greater iron mobilization per session (p=0.02). In 58% of patients, a plateau after an initial steady decline in SF was followed by a second decline under further phlebotomy. The improvement in ALT (p=0.002), AST (p=0.03), AP (p=0.01), and bilirubin (p<0.0001) did not correlate with the decline in SF. Mutant HFE-gene variants were detected in 14/55 (25%) pre-HCT and 22/55 (40%) patients post-HCT. Overall, dissimilar pre- and posttransplantational HFE-genotypes were detected in 20/55 (40%) patients. Posttransplantational mutant HFE variants correlated with a slower decline in SF (p=0.007). Conclusions: Phlebotomy is a convenient therapy of iron overload in survivors of HCT. A negative iron balance and a rise in hemoglobin were observed in the majority of

  18. In silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem-Cell Transplant Donors and Recipients: Understanding the Quantitative Immunobiology of Allogeneic Transplantation

    PubMed Central

    Jameson-Lee, Max; Koparde, Vishal; Griffith, Phil; Scalora, Allison F.; Sampson, Juliana K.; Khalid, Haniya; Sheth, Nihar U.; Batalo, Michael; Serrano, Myrna G.; Roberts, Catherine H.; Hess, Michael L.; Buck, Gregory A.; Neale, Michael C.; Manjili, Masoud H.; Toor, Amir Ahmed

    2014-01-01

    Donor T-cell mediated graft versus host (GVH) effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the human leukocyte antigen (HLA) molecules in each donor–recipient pair undergoing stem-cell transplantation (SCT). Whole exome sequencing has previously demonstrated a large number of non-synonymous single nucleotide polymorphisms (SNP) present in HLA-matched recipients of SCT donors (GVH direction). The nucleotide sequence flanking each of these SNPs was obtained and the amino acid sequence determined. All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms. The SMM algorithm predicted that a median of 18,396 peptides weakly bound HLA class I molecules in individual SCT recipients, and 2,254 peptides displayed strong binding. A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm. The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential. PMID:25414699

  19. Who is fit for allogeneic transplantation?

    PubMed

    Deeg, H Joachim; Sandmaier, Brenda M

    2010-12-01

    The use of allogeneic hematopoietic cell transplantation (HCT) has expanded progressively, facilitated by the increasing availability of unrelated donors and cord blood, and the inclusion of older patients as transplantation candidates. Indications remain diagnosis-dependent. As novel nontransplantation modalities have been developed concurrently, many patients come to HCT only when no longer responding to such therapy. However, patients with refractory or advanced disease frequently relapse after HCT, even with high-dose conditioning, and more so with reduced-intensity regimens as used for patients of older age or with comorbid conditions. Thus, patients with high-risk malignancies who have substantial comorbidities or are of advanced age are at high risk of both relapse and nonrelapse mortality and should probably not be transplanted. Being in remission or at least having shown responsiveness to pre-HCT therapy is generally associated with increased transplantation success. In addition, to handle the stress associated with HCT, patients need a good social support system and a secure financial net. They must be well informed, not only about the transplantation process, but also about expected or potential post-HCT events, including graft-versus-host disease and delayed effects that may become manifest only years after HCT. PMID:20702782

  20. Second Allogeneic Hematopoietic Cell Transplantation for Patients with Fanconi Anemia and Bone Marrow Failure.

    PubMed

    Ayas, Mouhab; Eapen, Mary; Le-Rademacher, Jennifer; Carreras, Jeanette; Abdel-Azim, Hisham; Alter, Blanche P; Anderlini, Paolo; Battiwalla, Minoo; Bierings, Marc; Buchbinder, David K; Bonfim, Carmem; Camitta, Bruce M; Fasth, Anders L; Gale, Robert Peter; Lee, Michelle A; Lund, Troy C; Myers, Kasiani C; Olsson, Richard F; Page, Kristin M; Prestidge, Tim D; Radhi, Mohamed; Shah, Ami J; Schultz, Kirk R; Wirk, Baldeep; Wagner, John E; Deeg, H Joachim

    2015-10-01

    A second allogeneic hematopoietic cell transplantation (HCT) is the sole salvage option for individuals who develop graft failure after their first HCT. Data on outcomes after second HCT in patients with Fanconi anemia (FA) are scarce. Here we report outcomes after second allogeneic HCT for FA (n = 81). The indication for second HCT was graft failure after the first HCT. Transplantations were performed between 1990 and 2012. The timing of the second HCT predicted subsequent graft failure and survival. Graft failure was high when the second HCT was performed less than 3 months from the first. The 3-month probability of graft failure was 69% when the interval between the first HCT and second HCT was less than 3 months, compared with 23% when the interval was longer (P < .001). Consequently, the 1-year survival rate was substantially lower when the interval between the first and second HCTs was less than 3 months compared with longer (23% vs 58%; P = .001). The corresponding 5-year probability of survival was 16% and 45%, respectively (P = .006). Taken together, these data suggest that fewer than one-half of patients with FA undergoing a second HCT for graft failure are long-term survivors. There is an urgent need to develop strategies to reduce the rate of graft failure after first HCT. PMID:26116087

  1. Utility of the Enzyme-Linked Immunospot Interferon-γ–Release Assay to Predict the Risk of Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients

    PubMed Central

    Nesher, Lior; Shah, Dimpy P.; Ariza-Heredia, Ella J.; Azzi, Jacques M.; Siddiqui, Hala K.; Ghantoji, Shasank S.; Marsh, Lisa Y.; Michailidis, Lamprinos; Makedonas, George; Rezvani, Katy; Shpall, Elizabeth J.; Chemaly, Roy F.

    2016-01-01

    The ability to distinguish allogeneic hematopoietic cell transplant (allo-HCT) recipients at risk for cytomegalovirus (CMV) reactivation from those who are not is central for optimal CMV management strategies. Interferon γ (IFN-γ) produced by CMV-challenged T cells may serve as an immune marker differentiating these 2 populations. We prospectively monitored 63 CMV-seropositive allo-HCT recipients with a CMV-specific enzyme-linked immunospot (ELISPOT) assay and for CMV infection from the period before transplantation to day 100 after transplantation. Assay results above certain thresholds (50 spots per 250 000 cells for immediate early 1 or 100 spots per 250 000 cells for phosphoprotein 65) identified patients who were protected against CMV infection as long as they had no graft-versus-host disease and/or were not receiving systemic corticosteroids. Based on the multivariable Cox proportional hazards regression model, the only significant factor for preventing CMV reactivation was a CMV-specific ELISPOT response above the determined thresholds (adjusted hazard ratio, 0.21; 95% confidence interval, .05–.97; P = .046). Use of this assay as an additional tool for managing allo-HCT recipients at risk for CMV reactivation needs further validation in future studies. Application of this new approach may reduce the duration and intensity of CMV monitoring and the duration of prophylaxis or treatment with antiviral agents in those who have achieved CMV-specific immune reconstitution. PMID:26908740

  2. Utility of the Enzyme-Linked Immunospot Interferon-γ-Release Assay to Predict the Risk of Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients.

    PubMed

    Nesher, Lior; Shah, Dimpy P; Ariza-Heredia, Ella J; Azzi, Jacques M; Siddiqui, Hala K; Ghantoji, Shasank S; Marsh, Lisa Y; Michailidis, Lamprinos; Makedonas, George; Rezvani, Katy; Shpall, Elizabeth J; Chemaly, Roy F

    2016-06-01

    The ability to distinguish allogeneic hematopoietic cell transplant (allo-HCT) recipients at risk for cytomegalovirus (CMV) reactivation from those who are not is central for optimal CMV management strategies. Interferon γ (IFN-γ) produced by CMV-challenged T cells may serve as an immune marker differentiating these 2 populations. We prospectively monitored 63 CMV-seropositive allo-HCT recipients with a CMV-specific enzyme-linked immunospot (ELISPOT) assay and for CMV infection from the period before transplantation to day 100 after transplantation. Assay results above certain thresholds (50 spots per 250 000 cells for immediate early 1 or 100 spots per 250 000 cells for phosphoprotein 65) identified patients who were protected against CMV infection as long as they had no graft-versus-host disease and/or were not receiving systemic corticosteroids. Based on the multivariable Cox proportional hazards regression model, the only significant factor for preventing CMV reactivation was a CMV-specific ELISPOT response above the determined thresholds (adjusted hazard ratio, 0.21; 95% confidence interval, .05-.97; P = .046). Use of this assay as an additional tool for managing allo-HCT recipients at risk for CMV reactivation needs further validation in future studies. Application of this new approach may reduce the duration and intensity of CMV monitoring and the duration of prophylaxis or treatment with antiviral agents in those who have achieved CMV-specific immune reconstitution. PMID:26908740

  3. Risk factors for invasive aspergillosis and related mortality in recipients of allogeneic SCT from alternative donors: an analysis of 306 patients.

    PubMed

    Mikulska, M; Raiola, A M; Bruno, B; Furfaro, E; Van Lint, M T; Bregante, S; Ibatici, A; Del Bono, V; Bacigalupo, A; Viscoli, C

    2009-09-01

    Invasive aspergillosis (IA) is a serious complication in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT), particularly from donors other than HLA-identical sibling. All 306 patients who underwent alternative donor HSCT between 01 January 1999 and 31 December 2006 were studied. Late IA was defined as occurring >or=40 days after HSCT. The median follow-up was 284 days (range, 1-2709). Donors were matched unrelated (n=185), mismatched related (n=69), mismatched unrelated (n=35) and unrelated cord blood (n=17). According to European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria, 2 patients already had IA at HSCT, 23 had early IA and 20 had late IA (IA incidence 15%). Eight patients had proven and 37 probable IA. Multivariate analyses showed that significant predictors of IA were delayed neutrophil engraftment, extensive chronic GVHD (cGVHD), secondary neutropenia and relapse after transplant. Early IA was associated with active malignancy at HSCT, CMV reactivation and delayed lymphocyte engraftment. Late IA was predicted by cGVHD, steroid therapy, secondary neutropenia and relapse after HSCT. IA-related mortality among IA patients was 67% and was influenced by use of anti-thymocyte globulin, steroids, higher levels of creatinine, and lower levels of IgA and platelets. The outcome of IA depends on the severity of immunodeficiency and the status of the underlying disease. PMID:19308042

  4. Cytomegalovirus infections in allogeneic stem cell recipients after reduced-intensity or myeloablative conditioning assessed by quantitative PCR and pp65-antigenemia.

    PubMed

    Schetelig, J; Oswald, O; Steuer, N; Radonic, A; Thulke, S; Held, T K; Oertel, J; Nitsche, A; Siegert, W

    2003-10-01

    Since the incidence of cytomegalovirus (CMV) infections after hematopoietic stem cell transplantation (HSCT) may depend on the intensity of the pretreatment, we studied the incidence of CMV infections after reduced-intensity compared to myeloablative conditioning. A total of 82 patients with matched related or unrelated donors were prospectively monitored for CMV infections after HSCT by CMV-PCR techniques, CMV-antigenemia and clinical observation. A total of 45 patients received reduced-intensity conditioning consisting of fludarabine, busulfan and ATG and 37 patients received myeloablative conditioning. Leukocyte engraftment occurred after a median of 15 vs 18 days (P=0.012) and platelet engraftment after 12 days vs 20 days (P=0.001), respectively. Acute graft-versus-host disease (GVHD) grade II-IV was observed in 58 vs 54% patients (P=0.737), respectively. The onset and peak values of CMV-antigenemia and DNAemia and the incidence of CMV infections did not differ statistically significantly between the two treatment groups. Multivariate analysis confirmed CMV seropositivity of the recipient (P=0.035), acute GVHD II-IV (P=0.001) but not the type of conditioning as significant risk factors for CMV-antigenemia. In conclusion, the kinetics of CMV-antigenemia and DNAemia and the incidence of CMV infections were not statistically different in patients who received HSCT after reduced-intensity conditioning with fludarabine, busulfan and ATG compared to myeloablative conditioning. PMID:13130317

  5. Outcomes in Patients With Relapsed or Refractory Acute Promyelocytic Leukemia Treated With or Without Autologous or Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Pemmaraju, Naveen; Tanaka, Maria Florencia; Ravandi, Farhad; Lin, Heather; Baladandayuthapani, Veerabhadran; Rondon, Gabriela; Giralt, Sergio A.; Chen, Julianne; Pierce, Sherry; Cortes, Jorge; Kantarjian, Hagop; Champlin, Richard E.; De Lima, Marcos; Qazilbash, Muzaffar H.

    2014-01-01

    Outcomes in patients with acute promyelocytic leukemia have improved; however, a subset of patients relapse despite receiving all-trans-retinoic acid and/or arsenic-based therapies. Among 40 patients with acute promyelocytic leukemia who were treated at our institution (1980–2010), 24 received hematopoietic stem cell transplantation (HCT) (autologous HCT, 7; allogeneic HCT, 14; both, 3); 16 received chemotherapy only. All 3 strategies (autologous HCT, allogeneic HCT, chemotherapy) were feasible in patients with relapsed acute promyelocytic leukemia and result in long-term disease control in selected patients. Background Outcomes in patients with acute promyelocytic leukemia (APL) have improved; however, a significant number of patients still relapse despite receiving all-trans-retinoic acid (ATRA) and arsenic-based therapies. Patients and Methods Outcomes of patients with relapsed APL who were treated at our institution (1980–2010) and who received HCT were compared with those who received chemotherapy (CT) only. Results Among 40 patients, 24 received HCT (autologous [auto] HCT, 7; allogeneic [allo] HCT, 14; both, 3); 16 received CT only. The median age at diagnosis was 36 years (range, 13–50 years), 31 years (range, 16–58 years), and 44 years (range, 24–79 years) for the auto-HCT, allo-HCT, and CT groups, respectively. Ten (100%) patients who received auto-HCT and 12 (71%) who received allo-HCT were in complete remission at the time of the HCT. The median follow-ups in the auto-HCT, allo-HCT, and CT groups were 74 months (range, 26–135 months), 118 months (range, 28–284 months), and 122 months (range, 32–216 months), respectively. Transplantation-related mortality (1 year) after auto-HCT and allo-HCT were 10% and 29%, respectively. The 7-year event-free survival after auto-HCT and allo-HCT was 68.6% and 40.6%, respectively (P = .45). The 7-year overall survival was 85.7%, 49.4%, and 40% in the auto-HCT, allo-HCT, and CT groups, respectively (P

  6. Incidence and risk factors of post-engraftment invasive fungal disease in adult allogeneic hematopoietic stem cell transplant recipients receiving oral azoles prophylaxis.

    PubMed

    Montesinos, P; Rodríguez-Veiga, R; Boluda, B; Martínez-Cuadrón, D; Cano, I; Lancharro, A; Sanz, J; Arilla, M J; López-Chuliá, F; Navarro, I; Lorenzo, I; Salavert, M; Pemán, J; Calvillo, P; Martínez, J; Carpio, N; Jarque, I; Sanz, G F; Sanz, M A

    2015-11-01

    Studies that analyze the epidemiology and risk factors for invasive fungal disease (IFD) after engraftment in alloSCT are few in number. This single-center retrospective study included 404 alloSCT adult recipients surviving >40 days who engrafted and were discharged without prior IFD. All patients who received ⩾20 mg/day of prednisone were assigned to primary oral prophylaxis (itraconazole or low-dose voriconazole). The primary end point was the cumulative incidence (CI) of probable/proven IFD using the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) criteria. The independent prognostic factors after multivariate analyses were used to construct a post-engraftment IFD risk score. The 1-year CI of IFD was 11%. The non-relapse mortality was 40% in those developing IFD and 16% in those who did not. The intent-to-treat analysis showed that 17% of patients abandoned the assigned prophylaxis. Age >40 years, ⩾1 previous SCT, pre-engraftment neutropenia >15 days, extensive chronic GVHD and CMV reactivation were independent risk factors. The post-engraftment IFD score stratified patients into low risk (0-1 factor, CI 0.7%), intermediate risk (2 factors, CI 9.9%) and high risk (3-5 factors, CI 24.7%) (P<0.0001). The antifungal prophylaxis strategy failed to prevent post-engraftment IFD in 11% of alloSCT. Our risk score could be useful to implement risk-adapted strategies using antifungal prophylaxis after engraftment. PMID:26281032

  7. Immunogenicity, Safety, and Tolerability of 13-Valent Pneumococcal Conjugate Vaccine Followed by 23-Valent Pneumococcal Polysaccharide Vaccine in Recipients of Allogeneic Hematopoietic Stem Cell Transplant Aged ≥2 Years: An Open-Label Study

    PubMed Central

    Cordonnier, Catherine; Ljungman, Per; Juergens, Christine; Maertens, Johan; Selleslag, Dominik; Sundaraiyer, Vani; Giardina, Peter C.; Clarke, Keri; Gruber, William C.; Scott, Daniel A.; Schmoele-Thoma, Beate

    2015-01-01

    Background. Life-threatening Streptococcus pneumoniae infections often occur after hematopoietic stem cell transplant (HSCT); vaccination is important for prevention. Methods. In an open-label study, patients (n = 251) 3–6 months after allogeneic HSCT received 3 doses of 13-valent pneumococcal conjugate vaccine (PCV13) at 1-month intervals, a fourth dose 6 months later, and 1 dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) 1 month later. Immunogenicity at prespecified time points and vaccine safety were assessed. Results. In the evaluable immunogenicity population (N = 216; mean age, 37.8 years), geometric mean fold rises (GMFRs) of immunoglobulin G geometric mean concentrations from baseline to postdose 3 showed significant increases in antibody levels across all PCV13 serotypes (GMFR range, 2.99–23.85; 95% confidence interval lower limit, >1); there were significant declines over the next 6 months, significant increases from predose 4 to postdose 4 (GMFR range, 3.00–6.97), and little change after PPSV23 (GMFR range, 0.86–1.12). Local and systemic reactions were more frequent after dose 4. Six patients experienced serious adverse events possibly related to PCV13 (facial diplegia, injection-site erythema and pyrexia, autoimmune hemolytic anemia, and suspected lack of vaccine efficacy after dose 3 leading to pneumococcal infection), PCV13 and PPSV23 (Guillain-Barré syndrome), or PPSV23 (cellulitis). There were 14 deaths, none related to study vaccines. Conclusions. A 3-dose PCV13 regimen followed by a booster dose may be required to protect against pneumococcal disease in HSCT recipients. Dose 4 was associated with increased local and systemic reactions, but the overall safety profile of a 4-dose regimen was considered acceptable. Clinical Trials Registration. NCT00980655. PMID:25870329

  8. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders.

    PubMed

    Laport, Ginna G; Sandmaier, Brenda M; Storer, Barry E; Scott, Bart L; Stuart, Monic J; Lange, Thoralf; Maris, Michael B; Agura, Edward D; Chauncey, Thomas R; Wong, Ruby M; Forman, Stephen J; Petersen, Finn B; Wade, James C; Epner, Elliot; Bruno, Benedetto; Bethge, Wolfgang A; Curtin, Peter T; Maloney, David G; Blume, Karl G; Storb, Rainer F

    2008-02-01

    Allogeneic hematopoietic cell transplantation (HCT) is the only curative strategy for patients with myelodysplastic syndrome (MDS) and myeloproliferative disorders (MPD). We report the results of 148 patients (median age = 59 years old) with de novo MDS (n = 40), acute myelogenous leukemia (AML) after antecedent MDS/MPD (n = 49), treatment-related MDS (t-MDS) (n = 25), MPD (n = 27), and chronic myelomonocytic leukemia (CMML) (n = 7) who underwent allogeneic HCT using a conditioning regimen of low-dose total body irradiation (TBI) alone (200 cGy) on day 0 (n = 5) or with the addition of fludarabine (Flu) 30 mg/m(2)/day on days -4 to -2 (n = 143). Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil (MMF). Seventy-five patients (51%) received an allograft from a matched related donor (MRD), and 73 patients (49%) were recipients of unrelated donor (URD) grafts. There was no significant difference in the incidence of acute (gr II-IV) and chronic extensive graft-versus-host disease (aGVHD, cGVHD) between the recipients of related and unrelated donor grafts. By day +28, 75% of patients demonstrated mixed T cell chimerism. Graft rejection was seen in 15% of patients. With a median follow-up of 47 (range: 6-89) months, the 3-year relapse-free survival (RFS) and overall survival (OS) are both 27% for all patients, with a relapse incidence of 41%. The 3-year RFS for the patients with de novo MDS, AML after antecedent MDS/MPD, t-MDS, MPD, and CMML were 22%, 20%, 29%, 37%, and 43%, respectively, and the 3-year OS was 20%, 23%, 27%, 43%, and 43%, respectively. The 3-year nonrelapse mortality (NRM) was 32%. Factors associated with a lower risk of relapse were the development of extensive cGVHD and having a low risk or intermediate-1 risk International Prognostic Score for the de novo MDS patients. Nonmyeloablative HCT confers remissions in patients who otherwise were not eligible for conventional HCT but for whom relapse is the leading cause of

  9. Factors Predicting Graft-versus-Host Disease-Free, Relapse-Free Survival after Allogeneic Hematopoietic Cell Transplantation: Multivariable Analysis from a Single Center.

    PubMed

    Solh, Melhem; Zhang, Xu; Connor, Katelin; Brown, Stacey; Solomon, Scott R; Morris, Lawrence E; Holland, H Kent; Bashey, Asad

    2016-08-01

    The ideal outcome of allogeneic hematopoietic cell transplantation (allo-HCT) is based on survival that is free of morbidity. The most common causes of treatment failure and morbidity after HCT are relapse, graft-versus-host disease (GVHD), and nonrelapse death. A composite endpoint that measures survival free of clinically significant negative events may be a useful way to determine the success of allo-HCT. We assessed GVHD and relapse-free survival (GRFS) where the events were acute GVHD grades III to IV, chronic GVHD requiring immunosuppression, relapse, or death in 531 consecutive adult patients who received an allo-HCT between 2006 and 2014 at our center. Median follow-up of living patients was 46 months (range, 12 to 123). HLA matched related donor (MRD, n = 198, 37%), matched unrelated donor (MUD, n = 205, 39%), and haploidentical donor with post-transplant cyclophosphamide (HID, n = 128, 24%) were used. Thirty-six percent of patients had a high/very-high Dana Farber disease risk index (DRI). Estimated rates of GRFS at 1 and 2 years after MRD, MUD, and HID transplantations were 34% and 26%, 26% and 17%, and 33% and 31%, respectively, with MRD recipients having a better GRFS than MUD (P < .05). On multivariable analysis, peripheral blood stem cell source (HR, 1.34; P = .04), MUD (HR, 1.41; P = .003), and high/very high DRI (HR, 1.66; P = .001) were all associated with a worse GFRS post-HCT. These data suggest that GRFS can be predicted by patient disease risk, stem cell source, and donor type. Importantly, MUDs produce inferior GRFS to MRDs, whereas HIDs do not. PMID:27095692

  10. Urinary Elafin and Kidney Injury in Hematopoietic Cell Transplant Recipients

    PubMed Central

    Finn, Laura S.; Pao, Emily; Lawler, Rick; Schoch, Gary; McDonald, George B.; Najafian, Behzad; Sandmaier, Brenda; Gooley, Ted

    2015-01-01

    Background and objectives Graft-versus-host disease (GVHD) is associated with kidney injury after hematopoietic cell transplantation (HCT). Because plasma elafin levels correlate with skin GVHD, this study examined urinary elafin as a potential marker of renal inflammation and injury. Design, setting, participants, & measurements Urine was collected prospectively on 205 patients undergoing their first HCT from 2003 to 2010. Collections were done at baseline, weekly through day 100, and monthly through year 1 to measure elafin and urine albumin-to-creatinine ratio (ACR). Associations between urinary elafin levels and microalbuminuria, macroalbuminuria, AKI and CKD, and mortality were examined using Cox proportional hazards or linear regression models. Available kidney biopsy specimens were processed for immunohistochemistry. Results Mean urinary elafin levels to day 100 were higher in patients with micro- or macroalbuminuria (adjusted mean difference, 529 pg/ml; P=0.03) at day 100 than in those with a normal ACR (adjusted mean difference, 1295 pg/ml; P<0.001). Mean urinary elafin levels were higher in patients with AKI compared with patients without AKI (adjusted mean difference, 558 pg/ml; P<0.01). The average urinary elafin levels within the first 100 days after HCT were higher in patients who developed CKD at 1 year than in patients without CKD (adjusted mean difference, 894 pg/ml; P=0.002). Among allogeneic recipients, a higher proportion of patients with micro- or macroalbuminuria at day 100 also had grade II-IV acute GVHD (80% and 86%, respectively) compared with patients with a normal ACR (58%; global P<0.01). Each increase in elafin of 500 pg/ml resulted in a 10% increase in risk of persistent macroalbuminuria (hazard ratio, 1.10; 95% confidence interval [95% CI], 1.06 to 1.13; P<0.001) and a 7% increase in the risk of overall mortality (95% CI, 1.02 to 1.13, P<0.01). Renal biopsy specimens from a separate cohort of HCT survivors demonstrated elafin staining

  11. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation

    PubMed Central

    Lee, Stephanie J.; Ahn, Kwang Woo; Spellman, Stephen; Wang, Hai-Lin; Aljurf, Mahmoud; Askar, Medhat; Dehn, Jason; Fernandez Viña, Marcelo; Gratwohl, Alois; Gupta, Vikas; Hanna, Rabi; Horowitz, Mary M.; Hurley, Carolyn K.; Inamoto, Yoshihiro; Kassim, Adetola A.; Nishihori, Taiga; Mueller, Carlheinz; Oudshoorn, Machteld; Petersdorf, Effie W.; Prasad, Vinod; Robinson, James; Saber, Wael; Schultz, Kirk R.; Shaw, Bronwen; Storek, Jan; Wood, William A.; Woolfrey, Ann E.; Anasetti, Claudio

    2014-01-01

    We examined current outcomes of unrelated donor allogeneic hematopoietic cell transplantation (HCT) to determine the clinical implications of donor-recipient HLA matching. Adult and pediatric patients who had first undergone myeloablative-unrelated bone marrow or peripheral blood HCT for acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome between 1999 and 2011 were included. All had high-resolution typing for HLA-A, -B, -C, and -DRB1. Of the total (n = 8003), cases were 8/8 (n = 5449), 7/8 (n = 2071), or 6/8 (n = 483) matched. HLA mismatch (6-7/8) conferred significantly increased risk for grades II to IV and III to IV acute graft vs host disease (GVHD), chronic GVHD, transplant-related mortality (TRM), and overall mortality compared with HLA-matched cases (8/8). Type (allele/antigen) and locus (HLA-A, -B, -C, and -DRB1) of mismatch were not associated with overall mortality. Among 8/8 matched cases, HLA-DPB1 and -DQB1 mismatch resulted in increased acute GVHD, and HLA-DPB1 mismatch had decreased relapse. Nonpermissive HLA-DPB1 allele mismatch was associated with higher TRM compared with permissive HLA-DPB1 mismatch or HLA-DPB1 match and increased overall mortality compared with permissive HLA-DPB1 mismatch in 8/8 (and 10/10) matched cases. Full matching at HLA-A, -B, -C, and -DRB1 is required for optimal unrelated donor HCT survival, and avoidance of nonpermissive HLA-DPB1 mismatches in otherwise HLA-matched pairs is indicated. PMID:25161269

  12. ABO mismatch is associated with increased non-relapse mortality after allogeneic hematopoietic cell transplantation

    PubMed Central

    Logan, Aaron C.; Wang, Zhiyu; Alimoghaddam, Kamran; Wong, Ruby M.; Lai, Tze; Negrin, Robert S.; Grumet, Carl; Logan, Brent R.; Zhang, Mei-Jie; Spellman, Stephen R.; Lee, Stephanie J.; Miklos, David B.

    2015-01-01

    We evaluated ABO associated outcomes in 1,737 patients who underwent allogeneic hematopoietic cell transplant (allo-HCT) at Stanford University between January 1986 and July 2011. Grafts were 61% ABO matched, 18% major mismatched (MM), 17% minor MM, and 4% bidirectional MM. Median follow-up was 6 years. In multivariate analysis, OS was inferior in minor MM HCT (median 2.1 vs 6.3 years; HR 1.56; 95%CI 1.19-2.05; p=0.001) in comparison with ABO matched grafts. ABO minor MM was associated with an increase in early NRM (18% vs 13%; HR 1.48, 95%CI 1.06-2.06; p=0.02). In an independent Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 435 lymphoma patients receiving mobilized peripheral blood grafts, impairment of OS (HR 1.55; 95%CI 1.07 – 2.25; p=0.021) and increased NRM (HR 1.72; 95%CI 1.11 – 2.68; p=0.03) was observed in recipients of ABO minor MM grafts. A second independent analysis of a CIBMTR dataset including 5,179 patients with AML and MDS identified a non-significant trend toward decreased OS in recipients of ABO minor MM grafts and also found ABO major MM to be significantly associated with decreased OS (HR 1.19, 95% CI 1.08 – 1.31, p<0.001) and increased NRM (HR 1.23, 95%CI 1.08 – 1.4, p=0.002). ABO minor and major MM are risk factors for worse transplant outcomes, although the associated hazards may not be uniform across different transplant populations. Further study is warranted to determine which patient populations are at greatest risk, and whether this risk can be modified by anti-B-cell therapy or other peri-transplant treatments. PMID:25572032

  13. Role of allogeneic stem cell transplantation in mantle cell lymphoma.

    PubMed

    Cohen, Jonathon B; Burns, Linda J; Bachanova, Veronika

    2015-04-01

    Despite a wide spectrum of treatment options, mantle cell lymphoma (MCL) remains a challenging hematologic malignancy to manage. Advances in front-line therapy, including the monoclonal antibody rituximab and increasing use of cytarabine, have improved remission rates. Autologous hematopoietic cell transplantation (HCT) can effectively consolidate remission of MCL, leading to encouraging survival beyond 5 yr. However, nearly all patients with MCL will relapse and require salvage therapy. Novel agents such as ibrutinib, bortezomib, and lenalidomide have dramatically expanded the options for treating relapsed MCL. In this review, we summarize the clinical evidence supporting the use of allogeneic donor HCT in MCL and make recommendations on indications for its use. Data suggest that allogeneic donor HCT is the only curative therapy for patients with poor prognosis or aggressive MCL. Patient selection, timing, and optimal use remain a matter of scientific debate and given the rapidly changing therapeutic landscape of MCL, the outcomes of allogeneic HCT should be interpreted in the context of novel therapeutics. PMID:25154430

  14. Allogeneic Transplantation for Chronic Lymphocytic Leukemia

    PubMed Central

    Laurenti, Luca; Tarnani, Michela; Chiusolo, Patrizia; Sorà, Federica; Sica, Simona

    2010-01-01

    Even if Chronic lymphocytic leukemia (CLL) often has an indolent behavior with good responsiveness to cytoreductive treatment, about 20% of the patients, so called “poor-risk” patients, show an aggressive course and die within a few years despite early intensive therapies. Criteria for poor-risk disease according to the European Bone Marrow Transplantation (EBMT) CLL Transplant Consensus are: purine analogue refractoriness, early relapse after purine analogue combination therapy, CLL with p53 lesion requiring treatment. Allogeneic transplant has potential curative role in CLL, however burden with very high transplant related mortality (TRM) rates of 38–50%. A major advance in reducing the short-term morbidity and mortality of allogeneic stem cell transplantation (SCT) has been the introduction of non-myeloablative or reduced intensity conditioning (RIC) regimens to allow engraftment of allogeneic stem cells. There is no doubt that the crucial therapeutic principle of allo-SCT in CLL is graft versus leukemia (GVL) activity. The major complications of allogeneic SCT in CLL are: chronic graft-versus-host-disease (GVHD) affecting quality of life, high graft rejection and infection rates correlated with preexisting immunosuppression. Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients. Sensitive minimal residual disease (MRD) quantification has strong prognostic impact after transplant. PMID:21415973

  15. Immune Tolerance in Recipients of Combined Haploidentical Bone Marrow and Kidney Transplantation

    PubMed Central

    Sykes, Megan

    2016-01-01

    The success of allogeneic HCT has been limited by transplant-associated toxicities related to the conditioning regimens used and to graft-vs-host disease (GVHD). The frequency and severity of GVHD observed when extensive HLA barriers are transgressed has greatly impeded the routine use of extensively HLA-mismatched HCT. Allogeneic HCT also has potential as an approach to organ allograft tolerance induction, but this potential has not been previously realized because of the toxicity associated with traditional conditioning. This paper reviews an approach to HCT involving reduced intensity conditioning that demonstrated sufficient safety in patients with hematologic malignancies, even in the HLA-mismatched transplant setting, to be applied for the induction of kidney allograft tolerance in humans with no other indication for HCT. These studies provided the first successful example of intentional organ allograft tolerance induction across HLA barriers in humans. Current data and hypotheses on the mechanisms of tolerance in these patients are reviewed. PMID:26039215

  16. Long-term oral complications of allogeneic haematopoietic SCT.

    PubMed

    Hull, K M; Kerridge, I; Schifter, M

    2012-02-01

    This study assessed the incidence of long-term oral complications in 88 survivors of allogeneic haematopoietic cell transplantation (HCT). Patients examined were between 6 months and 6 years post-HCT and aged from 19 to 65 years. Subjects were investigated for both the subjective and objective features of long-term adverse oral effects of HCT. The most common oral symptoms reported were xerostomia (44%, n=39) and reduction in taste (20%, n=18). Only a minority of patients (15%) reported that oral disease had a significant adverse impact upon their quality of life. The majority of patients (53%) had clinical markers of oral chronic GVHD (cGVHD). The most frequently identified feature was salivary hypofunction, with 34% of subjects demonstrating a reduction in stimulated saliva. Oral mucosal changes consistent with cGVHD affected 21% of subjects. Oral cGVHD commonly occurs after allogeneic HCT, often coexists with cutaneous, hepatic or ocular cGVHD and may lead to debilitating symptoms. Transplant type and pre-existing acute GVHD are the major risk factors for oral cGVHD. The identification of risk factors specific for oral cGVHD may allow clinicians some foresight into identifying patients at high risk of developing oral cGVHD and encourage attention to education, regular oral surveillance and rigorous preventative oral health strategies both pre- and post-transplant. PMID:21441960

  17. Engraftment syndrome after allogeneic hematopoietic cell transplantation predicts poor outcomes.

    PubMed

    Chang, Lawrence; Frame, David; Braun, Thomas; Gatza, Erin; Hanauer, David A; Zhao, Shuang; Magenau, John M; Schultz, Kathryn; Tokala, Hemasri; Ferrara, James L M; Levine, John E; Reddy, Pavan; Paczesny, Sophie; Choi, Sung Won

    2014-09-01

    Engraftment syndrome (ES), characterized by fever, rash, pulmonary edema, weight gain, liver and renal dysfunction, and/or encephalopathy, occurs at the time of neutrophil recovery after hematopoietic cell transplantation (HCT). In this study, we evaluated the incidence, clinical features, risk factors, and outcomes of ES in children and adults undergoing first-time allogeneic HCT. Among 927 patients, 119 (13%) developed ES at a median of 10 days (interquartile range 9 to 12) after HCT. ES patients experienced significantly higher cumulative incidence of grade 2 to 4 acute GVHD at day 100 (75% versus 34%, P < .001) and higher nonrelapse mortality at 2 years (38% versus 19%, P < .001) compared with non-ES patients, resulting in lower overall survival at 2 years (38% versus 54%, P < .001). There was no significant difference in relapse at 2 years (26% versus 31%, P = .772). Suppression of tumorigenicity 2, interleukin 2 receptor alpha, and tumor necrosis factor receptor 1 plasma biomarker levels were significantly elevated in ES patients. Our results illustrate the clinical significance and prognostic impact of ES on allogeneic HCT outcomes. Despite early recognition of the syndrome and prompt institution of corticosteroid therapy, outcomes in ES patients were uniformly poor. This study suggests the need for a prospective approach of collecting clinical features combined with correlative laboratory analyses to better characterize ES. PMID:24892262

  18. Allogeneic Hematopoietic Cell Transplantation for Children with Sickle Cell Disease Is Beneficial and Cost-Effective: A Single-Center Analysis.

    PubMed

    Arnold, Staci D; Jin, Zhezhen; Sands, Stephen; Bhatia, Monica; Kung, Andrew L; Satwani, Prakash

    2015-07-01

    Limited data exist regarding health care utilization (HCU) in patients receiving allogeneic hematopoietic cell transplantation (alloHCT) for sickle cell disease. Financial data from 2002 to 2011 were analyzed for 26 alloHCT patients and 48 control subjects (referred but without alloHCT). HCU of alloHCT was determined over 3 time periods: pre-alloHCT, during alloHCT (day 0 to day +365), and post-alloHCT. The median total cost per patient during the alloHCT year was $413,000 inpatient and $18,000 outpatient. Post-alloHCT HCU decreased when compared with pre-alloHCT and control subjects. The median cost of post-alloHCT outpatient visits per patient was significantly less when compared with pre-alloHCT (P = .044). The median cost of post-alloHCT inpatient visits per patient approached significance when compared with those pre-alloHCT (P = .079). Sixteen post-alloHCT patients, 19 control subjects, and 14 unaffected siblings were surveyed using Pediatric Quality of Life Inventory and EuroQOL questionnaires; however, the questionnaire scores across all 3 patient groups were not statistically significant (P = .2638). When adjusted for health-related quality of life, the analysis suggested alloHCT has a positive impact on health-related quality of life over control subjects. These pilot data support our hypothesis that alloHCT in children with sickle cell disease reduces HCU compared with control subjects without alloHCT. PMID:25615608

  19. Immune Reconstitution after Allogeneic Hematopoietic Cell Transplantation in Children.

    PubMed

    de Koning, Coco; Plantinga, Maud; Besseling, Paul; Boelens, Jaap Jan; Nierkens, Stefan

    2016-02-01

    Allogeneic (allo) hematopoietic cell transplantation (HCT) has evolved into a potent curative treatment option for a variety of malignant and nonmalignant diseases. The occurrence of complications and mortality after allo-HCT is, however, still high and is strongly associated with immune reconstitution (IR). Therefore, detailed information on IR through immunomonitoring is crucial to improve survival chances after HCT. To date, information about the reconstituting immune system after allo-HCT in pediatric patients is mostly derived from routine standard-of-care measurements. More profound knowledge on IR may provide tools to better predict and modulate adverse reactions and, subsequently, improve survival chances. Here, we provide an overview of IR (eg, immune cell subsets and circulating chemokines/cytokines) after allo-HCT in children, taking into account different cell sources and serotherapy, and discuss strategies to enhance immunomonitoring. We conclude that available IR data after allo-HCT contain limited information on immune cell families (mostly only generic T, B, and NK cells), which would improve with more detailed information on reconstituting cell subsets or effector cell functionality at earlier time points (<1 month). In addition, secretome data (eg, multiplex cytokine/chemokine profiles) could add to the understanding of IR mechanisms and cell functionality and may even provide (early) biomarkers for individual disease outcome, such as viral reactivity, graft-versus-host disease, or graft-versus-leukemia. The present data and suggestions for more detailed, standardized, and harmonized immunomonitoring in future (pediatric) allo-HCT studies will pave the path to "precision transplantation:" an individualized HCT approach (including conditioning), based on detailed information on IR and biomarkers, aiming to reduce transplantation related mortality and relapse, and subsequently improve survival chances. PMID:26341398

  20. Frequency of abnormal findings detected by comprehensive clinical evaluation at 1 year after allogeneic hematopoietic cell transplantation.

    PubMed

    Lee, Stephanie J; Seaborn, Travis; Mao, Frances J; Massey, Susan C; Luu, Ngoc Q; Schubert, Mary A; Chien, Jason W; Carpenter, Paul A; Moravec, Carina; Martin, Paul J; Flowers, Mary E D

    2009-04-01

    Consensus guidelines recommend various screening examinations for survivors after allogeneic hematopoietic cell transplantation (HCT), but how often these examinations detect abnormal findings is unknown. We reviewed the medical records of 118 patients who received comprehensive, standardized evaluations at 1 year after allogeneic HCT at Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance. Abnormal findings were common, including moderate to severe pulmonary dysfunction (16%), fasting hyperlipidemia (56%), osteopenia (52%), osteoporosis (6%), and active chronic graft-versus-host disease (cGVHD) (64%). Recurrent malignancy (4%) and cGVHD (29%) were detected in previously unsuspected cases. Only 3% of patients had no abnormal findings. We conclude that comprehensive evaluation at 1 year after allogeneic HCT detects a high prevalence of medical problems. Longer follow-up is needed to determine whether early detection and intervention affect later morbidity and mortality. PMID:19285628

  1. Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation

    PubMed Central

    Faridi, Rehan Mujeeb; Kemp, Taylor J.; Dharmani-Khan, Poonam; Lewis, Victor; Rajalingam, Raja; Berka, Noureddine; Storek, Jan; Masood Khan, Faisal

    2016-01-01

    Background Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT Methods and Findings The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into ‘discovery’ (135 pairs) and ‘validation’ (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50–5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33–5.11). High incidence of cGVHD associated

  2. SIMILAR OUTCOMES USING MYELOABLATIVE VERSUS REDUCED INTENSITY ALLOGENEIC TRANSPLANT PREPARATIVE REGIMENS FOR AML OR MDS

    PubMed Central

    Luger, Selina M.; Ringdén, Olle; Zhang, Mei-Jie; Pérez, Waleska S.; Bishop, Michael R.; Bornhauser, Martin; Bredeson, Christopher N.; Cairo, Mitchell S.; Copelan, Edward A.; Gale, Robert Peter; Giralt, Sergio A.; Gulbas, Zafer; Gupta, Vikas; Hale, Gregory A.; Lazarus, Hillard M.; Lewis, Victor Anthony; Lill, Michael C.; McCarthy, Philip L.; Weisdorf, Daniel J.; Pulsipher, Michael A.

    2011-01-01

    Although reduced intensity (RIC) and nonmyeloablative (NMA) conditioning regimens have been used for over a decade, their relative efficacy versus myeloablative (MA) approaches to allogeneic hematopoietic cell transplantation (HCT) in patients with acute myelogenous leukemia (AML) and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. Five year univariate probabilities and multivariate relative risk (RR) outcomes of relapse, transplant related mortality (TRM), disease free survival (DFS) and overall survival (OS) are reported. Adjusted OS at 5 years was 34%, 33%, and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs. leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning. PMID:21441963

  3. Frequent genomic alterations in epithelium measured by microsatellite instability following allogeneic hematopoietic cell transplantation in humans.

    PubMed

    Faber, Philipp; Fisch, Paul; Waterhouse, Miguel; Schmitt-Gräff, Annette; Bertz, Hartmut; Finke, Jürgen; Spyridonidis, Alexandros

    2006-04-15

    Although typically found in cancers, frameshift mutations in microsatellites have also been detected in chronically inflamed tissues. Allogeneic hematopoietic cell transplantation (HCT) may potentially produce chronic tissue stress through graft-versus-host reactions. We examined non-neoplastic epithelial tissues (colon, buccal) obtained 1 to 5061 days after human allogeneic HCT for the presence of genomic alterations at 3 tetranucleotide and 3 mononucleotide microsatellite loci. Novel bands indicative of microsatellite instability (MSI) at tetranucleotide repeats were detected in laser-microdissected colonic crypts and in buccal smears of 75% and 42% of patients who received an allograft, respectively. In contrast, no MSI was found in similar tissues from control subjects and from patients after intensive chemotherapy or in buccal cells from patients after autologous HCT. The MSI found in colon, which was often affected by graft-versus-host disease, was not due to loss of expression or nitrosylation of DNA repair proteins. MSI in clinically intact oral mucosa was more frequently found at later time points after HCT. MSI was also found in 3 posttransplant squamous cell cancers examined. Our data show that genomic alterations in epithelium regularly occur after allogeneic HCT and may be implicated in the evolution of posttransplantation diseases, including secondary cancer. PMID:16368884

  4. Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation.

    PubMed

    Fenske, Timothy S; Ahn, Kwang W; Graff, Tara M; DiGilio, Alyssa; Bashir, Qaiser; Kamble, Rammurti T; Ayala, Ernesto; Bacher, Ulrike; Brammer, Jonathan E; Cairo, Mitchell; Chen, Andy; Chen, Yi-Bin; Chhabra, Saurabh; D'Souza, Anita; Farooq, Umar; Freytes, Cesar; Ganguly, Siddhartha; Hertzberg, Mark; Inwards, David; Jaglowski, Samantha; Kharfan-Dabaja, Mohamed A; Lazarus, Hillard M; Nathan, Sunita; Pawarode, Attaphol; Perales, Miguel-Angel; Reddy, Nishitha; Seo, Sachiko; Sureda, Anna; Smith, Sonali M; Hamadani, Mehdi

    2016-07-01

    For diffuse large B-cell lymphoma (DLBCL) patients progressing after autologous haematopoietic cell transplantation (autoHCT), allogeneic HCT (alloHCT) is often considered, although limited information is available to guide patient selection. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 503 patients who underwent alloHCT after disease progression/relapse following a prior autoHCT. The 3-year probabilities of non-relapse mortality, progression/relapse, progression-free survival (PFS) and overall survival (OS) were 30, 38, 31 and 37% respectively. Factors associated with inferior PFS on multivariate analysis included Karnofsky performance status (KPS) <80, chemoresistance, autoHCT to alloHCT interval <1-year and myeloablative conditioning. Factors associated with worse OS on multivariate analysis included KPS<80, chemoresistance and myeloablative conditioning. Three adverse prognostic factors were used to construct a prognostic model for PFS, including KPS<80 (4 points), autoHCT to alloHCT interval <1-year (2 points) and chemoresistant disease at alloHCT (5 points). This CIBMTR prognostic model classified patients into four groups: low-risk (0 points), intermediate-risk (2-5 points), high-risk (6-9 points) or very high-risk (11 points), predicting 3-year PFS of 40, 32, 11 and 6%, respectively, with 3-year OS probabilities of 43, 39, 19 and 11% respectively. In conclusion, the CIBMTR prognostic model identifies a subgroup of DLBCL patients experiencing long-term survival with alloHCT after a failed prior autoHCT. PMID:26989808

  5. OBESITY DOES NOT PRECLUDE SAFE AND EFFECTIVE MYELOABLATIVE HEMATOPOIETIC CELL TRANSPLANTATION (HCT) FOR ACUTE MYELOID LEUKEMIA (AML) IN ADULTS

    PubMed Central

    Navarro, Willis H.; Agovi, Manza-A.; Logan, Brent R.; Ballen, Karen; Bolwell, Brian J.; Frangoul, Haydar; Gupta, Vikas; Hahn, Theresa; Ho, Vincent T.; Juckett, Mark; Lazarus, Hillard M.; Litzow, Mark R.; Liesveld, Jane L.; Moreb, Jan S.; Marks, David I.; McCarthy, Philip L.; Pasquini, Marcelo C.; Rizzo, J. Douglas

    2010-01-01

    The incidence of excessive adiposity is increasing worldwide and is associated with numerous adverse health outcomes. We compared outcomes by body mass index (BMI) for adult patients with acute myeloid leukemia (AML) who underwent autologous (auto, n=373), related donor (RD, n=2041), or unrelated donor (URD, n=1801) allogeneic myeloablative hematopoietic cell transplantation (HCT) using marrow or peripheral blood stem cells reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995-2004. Four weight groups by BMI (kg/m2) were defined: underweight < 18; normal 18 – 25; overweight >25 – 30; and obese > 30. Multivariable analysis referenced to the normal weight group showed an increased risk of death for underweight patients in the RD group (RR, 1.92; 95% CI, 1.28-2.89; P = 0.002) but not in the URD group. There were no other differences in outcomes among the other weight groups within the other HCT groups. Overweight and obese patients enjoyed a modest decrease in relapse incidence, though this did not translate into a survival benefit. Small numbers of patients limit the ability to better characterize the adverse outcomes seen in the underweight RD but not the underweight URD allogeneic HCT patients. Obesity alone should not be considered a barrier to HCT. PMID:20412867

  6. Actinomycosis after allogeneic hematopoietic stem cell transplantation despite penicillin prophylaxis.

    PubMed

    Barraco, F; Labussière-Wallet, H; Valour, F; Ducastelle-Leprêtre, S; Nicolini, F-E; Thomas, X; Ferry, T; Dumitrescu, O; Michallet, M; Ader, F

    2016-08-01

    Actinomycosis is a rare chronic and multifaceted disease caused by Actinomyces species frequently mimicking malignancy or other chronic granulomatous lung diseases. We report 4 original presentations of actinomycosis arising under supposed penicillin prophylaxis in allogeneic stem cell transplantation recipients. PMID:27203624

  7. Management of respiratory viral infections in hematopoietic cell transplant recipients.

    PubMed

    Shah, Dimpy P; Ghantoji, Shashank S; Mulanovich, Victor E; Ariza-Heredia, Ella J; Chemaly, Roy F

    2012-01-01

    Advances in stem cell transplantation procedures and the overall improvement in the clinical management of hematopoietic cell transplant (HCT) recipients over the past 2 decades have led to an increase in survival duration, in part owing to better strategies for prevention and treatment of post-transplant complications, including opportunistic infections. However, post-HCT infections remain a concern for HCT recipients, particularly infections caused by community respiratory viruses (CRVs), which can lead to significant morbidity and mortality. These viruses can potentially cause lower respiratory tract illness, which is associated with a higher mortality rate among HCT recipients. Clinical management of CRV infections in HCT recipients includes supportive care and antiviral therapy, especially in high-risk individuals, when available. Directed antiviral therapy is only available for influenza infections, where successful use of neuraminidase inhibitors (oseltamivir or zanamivir) and/or M2 inhibitors (amantadine or rimantadine) has been reported. Data on the successful use of ribavirin, with or without immunomodulators, for respiratory syncytial virus infections in HCT recipients has emerged over the past 2 decades but is still controversial at best because of a lack of randomized controlled trials. Because of the lack of directed antiviral therapy for most of these viruses, prevention should be emphasized for healthcare workers, patients, family, and friends and should include the promotion of the licensed inactivated influenza vaccine for HCT recipients, when indicated. In this review, we discuss the clinical management of respiratory viruses in this special patient population, focusing on commercially available antivirals, adjuvant therapy, and novel drugs under investigation, as well as on available means for prevention. PMID:23226621

  8. Management of respiratory viral infections in hematopoietic cell transplant recipients

    PubMed Central

    Shah, Dimpy P; Ghantoji, Shashank S; Mulanovich, Victor E; Ariza-heredia, Ella J; Chemaly, Roy F

    2012-01-01

    Advances in stem cell transplantation procedures and the overall improvement in the clinical management of hematopoietic cell transplant (HCT) recipients over the past 2 decades have led to an increase in survival duration, in part owing to better strategies for prevention and treatment of post-transplant complications, including opportunistic infections. However, post-HCT infections remain a concern for HCT recipients, particularly infections caused by community respiratory viruses (CRVs), which can lead to significant morbidity and mortality. These viruses can potentially cause lower respiratory tract illness, which is associated with a higher mortality rate among HCT recipients. Clinical management of CRV infections in HCT recipients includes supportive care and antiviral therapy, especially in high-risk individuals, when available. Directed antiviral therapy is only available for influenza infections, where successful use of neuraminidase inhibitors (oseltamivir or zanamivir) and/or M2 inhibitors (amantadine or rimantadine) has been reported. Data on the successful use of ribavirin, with or without immunomodulators, for respiratory syncytial virus infections in HCT recipients has emerged over the past 2 decades but is still controversial at best because of a lack of randomized controlled trials. Because of the lack of directed antiviral therapy for most of these viruses, prevention should be emphasized for healthcare workers, patients, family, and friends and should include the promotion of the licensed inactivated influenza vaccine for HCT recipients, when indicated. In this review, we discuss the clinical management of respiratory viruses in this special patient population, focusing on commercially available antivirals, adjuvant therapy, and novel drugs under investigation, as well as on available means for prevention. PMID:23226621

  9. Acute kidney injury in HCT: an update.

    PubMed

    Lopes, J A; Jorge, S; Neves, M

    2016-06-01

    Acute kidney injury (AKI) is highly prevalent whether the patients undergo myeloablative or non-myeloablative hematopoietic cell transplantation (HCT); however, the pathogenesis and risk factors leading to AKI can differ between the two. The prognosis of AKI in patients receiving HCT is poor. In fact, AKI following HCT is associated not only with increased short- and long-term mortality, but also with progression to chronic kidney disease. Herein, the authors provide a comprehensive and up-to-date review of the definition and diagnosis, as well as of the incidence, pathogenesis and outcome of AKI in patients undergoing HCT, centering on the differences between myeloablative and non-myeloablative regimens. PMID:26855155

  10. Significance of Persistent Cytogenetic Abnormalities at Myeloablative Allogeneic Stem Cell Transplantation in First Complete Remission

    PubMed Central

    Oran, Betul; Popat, Uday; Rondon, Gabriella; Ravandi, Farhad; Garcia-Manero, Guillermo; Abruzzo, Lynn; Andersson, Borje S.; Bashir, Qaiser; Chen, Julianne; Kebriaei, Partow; Khouri, Issa F.; Koca, Ebru; Qazilbash, Muzaffar H.; Champlin, Richard; de Lima, Marcos

    2014-01-01

    Risk stratification is important to identify acute myeloid leukemia (AML) patients that might benefit from allogeneic hematopoietic stem cell transplantation (allo-HCT) in first complete remission (CR1). We retrospectively studied 150 AML patients with diagnostic cytogenetic abnormalities receiving myeloablative allo-HCT in CR1 to determine the prognostic impact of persistent cytogenetic abnormalities at allo-HCT. Three risk groups were identified: First group of patients with favorable/intermediate cytogenetics at diagnosis (n=49) and the second group with unfavorable cytogenetics at diagnosis but without the presence of persistent abnormal clone at allo-HCT (n=83) had similar 3-year leukemia free survival (LFS) of 58%-60% despite increased 3-year relapse incidence (RI) of 32.3% observed in the second risk group versus 16.8% in the first group. Third group of patients with unfavorable cytogenetics at diagnosis and persistence of that clone at allo-HCT (n=15) represented the worst prognostic group with 3-year RI of 57.5% and 3-year LFS of 29.2%. These data suggest that AML patients with unfavorable cytogenetics at diagnosis and persistence of abnormal clone at allo-HCT have high risk of relapse after allo-HCT. These patients should be considered for clinical trials designed to optimize conditioning regimens and/or to use preemptive strategies in the post-transplant setting to decrease the relapse incidence. PMID:22982533

  11. Tandem autologous versus autologous/allogeneic transplantation for multiple myeloma: propensity score analysis.

    PubMed

    Kawamura, Koji; Ikeda, Takashi; Hagiwara, Shotaro; Mori, Takehiko; Shinagawa, Atsushi; Nishiwaki, Kaichi; Ohashi, Kazuteru; Kubonishi, Shiro; Fukuda, Takahiro; Ito, Toshiro; Tomita, Naoto; Ichinohe, Tatsuo; Kato, Koji; Morishima, Yasuo; Atsuta, Yoshiko; Sunami, Kazutaka; Kanda, Yoshinobu

    2016-09-01

    Autologous hematopoietic stem cell transplantation (auto-HCT) is considered a standard therapy for transplant-eligible patients with multiple myeloma, while allogeneic HCT (allo-HCT) is controversial. We retrospectively analyzed 765 patients with myeloma who underwent tandem transplantation between 1998 and 2012 using Japanese registry data. We evaluated the clinical outcomes of tandem auto-HCT (n = 676) and auto/allo-HCT (n = 89). To adjust for a selection bias, we compared overall survival (OS) between the two groups by a propensity score analysis. The probability of OS at six years was 58.5% for the tandem auto-HCT group and 54.4% for the tandem auto/allo-HCT group (p = 0.47). In a matched-pair analysis based on the propensity score, the difference in survival between the two groups was not statistically significant, although the survival curve appeared to reach a plateau beyond five years in the auto/allo group. Further strategies to reduce treatment-related mortality and enhance a graft-versus-myeloma effect are necessary to improve OS. PMID:26961137

  12. Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML.

    PubMed

    Ustun, C; Wiseman, A C; Defor, T E; Yohe, S; Linden, M A; Oran, B; Burke, M; Warlick, E; Miller, J S; Weisdorf, D

    2013-11-01

    Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) can cure patients with AML in CR. However, relapse after RIC allo-HCT may indicate heterogeneity in the stringency of CR. Strict definition of CR requires no evidence of leukemia by both morphologic and flow cytometric criteria. We re-evaluated 85 AML patients receiving RIC allo-HCT in CR to test if a strict definition of CR had direct implications for the outcome. These patients had leukemia immunophenotype documented at diagnosis and analyzed at allo-HCT. Eight (9.4%) had persistent leukemia by flow cytometric criteria at allo-HCT. The patients with immunophenotypic persistent leukemia had a significantly increased relapse (hazard ratio (HR): 3.7; 95% confidence interval (CI): 1.3-10.3, P=0.01) and decreased survival (HR: 2.9; 95% CI: 1.3-6.4, P<0.01) versus 77 patients in CR by both morphology and flow cytometry. However, the pre-allo-HCT bone marrow (BM) blast count (that is, 0-4%) was not significantly associated with risks of relapse or survival. These data indicate the presence of leukemic cells, but not the BM blast count affects survival. A strict morphologic and clinical lab flow cytometric definition of CR predicts outcomes after RIC allo-HCT, and therefore is critical to achieve at transplantation. PMID:23933764

  13. Present and Future of Allogeneic Natural Killer Cell Therapy

    PubMed Central

    Lim, Okjae; Jung, Mi Young; Hwang, Yu Kyeong; Shin, Eui-Cheol

    2015-01-01

    Natural killer (NK) cells are innate lymphocytes that are capable of eliminating tumor cells and are therefore used for cancer therapy. Although many early investigators used autologous NK cells, including lymphokine-activated killer cells, the clinical efficacies were not satisfactory. Meanwhile, human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation revealed the antitumor effect of allogeneic NK cells, and HLA-haploidentical, killer cell immunoglobulin-like receptor ligand-mismatched allogeneic NK cells are currently used for many protocols requiring NK cells. Moreover, allogeneic NK cells from non-HLA-related healthy donors have been recently used in cancer therapy. The use of allogeneic NK cells from non-HLA-related healthy donors allows the selection of donor NK cells with higher flexibility and to prepare expanded, cryopreserved NK cells for instant administration without delay for ex vivo expansion. In cancer therapy with allogeneic NK cells, optimal matching of donors and recipients is important to maximize the efficacy of the therapy. In this review, we summarize the present state of allogeneic NK cell therapy and its future directions. PMID:26089823

  14. ALLOGENEIC STEM CELL TRANSPLANTATION IN FIRST COMPLETE REMISSION

    PubMed Central

    Oran, Betul; Weisdorf, Daniel J.

    2016-01-01

    Purpose of review The optimal post-remission therapy of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. This review summarizes the recent developments in the clinical research and therapeutic applications defining the role of allogeneic hematopoietic stem cell transplantation (allo-HCT) in CR1. Recent findings Molecular markers in combinations with cytogenetics have improved the risk stratification and informed decision-making in patients with AML in CR1. In parallel, several important advances in the transplant field, such as better supportive care, improved transplant technology, increased availability of alternative donors, and reduced-intensity conditioning have improved the safety as well as access of allo-HCT for a larger number of patients. Summary The progress in risk stratification and transplant technology dictate that early donor identification search should be initiated for all eligible AML patients in CR1. PMID:21912256

  15. Recovery of antibody production in human allogeneic marrow graft recipients: influence of time posttransplantation, the presence or absence of chronic graft-versus-host disease, and antithymocyte globulin treatment.

    PubMed

    Witherspoon, R P; Storb, R; Ochs, H D; Fluornoy, N; Kopecky, K J; Sullivan, K M; Deeg, J H; Sosa, R; Noel, D R; Atkinson, K; Thomas, E D

    1981-08-01

    One-hundred fifty-three recipients of HLA-identical sibling marrow transplants for aplastic anemia or hematologic malignancy were injected with bacteriophage phi X174 (phage), pneumococcal polysaccharide antigen (PPA), or keyhole limpet hemocyanin (KLH). Antibody levels were determined several times in the 6 wk after injection. Multiple regression techniques were used to determine what factors played significant roles in the antibody response. The most significant factors were the time elapsed from transplantation, chronic graft-versus-host disease (GVHD), and antithymocyte globulin (ATG) treatment. All patients had low antibody responses to all antigens in the first 180 days from transplant. Beyond 180 days patients without chronic GVHD showed antibody responses indistinguishable from those of normal donors. However, patients with chronic GVHD had the following impairments: (1) primary response to phage, (2) conversion from IgM to IgG in secondary response to phage, (3) secondary response to KLH, and (4) response to PPA. ATG treatment given to patients either prophylactically or therapeutically for acute GVHD was followed by lower primary responses to phage in the first 180 days and poor ability to switch from IgM to IgG antibody in the secondary response beyond 180 days postgrafting. Other factors did not yield additional significant information about ability to predict antibody responses including diagnosis, conditioning regimen, treatment in or out of laminar air flow rooms, transplantation, pretransplant refractoriness of the recipient to platelet transfusions from random donors, donor age or donor sex, and steroid administration for treatment for prevention of GVHD. The data indicate that, given enough time after transplantation, the ability to produce normal antibody function recovers except in those patients experiencing chronic GVHD. PMID:6454452

  16. Controversies in autologous and allogeneic hematopoietic cell transplantation in peripheral T/NK-cell lymphomas.

    PubMed

    Shustov, Andrei

    2013-03-01

    Peripheral T-cell and NK-cell lymphomas (PT/NKCL) are a heterogeneous group of lymphoid neoplasms with poor outcomes. There is no consensus on the best front line therapy or management of relapsed/refractory disease. The use of autologous and allogeneic hematopoietic cell transplantation (HCT) has been studied in both settings to improve outcomes. Multiple retrospective and several prospective trials were reported. While at first sight the outcomes in the relapsed/refractory setting appear similar in B-cell and T-cell lymphomas when treated with high dose therapy (HDT) and autologous HCT, it is becoming obvious that only specific subtypes of PTCL benefit from this approach (i.e. anaplastic large cell lymphoma [ALCL] and angioimmunoblastic lymphoma [AITL] in second CR). In less favorable histologies, HDT seems to provide limited benefit, with the majority of patients experiencing post-transplant relapse. The use of autologous HCT to consolidate first remission has been evaluated in several prospective trials. Again, the best results were observed in ALCL, but the superiority of this approach over chemotherapy alone needs confirmation in randomized trials. In less favorable histologies, high-dose consolidation resulted in low survival rates comparable to those obtained with chemotherapy alone, and without randomized trials it is hard to recommend this strategy to all patients with newly diagnosed PT/NKCL. Allogeneic HCT might provide potent and potentially curative graft-vs-lymphoma effect and overcome chemotherapy resistance. Only a few studies have been reported to date on allogeneic HCT in PT/NKCL. Based on available data, eligible patients benefit significantly from this approach, with 50% or more patients achieving long-term disease control or cure, although at the expense of significant treatment related mortality (TRM). Reduced-intensity conditioning regimens appear to have lower TRM and might extend this approach to older patients. With the recent approval of

  17. Plasmacytoid dendritic cells in allogeneic hematopoietic cell transplantation: benefit or burden?

    PubMed Central

    Auletta, JJ; Devine, SM; Waller, EK

    2016-01-01

    Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and have important roles in hematopoietic engraftment, GvHD and graft-versus-leukemia responses following allogeneic hematopoietic cell transplantation (HCT). In addition, pDCs mediate antiviral immunity, particularly as they are the body’s primary cellular source of type I interferon. Given their pleiotropic roles, pDCs have emerged as cells that critically impact transplant outcomes, including overall survival. In this article, we will review the pre-clinical and clinical literature, supporting the crucial roles that pDCs assume as key immune effector cells during HCT. PMID:26642333

  18. High-throughput allogeneic antibody detection using protein microarrays.

    PubMed

    Paul, Jed; Sahaf, Bita; Perloff, Spenser; Schoenrock, Kelsi; Wu, Fang; Nakasone, Hideki; Coller, John; Miklos, David

    2016-05-01

    Enzyme-linked immunosorbent assays (ELISAs) have traditionally been used to detect alloantibodies in patient plasma samples post hematopoietic cell transplantation (HCT); however, protein microarrays have the potential to be multiplexed, more sensitive, and higher throughput than ELISAs. Here, we describe the development of a novel and sensitive microarray method for detection of allogeneic antibodies against minor histocompatibility antigens encoded on the Y chromosome, called HY antigens. Six microarray surfaces were tested for their ability to bind recombinant protein and peptide HY antigens. Significant allogeneic immune responses were determined in male patients with female donors by considering normal male donor responses as baseline. HY microarray results were also compared with our previous ELISA results. Our overall goal was to maximize antibody detection for both recombinant protein and peptide epitopes. For detection of HY antigens, the Epoxy (Schott) protein microarray surface was both most sensitive and reliable and has become the standard surface in our microarray platform. PMID:26902899

  19. BK nephropathy in pediatric hematopoeitic stem cell transplant recipients

    PubMed Central

    Verghese, Priya S; Finn, Laura S; Englund, Janet A; Sanders, Jean E; Hingorani, Sangeeta

    2009-01-01

    BK nephropathy is a known cause of renal insufficiency in kidney transplant recipients. Activation of the polyoma virus may also occur in the native kidneys of non-renal allograft recipients. BK nephropathy has only been reported in a few patients after hematopoetic stem cell transplantation (HCT), most being adult patients, and the single reported pediatric case had evidence of hemorrhagic cystitis. The response to anti-viral therapy also seems to differ widely. Here, we describe two cases of BK nephropathy in the native kidneys of HCT recipients exposed to high levels of immunosuppression due to graft-versus-host-disease. Neither of our patients had any evidence of hemorrhagic cystitis. We present definitive renal pathology and detailed chronological evidence of the rising serum creatinine with simultaneous serum and urine BK PCR titers. In one of our cases, anti-viral therapy did not seem beneficial as documented by continued renal dysfunction and serum/urine BK PCR titers. Based on our report, intense immunosuppression in pediatric HCT recipients seems to be involved in the activation of BK virus and BK nephropathy should be suspected even in the absence of hematuria in HCT recipients with unexplained renal dysfunction. PMID:19067914

  20. Solid cancers after allogeneic hematopoietic cell transplantation

    PubMed Central

    Curtis, Rochelle E.; Socié, Gérard; Sobocinski, Kathleen A.; Gilbert, Ethel; Landgren, Ola; Travis, Lois B.; Travis, William D.; Flowers, Mary E. D.; Friedman, Debra L.; Horowitz, Mary M.; Wingard, John R.; Deeg, H. Joachim

    2009-01-01

    Transplant recipients have been reported to have an increased risk of solid cancers but most studies are small and have limited ability to evaluate the interaction of host, disease, and treatment-related factors. In the largest study to date to evaluate risk factors for solid cancers, we studied a multi-institutional cohort of 28 874 allogeneic transplant recipients with 189 solid malignancies. Overall, patients developed new solid cancers at twice the rate expected based on general population rates (observed-to-expected ratio 2.1; 95% confidence interval 1.8-2.5), with the risk increasing over time (P trend < .001); the risk reached 3-fold among patients followed for 15 years or more after transplantation. New findings showed that the risk of developing a non–squamous cell carcinoma (non-SCC) following conditioning radiation was highly dependent on age at exposure. Among patients irradiated at ages under 30 years, the relative risk of non-SCC was 9 times that of nonirradiated patients, while the comparable risk for older patients was 1.1 (P interaction < .01). Chronic graft-versus-host disease and male sex were the main determinants for risk of SCC. These data indicate that allogeneic transplant survivors, particularly those irradiated at young ages, face increased risks of solid cancers, supporting strategies to promote lifelong surveillance among these patients. PMID:18971419

  1. Clinical guide to fertility preservation in hematopoietic cell transplant recipients.

    PubMed

    Joshi, S; Savani, B N; Chow, E J; Gilleece, M H; Halter, J; Jacobsohn, D A; Pidala, J; Quinn, G P; Cahn, J-Y; Jakubowski, A A; Kamani, N R; Lazarus, H M; Rizzo, J D; Schouten, H C; Socie, G; Stratton, P; Sorror, M L; Warwick, A B; Wingard, J R; Loren, A W; Majhail, N S

    2014-04-01

    With broadening indications, more options for hematopoietic cell transplantation (HCT) and improvement in survival, the number of long-term HCT survivors is expected to increase steadily. Infertility is a frequent problem that long-term HCT survivors and their partners face and it can negatively impact on the quality of life. The most optimal time to address fertility issues is before the onset of therapy for the underlying disease; however, fertility preservation should also be addressed before HCT in all children and patients of reproductive age, with referral to a reproductive specialist for patients interested in fertility preservation. In vitro fertilization (IVF) and embryo cryopreservation, oocyte cryopreservation and ovarian tissue banking are acceptable methods for fertility preservation in adult women/pubertal females. Sperm banking is the preferred method for adult men/pubertal males. Frequent barriers to fertility preservation in HCT recipients may include the perception of lack of time to preserve fertility given an urgency to move ahead with transplant, lack of patient-physician discussion because of several factors (for example, time constraints, lack of knowledge), inadequate access to reproductive specialists, and costs and lack of insurance coverage for fertility preservation. There is a need to raise awareness in the medical community about fertility preservation in HCT recipients. PMID:24419521

  2. Clinical guide to fertility preservation in hematopoietic cell transplant recipients

    PubMed Central

    Joshi, S; Savani, BN; Chow, EJ; Gilleece, MH; Halter, J; Jacobsohn, DA; Pidala, J; Quinn, GP; Cahn, J-Y; Jakubowski, AA; Kamani, NR; Lazarus, HM; Rizzo, JD; Schouten, HC; Socie, G; Stratton, P; Sorror, ML; Warwick, AB; Wingard, JR; Loren, AW; Majhail, NS

    2014-01-01

    With broadening indications, more options for hematopoietic cell transplantation (HCT) and improvement in survival, the number of long-term HCT survivors is expected to increase steadily. Infertility is a frequent problem that long-term HCT survivors and their partners face and it can negatively impact on the quality of life. The most optimal time to address fertility issues is before the onset of therapy for the underlying disease; however, fertility preservation should also be addressed before HCT in all children and patients of reproductive age, with referral to a reproductive specialist for patients interested in fertility preservation. In vitro fertilization (IVF) and embryo cryopreservation, oocyte cryopreservation and ovarian tissue banking are acceptable methods for fertility preservation in adult women/pubertal females. Sperm banking is the preferred method for adult men/pubertal males. Frequent barriers to fertility preservation in HCT recipients may include the perception of lack of time to preserve fertility given an urgency to move ahead with transplant, lack of patient–physician discussion because of several factors (for example, time constraints, lack of knowledge), inadequate access to reproductive specialists, and costs and lack of insurance coverage for fertility preservation. There is a need to raise awareness in the medical community about fertility preservation in HCT recipients. PMID:24419521

  3. Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II.

    PubMed

    McCune, Jeannine S; Bemer, Meagan J; Long-Boyle, Janel

    2016-05-01

    Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses. PMID:26620047

  4. Long-Term Survival and Late Deaths After Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Wingard, John R.; Majhail, Navneet S.; Brazauskas, Ruta; Wang, Zhiwei; Sobocinski, Kathleen A.; Jacobsohn, David; Sorror, Mohamed L.; Horowitz, Mary M.; Bolwell, Brian; Rizzo, J. Douglas; Socié, Gérard

    2011-01-01

    Purpose Allogeneic hematopoietic cell transplantation (HCT) is curative but is associated with life-threatening complications. Most deaths occur within the first 2 years after transplantation. In this report, we examine long-term survival in 2-year survivors in the largest cohort ever studied. Patients and Methods Records of 10,632 patients worldwide reported to the Center for International Blood and Marrow Transplant Research who were alive and disease free 2 years after receiving a myeloablative allogeneic HCT before 2004 for acute myelogenous or lymphoblastic leukemia, myelodysplastic syndrome, lymphoma, or severe aplastic anemia were reviewed. Results Median follow-up was 9 years, and 3,788 patients had been observed for 10 or more years. The probability of being alive 10 years after HCT was 85%. The chief risk factors for late death included older age and chronic graft-versus-host disease (GVHD). For patients who underwent transplantation for malignancy, relapse was the most common cause of death. The greatest risk factor for late relapse was advanced disease at transplantation. Principal risk factors for nonrelapse deaths were older age and GVHD. When compared with age, sex, and nationality-matched general population, late deaths remained higher than expected for each disease, with the possible exception of lymphoma, although the relative risk generally receded over time. Conclusion The prospect for long-term survival is excellent for 2-year survivors of allogeneic HCT. However, life expectancy remains lower than expected. Performance of HCT earlier in the course of disease, control of GVHD, enhancement of immune reconstitution, less toxic regimens, and prevention and early treatment of late complications are needed. PMID:21464398

  5. Aspergillus Thyroiditis after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Ataca, Pinar; Atilla, Erden; Saracoglu, Pelin; Yilmaz, Gulden; Civriz Bozdag, Sinem; Toprak, Selami Kocak; Yuksel, Meltem Kurt; Ceyhan, Koray; Topcuoglu, Pervin

    2015-01-01

    Aspergillus thyroiditis is a rare disorder detected in immunocompromised patients during disseminated infections. Early management is essential to prevent high mortality. A 61-year-old allogeneic stem cell male recipient presented with painful thyroid nodular enlargement. He had low TSH and low free T4 levels. The thyroid ultrasound showed a hypoechoic nodule; biopsy indicated suppurative Aspergillus thyroiditis. He was successfully treated by amphotericin B. PMID:26640727

  6. Regulation of Adaptive NK Cells and CD8 T Cells by HLA-C Correlates with Allogeneic Hematopoietic Cell Transplantation and with Cytomegalovirus Reactivation.

    PubMed

    Horowitz, Amir; Guethlein, Lisbeth A; Nemat-Gorgani, Neda; Norman, Paul J; Cooley, Sarah; Miller, Jeffrey S; Parham, Peter

    2015-11-01

    Mass cytometry was used to investigate the effect of CMV reactivation on lymphocyte reconstitution in hematopoietic cell transplant patients. For eight transplant recipients (four CMV negative and four CMV positive), we studied PBMCs obtained 6 mo after unrelated donor hematopoietic cell transplantation (HCT). Forty cell-surface markers, distinguishing all major leukocyte populations in PBMC, were analyzed with mass cytometry. This group included 34 NK cell markers. Compared with healthy controls, transplant recipients had higher HLA-C expression on CD56(-)CD16(+) NK cells, B cells, CD33(bright) myeloid cells, and CD4CD8 T cells. The increase in HLA-C expression was greater for CMV-positive HCT recipients than for CMV negative recipients. Present in CMV-positive HCT recipients, but not in CMV-negative HCT recipients or controls, is a population of killer cell Ig-like receptor (KIR)-expressing CD8 T cells not previously described. These CD8 T cells coexpress CD56, CD57, and NKG2C. The HCT recipients also have a population of CD57(+)NKG2A(+) NK cells that preferentially express KIR2DL1. An inverse correlation was observed between the frequencies of CD57(+)NKG2C(+) NK cells and CD57(+)NKG2A(+) NK cells. Although CD57(+)NKG2A(+) NK cells are less abundant in CMV-positive recipients, their phenotype is of a more activated cell than the CD57(+)NKG2A(+) NK cells of controls and CMV-negative HCT recipients. These data demonstrate that HCT and CMV reactivation are associated with an increased expression of HLA-C. This could influence NK cell education during lymphocyte reconstitution. The increased inhibitory KIR expression by proliferating CMV-specific CD8 T cells suggests regulatory interactions between HLA-C and KIR might promote Graft-versus-Leukemia effects following transplantation. PMID:26416275

  7. Engraftment syndrome after nonmyeloablative allogeneic hematopoietic stem cell transplantation: incidence and effects on survival.

    PubMed

    Gorak, Edward; Geller, Nancy; Srinivasan, Ramaprasad; Espinoza-Delgado, Igor; Donohue, Teresa; Barrett, A John; Suffredini, Anthony; Childs, Richard

    2005-07-01

    Engraftment syndrome (ES) encompasses a constellation of symptoms that occur during neutrophil recovery after both autologous and allogeneic hematopoietic stem cell transplantation (HCT). Although it is well characterized after conventional myeloablative procedures, limited data exist on this complication after nonmyeloablative allogeneic HCT. The clinical manifestations, incidence, and risk factors associated with ES were investigated in a consecutive series of patients undergoing cyclophosphamide/fludarabine-based nonmyeloablative allogeneic HCT from a related HLA-compatible donor. Fifteen (10%) of 149 patients (median age, 53 years; range, 27-66 years) developed ES; the onset of symptoms occurred at a median of 10 days (range, 3-14 days), and they consisted of fever (100%), cough (53%), diffuse pulmonary infiltrates (100%), rash (13%), and room air hypoxia (87%). ES was more likely to develop in patients who received empiric amphotericin formulations after transplant conditioning (Fisher exact test; P=.007). In a multivariate analysis, older patient age, female sex, and treatment with amphotericin were predictors for the development of ES. Intravenous methylprednisolone led to the rapid resolution of ES; however, transplant-related mortality was significantly higher (cumulative incidence, 49% versus 16%; P=.0005), and median survival was significantly shorter (168 versus 418 days; P=.005) in patients with ES compared with non-ES patients. In conclusion, ES occurs commonly after cyclophosphamide/fludarabine-based nonmyeloablative transplantation and responds rapidly to corticosteroid treatment, but it is associated with a higher risk of nonrelapse mortality and with shorter overall survival. PMID:15983554

  8. Allogeneic hematopoietic cell transplantation for consolidation of VGPR or CR for newly diagnosed multiple myeloma.

    PubMed

    Nishihori, T; Ochoa-Bayona, J L; Kim, J; Pidala, J; Shain, K; Baz, R; Sullivan, D; Jim, H S; Anasetti, C; Alsina, M

    2013-09-01

    Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative approach in patients with multiple myeloma, but its use for consolidation of first remission has not yet been fully explored. Twenty-two myeloma patients with very good partial response (VGPR) or CR received allogeneic peripheral blood grafts as consolidation from HLA-matched donors between 2007 and 2012. Conditioning regimens were fludarabine (30 mg/m(2) i.v. if with bortezomib and 40 mg/m(2) i.v. when without bortezomib, × 4 days) plus melphalan (70 mg/m(2) intravenously × 2 days) with (n=13) or without (n=9) bortezomib (1.3 mg/m(2)). The cumulative incidence of grades II - IV acute GVHD at day 100 was 45% (95% CI: 24-65%) and moderate-to-severe chronic GVHD at 2 years was 46% (95% CI: 19-69%). With a median follow-up of 18 (range, 2-61) months, the 2-year PFS estimate is 74.8% (95% CI: 45-90%), which compares favorably with the 52% (95% CI: 35-66%) after autologous HCT for similar patients (a median follow-up of 30 (range, 9-55) months). We are conducting a phase 2 study to assess the efficacy of allogeneic HCT as post-remission therapy. PMID:23542223

  9. Immunotherapy of invasive fungal infection in hematopoietic stem cell transplant recipients

    PubMed Central

    Lehrnbecher, Thomas; Schmidt, Stanislaw; Tramsen, Lars; Klingebiel, Thomas

    2013-01-01

    Despite the availability of new antifungal compounds, invasive fungal infection remains a significant cause of morbidity and mortality in children and adults undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT recipients suffer from a long lasting defect of different arms of the immune system, which increases the risk for and deteriorates the prognosis of invasive fungal infections. In turn, advances in understanding these immune deficits have resulted in promising strategies to enhance or restore critical immune functions in allogeneic HSCT recipients. Potential approaches include the administration of granulocytes, since neutropenia is the single most important risk factor for invasive fungal infection, and preliminary clinical results suggest a benefit of adoptively transferred donor-derived antifungal T cells. In vitro data and animal studies demonstrate an antifungal effect of natural killer cells, but clinical data are lacking to date. This review summarizes and critically discusses the available data of immunotherapeutic strategies in allogeneic HSCT recipients suffering from invasive fungal infection. PMID:23404543

  10. Conditioning with α-emitter based radioimmunotherapy in canine allogeneic hematopoietic cell transplantation

    PubMed Central

    Kornblit, Brian; Chen, Yun; Sandmaier, Brenda M.

    2012-01-01

    With the introduction of nonmyeloablative conditioning, hematopoietic cell transplantation (HCT) has become a viable treatment option for patients who due to age or comorbidities are ineligible for high dose conditioning. However, relapse and toxicities are still major problems in HCT. Radioimmunotherapy (RIT)-based conditioning is a promising approach that has the ability to specifically target radiation to hematopoietic cells. The most widely investigated isotopes are the β-emitters, but because of long path lengths and low linear energy transfer, α-emitters which have more favorable physical characteristics, might prove to be a better alternative. In the current study we have investigated the efficacy and safety of α-emitter based RIT as the only form of conditioning in a preclinical model of canine allogeneic HCT. PMID:22772070

  11. Pushing the envelope—nonmyeloablative and reduced intensity preparative regimens for allogeneic hematopoietic transplantation

    PubMed Central

    Pingali, SR; Champlin, RE

    2016-01-01

    Allogeneic hematopoietic cell transplantation (HCT) was originally developed to allow delivery of myeloablative doses of chemotherapy and radiotherapy. With better understanding of disease pathophysiology, the graft vs malignancy (GVM) effect of allogeneic hematopoietic transplantation and toxicities associated with myeloablative conditioning (MAC) regimens, the focus shifted to developing less toxic conditioning regimens to reduce treatment-related morbidity without compromising survival. Although HCT with MAC is preferred to reduced intensity conditioning (RIC) for most patients ≤ 60 years with AML/myelodysplastic syndrome and ALL, RIC and nonmyeloablative (NMA) regimens allow HCT for many otherwise ineligible patients. Reduced intensity preparative regimens have produced high rates of PFS for diagnoses, which are highly sensitive to GVM. Relapse of the malignancy is the major cause of treatment failure with RIC/NMA HCT. Incorporation of novel agents like bortezomib or lenalidomide, addition of cellular immunotherapy and use of targeted radiation therapies could further improve outcome. In this review, we discuss commonly used RIC/NMA regimens and promising novel regimens. PMID:25985053

  12. Allogeneic Hematopoietic Cell Transplantation as Curative Therapy for Patients with Non-Hodgkin Lymphoma: Increasingly Successful Application to Older Patients.

    PubMed

    Fenske, Timothy S; Hamadani, Mehdi; Cohen, Jonathon B; Costa, Luciano J; Kahl, Brad S; Evens, Andrew M; Hamlin, Paul A; Lazarus, Hillard M; Petersdorf, Effie; Bredeson, Christopher

    2016-09-01

    Non-Hodgkin lymphoma (NHL) constitutes a collection of lymphoproliferative disorders with widely varying biological, histological, and clinical features. For the B cell NHLs, great progress has been made due to the addition of monoclonal antibodies and, more recently, other novel agents including B cell receptor signaling inhibitors, immunomodulatory agents, and proteasome inhibitors. Autologous hematopoietic cell transplantation (auto-HCT) offers the promise of cure or prolonged remission in some NHL patients. For some patients, however, auto-HCT may never be a viable option, whereas in others, the disease may progress despite auto-HCT. In those settings, allogeneic HCT (allo-HCT) offers the potential for cure. Over the past 10 to 15 years, considerable progress has been made in the implementation of allo-HCT, such that this approach now is a highly effective therapy for patients up to (and even beyond) age 75 years. Recent advances in conventional lymphoma therapy, peritransplantation supportive care, patient selection, and donor selection (including the use of alternative hematopoietic cell donors), has allowed broader application of allo-HCT to patients with NHL. As a result, an ever-increasing number of NHL patients over age 60 to 65 years stand to benefit from allo-HCT. In this review, we present data in support of the use of allo-HCT for patients with diffuse large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma. These histologies account for a large majority of allo-HCTs performed for patients over age 60 in the United States. Where possible, we highlight available data in older patients. This body of literature strongly supports the concept that allo-HCT should be offered to fit patients well beyond age 65 and, accordingly, that this treatment should be covered by their insurance carriers. PMID:27131863

  13. CT60 single-nucleotide polymorphism as a surrogate marker for donor lymphocyte infusion outcome after allogeneic cell transplantation for acute leukemia.

    PubMed

    Metaxas, Y; Bertz, H; Spyridonidis, A; Spyroupoulou-Vlachou, M; Porzelius, C; Finke, J

    2012-03-01

    The benefit of survival at the expense of new GVHD after DLI for acute leukemia following human allogeneic hematopoietic cell transplantation (allo-HCT) remains a matter of controversy. The detection of biological markers predicting this outcome would be an enormous breakthrough. The purpose of this study was the analysis of CT60 single-nucleotide polymorphism (SNP) of the CTLA-4 T-regulatory gene as a surrogate marker for DLI outcome in this difficult setting. Using Pyrosequencing, we genotyped the alleles of the CT60 SNP of 79 DLI donors and correlated them with the post-DLI outcome of their matching recipients. The presence of a donor 'AA' or 'AG' CT60 genotype vs a 'GG' genotype was an independent factor for remaining in complete chimerism/remission post-DLI (odds ratio (OR) 2.61 vs 0.42, respectively, P=0.05). Further, in cases with evident post-DLI allo-reactivity the importance of an 'AA' or 'AG' vs a 'GG' genotype gained significance for ongoing complete chimerism (OR 4.35 vs 0.32, P=0.03). Neither alterations in cumulative DLI dose nor any other clinical parameter significantly weakened the importance of CT60 SNP. Our results provide evidence for the necessity of genotyping CT60 SNP prior to DLI administration in patients with acute leukemia. PMID:21552305

  14. Mechanisms of suppression in mixed allogeneic chimeras

    SciTech Connect

    Sykes, M.; Sachs, D.H.

    1988-08-01

    Cells with the ability to suppress cytotoxic T lymphocyte generation are found in the spleens of whole-body-irradiated (WBI) mixed allogeneic and syngeneic bone marrow transplant recipients in the early weeks after BMT. Previous studies have indicated that suppression is mediated by null cells similar to natural suppressor (NS) cells (1), and have ruled out several possible trivial explanations for the suppressive effect. We report here the results of additional experiments designed to assess possible mechanisms of suppression. We compared the cell populations after 5 days' incubation of cultures containing normal responding splenocytes plus irradiated allogeneic stimulator cells, with or without a cocultured suppressive chimeric splenocyte population. The data indicate that total viable cell yields are only slightly reduced, if at all, in suppressed cultures, but that the proportion of T cells is markedly reduced as measured at the end of the incubation period. Splenocytes from early BMT recipients do not appear to proliferate during the suppression of a mixed lymphocyte culture, and such populations represent only 15% of cells at the end of the 5-day incubation period. Suppression is strongest when the suppressive population is added at the initiation of MLC, and is lost if addition is delayed beyond day 3. Suppression can be overcome by T cell growth factor (TCGF)--and, to a lesser extent, by recombinant IL-2 (rIL-2), although resting suppressive populations do not consume appreciable amounts of these lymphokines. These results therefore suggest that suppression in MLC may occur primarily during the induction of helper T lymphocytes.

  15. Allogeneic Hematopoietic Cell Transplant for Prolymphocytic Leukemia

    PubMed Central

    Kalaycio, Matt E.; Kukreja, Manisha; Woolfrey, Ann E.; Szer, Jeffrey; Cortes, Jorge; Maziarz, Richard T.; Bolwell, Brian J.; Buser, Andreas; Copelan, Edward; Gale, Robert Peter; Gupta, Vikas; Maharaj, Dipnarine; Marks, David I; Pavletic, Steven Z.; Horowitz, Mary M.; Arora, Mukta

    2009-01-01

    The poor prognosis of patients with prolymphocytic leukemia (PLL) has led some clinicians to recommend allogeneic hematopoietic cell transplant (HCT). However, the data to support this approach is limited to case-reports and small case-series. We reviewed the database of the Center for International Blood & Marrow Transplant Research to determine outcomes after allotransplant for patients with PLL. We identified 47 patients with a median age of 54 years (range, 30–75). With a median follow-up of 13 months, progression-free survival was 33% (95% Confidence Interval 20–47%) at 2 years. The most common cause of death was relapse or progression in 49%. The cumulative incidence of treatment-related mortality at 1-year post transplant was 28%. The small patient population prohibited prognostic factor analysis but these data support consideration of allotransplant for PLL. Further study of a larger population of patients is needed to determine which patients are more likely to benefit. PMID:19961946

  16. Survival improvements in adolescents and young adults after myeloablative allogeneic transplantation for acute lymphoblastic leukemia.

    PubMed

    Wood, William A; Lee, Stephanie J; Brazauskas, Ruta; Wang, Zhiwei; Aljurf, Mahmoud D; Ballen, Karen K; Buchbinder, David K; Dehn, Jason; Freytes, Cesar O; Lazarus, Hillard M; Lemaistre, Charles F; Mehta, Paulette; Szwajcer, David; Joffe, Steven; Majhail, Navneet S

    2014-06-01

    Adolescents and young adults (AYAs, ages 15 to 40 years) with cancer have not experienced survival improvements to the same extent as younger and older patients. We compared changes in survival after myeloablative allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL) among children (n = 981), AYAs (n = 1218), and older adults (n = 469) who underwent transplantation over 3 time periods: 1990 to 1995, 1996 to 2001, and 2002 to 2007. Five-year survival varied inversely with age group. Survival improved over time in AYAs and paralleled that seen in children; however, overall survival did not change over time for older adults. Survival improvements were primarily related to lower rates of early treatment-related mortality in the most recent era. For all cohorts, relapse rates did not change over time. A subset of 222 AYAs between the ages of 15 and 25 at 46 pediatric or 49 adult centers were also analyzed to describe differences by center type. In this subgroup, there were differences in transplantation practices among pediatric and adult centers, although HCT outcomes did not differ by center type. Survival for AYAs undergoing myeloablative allogeneic HCT for ALL improved at a similar rate as survival for children. PMID:24607554

  17. Treosulfan, Fludarabine and 2 Gy Total Body Irradiation Followed by Allogeneic Hematopoietic Cell Transplantation in Patients with MDS and AML

    PubMed Central

    Gyurkocza, Boglarka; Gutman, Jonathan; Nemecek, Eneida R.; Bar, Merav; Milano, Filippo; Ramakrishnan, Aravind; Scott, Bart; Fang, Min; Wood, Brent; Pagel, John M.; Baumgart, Joachim; Delaney, Colleen; Maziarz, Richard T.; Sandmaier, Brenda M.; Estey, Elihu H.; Appelbaum, Frederick R.; Storer, Barry E.; Deeg, H. Joachim

    2014-01-01

    Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial we assessed the efficacy and toxicity of treosulfan, fludarabine and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n=36; 15 RMCD; 10 RAEB-1; 10 RAEB-2; 1 CMML-1) or AML (n=60; 35 CR1; 18 CR2; 3 advanced CR; 4 refractory relapse) were enrolled; median age was 51 (range: 1–60) years. Twelve patients had undergone a prior HCT with high intensity conditioning. Patients received intravenous (IV) treosulfan, 14 g/m2/day on days −6 to −4, IV fludarabine, 30 mg/m2/day on days −6 to −2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n=27) or unrelated (n=69) donors. Graft-vs.-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30 months, the 2-year overall survival (OS), relapse incidence and non-relapse mortality were 73%, 27% and 8%, respectively. The incidences of grades II–IV (III–IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor risk and good/intermediate risk cytogenetics (69% and 85%, respectively), or between AML patients with unfavorable and favorable/intermediate risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n=10) at the time of HCT predicted higher relapse incidence (70% vs. 18%) and lower OS (41% vs. 79%) at 2 years, when compared to patients without MRD. In conclusion, treosulfan, fludarabine and low-dose TBI provided effective conditioning for allogeneic HCT in patients with MDS or AML, and resulted in low relapse incidence, regardless

  18. Detection of Human Herpesvirus 6B (HHV-6B) Reactivation in Hematopoietic Cell Transplant Recipients with Inherited Chromosomally Integrated HHV-6A by Droplet Digital PCR.

    PubMed

    Sedlak, Ruth Hall; Hill, Joshua A; Nguyen, Thuy; Cho, Michelle; Levin, Greg; Cook, Linda; Huang, Meei-Li; Flamand, Louis; Zerr, Danielle M; Boeckh, Michael; Jerome, Keith R

    2016-05-01

    The presence of inherited chromosomally integrated human herpesvirus 6 (ciHHV-6) in hematopoietic cell transplant (HCT) donors or recipients confounds molecular testing for HHV-6 reactivation, which occurs in 30 to 50% of transplants. Here we describe a multiplex droplet digital PCR clinical diagnostic assay that concurrently distinguishes between HHV-6 species (A or B) and identifies inherited ciHHV-6. By applying this assay to recipient post-HCT plasma and serum samples, we demonstrated reactivation of HHV-6B in 25% (4/16 recipients) of HCT recipients with donor- or recipient-derived inherited ciHHV-6A, underscoring the need for diagnostic testing for HHV-6 infection even in the presence of ciHHV-6. PMID:26888901

  19. Induction of Allogeneic Unresponsiveness in Adult Dogs

    PubMed Central

    Rapaport, F. T.; Bachvaroff, R. J.; Watanabe, K.; Hirasawa, H.; Mollen, N.; Ferrebee, J. W.; Amos, D. B.; Cannon, F. D.; Blumenstock, D. A.

    1978-01-01

    Exposure to supralethal total body irradiation and transplantation of bone marrow from a DLA- and pedigree-identical donor have regularly produced successful engraftment and the establishment of stable long-term chimerism in beagles of the Cooperstown colony. Bone marrow allografts performed in pairs of dogs bearing identical DLA haplotypes derived from different pedigree origins (i.e., different classes of the same haplotype) yielded two different results. Depending upon the particular haplotype pedigree combination used, such transplants either led to long-term chimerism or to failures of engraftment, secondary disease, and death of the recipients (i.e., pedigree-incompatible combinations). Radiation chimeras given bone marrow from a DLA-and pedigree-identical donor were challenged within 8-12 h after marrow transplantation with a renal allograft obtained from another DLA- and pedigree-identical donor. The recipients have remained unresponsive to such renal allografts and have survived indefinitely with normal renal function. In contrast, renal allografts obtained from donors bearing the same DLA haplotypes derived from pedigree-incompatible sources were rejected within 25-50 days after transplantation. The long-term surviving recipients have also been unresponsive to skin allografts obtained from their donor of marrow and the kidney donor. Skin grafts obtained from other DLA- and pedigree-identical dogs were rejected within 13-41 days, and grafts from DLA-incompatible donors survived for 10-25 days. These results highlight the potential importance of genetically controlled histocompatibility determinants other than DLA in conditioning allograft reactivity. The determinants uncovered in the present study appear to be linked to the DLA complex, as demonstrated by the ability of the pedigree origins of DLA haplotypes present in individual dogs to serve as an effective marker system for such non-DLA antigen(s). The results also point to the potential usefulness of

  20. Toll like receptor polymorphisms in allogeneic hematopoietic cell transplantation

    PubMed Central

    Kornblit, Brian; Enevold, Christian; Wang, Tao; Spellman, Stephen; Haagenson, Mike; Lee, Stephanie J; Müller, Klaus

    2014-01-01

    To assess the impact of the genetic variation in toll-like receptors (TLR) on outcome after allogeneic myeloablative conditioning hematopoietic cell transplantation (HCT) we have investigated 29 single nucleotide polymorphisms (SNP) across 10 TLRs in 816 patients and donors. Only donor genotype of TLR8 rs3764879, which is located on the X chromosome, was significantly associated with outcome at the Bonferroni corrected level P≤0.001. Male hemizygosity and female homozygosity for the minor allele were significantly associated with disease free survival (DFS) (hazard ratio (HR) 1.47 (95% confidence interval (CI) 1.16–1.85); P=0.001). Further analysis stratified by donor sex due to confounding by sex, was suggestive for associations with overall survival (male donor: HR 1.41 (95% CI 1.09–1.83), P=0.010); female donor: (HR 2.78 (95% CI 1.43–5.41), P=0.003), DFS (male donor: HR 1.45 (95% CI 1.12–1.87), P=0.005; female donor: HR 2.34 (95% CI 1.18–4.65), P=0.015) and treatment related mortality (male donor: HR 1.49 (95% CI 1.09–2.04), P=0.012; female donor: HR 3.12 (95% CI 1.44–6.74), P=0.004). In conclusion our findings suggest that the minor allele of TLR8 rs3764879 of the donor is associated with outcome after myeloablative conditioned allogeneic HCT. PMID:25464115

  1. Pretransplant β2-Microglobulin Is Associated with the Risk of Acute Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplant.

    PubMed

    Costa-Lima, Carolina; Miranda, Eliana Cristina Martins; Colella, Marcos Paulo; Aranha, Francisco Jose Penteado; de Souza, Carmino Antonio; Vigorito, Afonso Celso; De Paula, Erich Vinicius

    2016-07-01

    The risk of acute graft-versus-host disease (aGVHD) can be reliably estimated by the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), which can be further refined by the incorporation of pre-hematopoietic cell transplantation (HCT) serum levels of inflammatory biomarkers such as ferritin and albumin. β2-Microglobulin (β2-m) is a key component of the MHC class I complex, which is independently associated with mortality and frailty in the general population. We took advantage of our institutional protocol that includes measurement of pre-HCT β2-m serum levels in the most patients to investigate whether pre-transplant β2-m levels were associated with the risk of aGVHD. One hundred three consecutive patients submitted to allogeneic HCT, of which 26 developed grades II to IV aGVHD, were included in the analysis. β2-m was significantly associated with age and HCT-CI. Higher levels of β2-m were observed in patients who developed aGVHD (P = .008). In the multivariate Cox regression model, β2-m and HCT-CI remained independently associated with the risk of developing aGVHD. In conclusion, the association between β2-m and the occurrence of aGVHD suggests that the measurement of this protein before HCT might represent an additional element for risk stratification of aGVHD. PMID:27044906

  2. [Human Herpesvirus-6 Encephalitis in Allogeneic Hematopoietic Stem Cell Transplantation].

    PubMed

    Ogata, Masao

    2015-07-01

    The reactivation of human herpesvirus-6B (HHV-6B) is common after allogeneic hematopoietic cell transplantation (allo-HCT), and it is sporadically associated with the development of HHV-6 encephalitis. HHV-6 encephalitis typically develops around 2-6 weeks after allo-HCT, and it is characterized by short-term memory loss. Magnetic resonance imaging typically shows bilateral signal abnormalities in the limbic system. The incidence of HHV-6 encephalitis is reportedly 0-11.6% after bone marrow or peripheral blood stem cell transplantation and 4.9-21.4% after cord blood transplantation. The mortality of HHV-6 encephalitis is high, and survivors are often left with serious sequelae. Antiviral therapy using foscarnet or ganciclovir is recommended for the treatment of HHV-6 encephalitis, but the efficacy of the currently available treatment is insufficient once HHV-6 encephalitis has developed. The elucidation of the pathogenesis of HHV-6 encephalitis and the establishment of preventative therapy are needed to overcome this disease. PMID:26160819

  3. Survival of AML patients relapsing after allogeneic hematopoietic cell transplantation: a CIBMTR study

    PubMed Central

    Bejanyan, Nelli; Weisdorf, Daniel J.; Logan, Brent R.; Wang, Hai-Lin; Devine, Steven M.; de Lima, Marcos; Bunjes, Donald W.; Zhang, Mei-Jie

    2015-01-01

    Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (alloHCT) remains a major therapeutic challenge. We studied outcomes of 1788 AML patients relapsing after alloHCT (1990–2010) during first or second complete remission (CR) to identify factors associated with longer post-relapse survival. Median time of post HCT relapse was 7 months (mo; range, 1–177). At relapse, 1231 patients (69%) received intensive therapy, including chemotherapy (CT) alone (n=660), donor lymphocyte infusion (DLI)±CT (n=202; %), or 2nd alloHCT±CT ±DLI (n=369), with subsequent CR rates of 29%. Median follow-up after relapse was 39 mo (range, <1–193). Survival for all patients was 23% at 1 year post-relapse; however, 3-yr overall survival correlated with time from HCT to relapse (4% for relapse during 1–6 mo period, 12% during 6 mo-2 yr, 26% during 2–3 yr, and 38% for ≥3 yr). In multivariable analysis, lower mortality was significantly associated with longer time from alloHCT to relapse (RR 0.55 for 6 mo-2 yr, RR 0.39 for 2–3 yr, and RR 0.28 for ≥3 yr; p<0.0001) and a 1st HCT using reduced-intensity conditioning (RR=0.77; 95% CI 0.66–0.88, p=0.0002). In contrast, inferior survival was associated with age >40 yr (RR=1.42, 95% CI 1.24–1.64; p<0.0001), active GVHD at relapse (RR=1.25, 95% CI 1.13–1.39; p<0.0001), adverse cytogenetics (RR=1.37, 95% CI 1.09–1.71; p=0.0062), mismatched URD (RR=1.61, 95% CI 1.22–2.13; p=0.0008), and use of cord blood for 1st HCT (RR=1.23, 95% CI 1.06–1.42; p=0.0078). AML relapse after alloHCT predicted poor survival; however, patients who relapsed ≥6 mo after their initial alloHCT had better survival and may benefit from intensive therapy such as 2nd alloHCT±DLI. PMID:25460355

  4. UNRELATED DONOR REDUCED INTENSITY ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR RELAPSED AND REFRACTORY HODGKIN LYMPHOMA

    PubMed Central

    Devetten, Marcel P.; Hari, Parameswaran N.; Carreras, Jeanette; Logan, Brent R.; van Besien, Koen; Bredeson, Christopher N.; Freytes, César O.; Peter Gale, Robert; Gibson, John; Giralt, Sergio A.; Goldstein, Steven C.; Gupta, Vikas; Marks, David I.; Maziarz, Richard T.; Vose, Julie M.; Lazarus, Hillard M.; Anderlini, Paolo

    2010-01-01

    Myeloablative allogeneic hematopoietic cell transplantation (HCT) may cure patients with relapsed or refractory Hodgkin Lymphoma (HL), but is associated with a high treatment-related mortality (TRM). Reduced intensity and nonmyeloablative (RIC/NST) conditioning regimens aim to lower TRM. We analyzed the outcomes of 143 patients undergoing unrelated donor RIC/NST HCT for relapsed and refractory HL between 1999 and 2004 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients were heavily pretreated, including autologous HCT in 89%. With a median follow-up of 25 months, the probability of TRM at day 100 and 2 years was 15% (95% CI 10-21%) and 33% (95% CI 25-41%) respectively. The probabilities of progression free survival (PFS) and overall survival (OS) were 30% and 56% at 1 year and 20% and 37% at 2 years. The presence of extranodal disease and KPS < 90 were significant risk factors for TRM, PFS and OS, whereas chemosensitivity at transplantation was not. Dose intensity of the conditioning regimen (RIC vs NST) did not impact outcomes. Unrelated donor HCT with RIC/NST can salvage some patients with relapsed/refractory HL, but relapse remains a common reason for treatment failure. Clinical studies should be aimed at reducing the incidence of acute Graft-versus-Host Disease and relapse. PMID:19135949

  5. Allogeneic hematopoietic cell transplantation as curative therapy for non-transformed follicular lymphomas.

    PubMed

    Heinzelmann, F; Bethge, W; Beelen, D W; Engelhard, M; Kröger, N; Dreger, P; Niederwieser, D; Finke, J; Bunjes, D; Tischer, J; Kobbe, G; Holler, E; Bornhäuser, M; Stelljes, M; Baurmann, H; Müller, A; Haubitz, I; Schrezenmeier, H; Müller, C; Ottinger, H

    2016-05-01

    Allogeneic hematopoietic cell transplantation (HCT) offers the chance of cure for patients with non-transformed follicular lymphoma (FL), but is associated with the risk of non-relapse mortality (NRM). The aim of this study was to identify subgroups of FL patients who benefit from HCT. The European Society for Blood and Marrow Transplantation (EBMT) Minimum-Essential-A Data of 146 consecutive patients who received HCT for FL between 1998 and 2008 were extracted from the database of the German Registry 'DRST'. Diagnosis of FL was verified by contact with the reference pathologists. Estimated 1-, 2- and 5-year overall survivals (OS) were 67%, 60% and 53%, respectively. Day 100 NRM was 15%. Thirteen out of 33 patients (40%) with treatment-refractory disease (RD) at the time of transplantation survived long term. Univariate statistical analysis suggested limited chronic GvHD, donor age ⩽42 years and TBI-based conditioning in treatment refractory patients to correlate with favorable OS. Independent prognostic factors for OS were treatment-sensitive disease and limited chronic GvHD for the whole cohort, and additionally TBI-based conditioning for the treatment refractory subgroup. In contrast, patient age ⩾55 years had no impact on outcome. Thus, HCT for FL is associated with acceptable NRM, and offers a substantial chance of cure for patients with RD or advanced age. Donors ⩽42 years should be preferred if available. PMID:26855152

  6. Reduced-intensity conditioning allogeneic hematopoietic-cell transplantation for older patients with acute myeloid leukemia

    PubMed Central

    Goyal, Gaurav; Gundabolu, Krishna; Vallabhajosyula, Saraschandra; Silberstein, Peter T.; Bhatt, Vijaya Raj

    2016-01-01

    Elderly patients (>60 years) with acute myeloid leukemia have a poor prognosis with a chemotherapy-alone approach. Allogeneic hematopoietic-cell transplantation (HCT) can improve overall survival (OS). However, myeloablative regimens can have unacceptably high transplant-related mortality (TRM) in an unselected group of older patients. Reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens preserve the graft-versus-leukemia effects but reduce TRM. NMA regimens result in minimal cytopenia and may not require stem cell support for restoring hematopoiesis. RIC regimens, intermediate in intensity between NMA and myeloablative regimens, can cause prolonged myelosuppresion and usually require stem cell support. A few retrospective and prospective studies suggest a possibility of lower risk of relapse with myeloablative HCT in fit older patients with lower HCT comorbidity index; however, RIC and NMA HCTs have an important role in less-fit patients and those with significant comorbidities because of lower TRM. Whether early tapering of immunosuppression, monitoring of minimal residual disease, and post-transplant maintenance therapy can improve the outcomes of RIC and NMA HCT in elderly patients will require prospective trials. PMID:27247754

  7. Iron Overload in Allogeneic Hematopoietic Cell Transplantation Outcome: A Meta-Analysis

    PubMed Central

    Armand, Philippe; Kim, Haesook T.; Virtanen, Johanna M.; Parkkola, Riitta K.; Itälä-Remes, Maija A.; Majhail, Navneet S.; Burns, Linda J.; DeFor, Todd; Trottier, Bryan; Platzbecker, Uwe; Antin, Joseph H.; Wermke, Martin

    2014-01-01

    An elevated ferritin before allogeneic hematopoietic cell transplantation (HCT) is an adverse prognostic factor for overall survival (OS) and non-relapse mortality (NRM). Because ferritin is an imperfect surrogate of iron stores, the prognostic role of iron overload remains unclear. We conducted a patient-level meta-analysis of 4 studies that used magnetic resonance imaging to estimate pre-HCT liver iron content (LIC). An elevated LIC was not associated with a significant increase in mortality: the hazard ratio (HR) for mortality associated with LIC>7 mg/gdw (primary endpoint) was 1.4 (p=0.18). In contrast, ferritin >1000 ng/ml was a significant prognostic factor (HR for mortality 1.7, p=0.036). There was, however, no significant association between ferritin>2500 and mortality. This meta-analysis suggests that iron overload, as assessed by LIC, is not a strong prognostic factor for OS in a general adult HCT population. Our data also suggest that ferritin is an inadequate surrogate for iron overload in HCT. PMID:24769316

  8. Reduced-intensity conditioning allogeneic hematopoietic-cell transplantation for older patients with acute myeloid leukemia.

    PubMed

    Goyal, Gaurav; Gundabolu, Krishna; Vallabhajosyula, Saraschandra; Silberstein, Peter T; Bhatt, Vijaya Raj

    2016-06-01

    Elderly patients (>60 years) with acute myeloid leukemia have a poor prognosis with a chemotherapy-alone approach. Allogeneic hematopoietic-cell transplantation (HCT) can improve overall survival (OS). However, myeloablative regimens can have unacceptably high transplant-related mortality (TRM) in an unselected group of older patients. Reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens preserve the graft-versus-leukemia effects but reduce TRM. NMA regimens result in minimal cytopenia and may not require stem cell support for restoring hematopoiesis. RIC regimens, intermediate in intensity between NMA and myeloablative regimens, can cause prolonged myelosuppresion and usually require stem cell support. A few retrospective and prospective studies suggest a possibility of lower risk of relapse with myeloablative HCT in fit older patients with lower HCT comorbidity index; however, RIC and NMA HCTs have an important role in less-fit patients and those with significant comorbidities because of lower TRM. Whether early tapering of immunosuppression, monitoring of minimal residual disease, and post-transplant maintenance therapy can improve the outcomes of RIC and NMA HCT in elderly patients will require prospective trials. PMID:27247754

  9. Sleep disruption in hematopoietic cell transplantation recipients: prevalence, severity, and clinical management.

    PubMed

    Jim, Heather S L; Evans, Bryan; Jeong, Jiyeon M; Gonzalez, Brian D; Johnston, Laura; Nelson, Ashley M; Kesler, Shelli; Phillips, Kristin M; Barata, Anna; Pidala, Joseph; Palesh, Oxana

    2014-10-01

    Sleep disruption is common among hematopoietic cell transplant (HCT) recipients, with over 50% of recipients experiencing sleep disruption pre-transplant, with up to 82% of patients experiencing moderate to severe sleep disruption during hospitalization for transplant and up to 43% after transplant. These rates of sleep disruption are substantially higher than what we see in the general population. Although sleep disruption can be distressing to patients and contribute to diminished quality of life, it is rarely discussed during clinical visits. The goal of the current review is to draw attention to sleep disruption and disorders (ie, insomnia, obstructive sleep apnea, restless legs syndrome) as a clinical problem in HCT in order to facilitate patient education, intervention, and research. We identified 35 observational studies published in the past decade that examined sleep disruption or disorders in HCT. Most studies utilized a single item measure of sleep, had small sample size, and included heterogeneous samples of patients. Six studies of the effects of psychosocial and exercise interventions on sleep in HCT have reported no significant improvements. These results highlight the need for rigorous observational and interventional studies of sleep disruption and disorders in HCT recipients.. PMID:24747335

  10. Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016.

    PubMed

    Ullmann, Andrew J; Schmidt-Hieber, Martin; Bertz, Hartmut; Heinz, Werner J; Kiehl, Michael; Krüger, William; Mousset, Sabine; Neuburger, Stefan; Neumann, Silke; Penack, Olaf; Silling, Gerda; Vehreschild, Jörg Janne; Einsele, Hermann; Maschmeyer, Georg

    2016-09-01

    Infectious complications after allogeneic haematopoietic stem cell transplantation (allo-HCT) remain a clinical challenge. This is a guideline provided by the AGIHO (Infectious Diseases Working Group) of the DGHO (German Society for Hematology and Medical Oncology). A core group of experts prepared a preliminary guideline, which was discussed, reviewed, and approved by the entire working group. The guideline provides clinical recommendations for the preventive management including prophylactic treatment of viral, bacterial, parasitic, and fungal diseases. The guideline focuses on antimicrobial agents but includes recommendations on the use of vaccinations. This is the updated version of the AGHIO guideline in the field of allogeneic haematopoietic stem cell transplantation utilizing methods according to evidence-based medicine criteria. PMID:27339055

  11. Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index: A CIBMTR® Study

    PubMed Central

    Sorror, Mohamed L.; Logan, Brent R.; Zhu, Xiaochun; Rizzo, J. Douglas; Cooke, Kenneth R.; McCarthy, Philip L; Ho, Vincent T.; Horowitz, Mary M.; Pasquini, Marcelo C.

    2015-01-01

    Prospective validation of the hematopoietic cell transplantation-comorbidity index (HCT-CI) using contemporary patients treated with HCT across the Unites States is necessary to confirm its widespread applicability. We performed a prospective observational study including all patients (8115 recipients of allogeneic and 11,652 recipients of autologous HCT) who underwent first HCT that was reported to the CIBMTR between 2007 and 2009. In proportional hazards models, increased HCT-CI scores were independently associated with increases in hazard ratios for NRM (p<0.0001) and overall mortality (p<0.0001) among recipients of allogeneic HCT. HCT-CI Scores of ≥3 were uniformly associated with higher risks for outcomes in both allogeneic and autologous HCT, and all subgroups regardless of diagnoses, age, and conditioning intensity. Recipients of allogeneic HCT with scores of 1–2 who were aged <18 or were treated with lower intensity conditioning regimens had similar outcomes compared to those with score 0. Higher risks for overall mortality, but not for NRM, were observed among recipients of autologous HCT with scores of 1–2 versus 0. Our results confirm the validity the HCT-CI in both allogeneic and autologous HCT. The index should be used as a valid standard-of-care health measure in counseling patients for HCT, in clinical trial design, and in adjusting outcome analyses. PMID:25862591

  12. Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index: A Center for International Blood and Marrow Transplant Research Study.

    PubMed

    Sorror, Mohamed L; Logan, Brent R; Zhu, Xiaochun; Rizzo, J Douglas; Cooke, Kenneth R; McCarthy, Philip L; Ho, Vincent T; Horowitz, Mary M; Pasquini, Marcelo C

    2015-08-01

    Prospective validation of the hematopoietic cell transplantation-comorbidity index (HCT-CI) using contemporary patients treated with hematopoietic cell transplantation (HCT) across the Unites States is necessary to confirm its widespread applicability. We performed a prospective observational study including all patients (8115 recipients of allogeneic and 11,652 recipients of autologous HCT) who underwent a first HCT that was reported to the Center for International Blood and Marrow Transplant Research between 2007 and 2009. In proportional hazards models, increased HCT-CI scores were independently associated with increases in hazard ratios for nonrelapse mortality (NRM) (P < .0001) and overall mortality (P < .0001) among recipients of allogeneic HCT. HCT-CI scores of ≥3 were uniformly associated with higher risks for outcomes in both allogeneic and autologous HCT and in all subgroups, regardless of diagnoses, age, and conditioning intensity. Recipients of allogeneic HCT with scores of 1 and 2 who were ages < 18 years or were treated with lower intensity conditioning regimens had similar outcomes compared with those with a score of 0. Higher risks for overall mortality, but not for NRM, were observed among recipients of autologous HCT with scores of 1 and 2 versus 0. Our results confirm the validity the HCT-CI in both allogeneic and autologous HCT. The index should be used as a valid standard-of-care health measure in counseling patients for HCT, in clinical trial design, and in adjusting outcome analyses. PMID:25862591

  13. Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia: relapse-free survival is determined by karyotype and comorbidities.

    PubMed

    Eissa, Hesham; Gooley, Ted A; Sorror, Mohamed L; Nguyen, Franchesca; Scott, Bart L; Doney, Kristine; Loeb, Keith R; Martin, Paul J; Pagel, John M; Radich, Jerry P; Sandmaier, Brenda M; Warren, E Houston; Storb, Rainer; Appelbaum, Frederick R; Deeg, H Joachim

    2011-06-01

    Hematopoietic cell transplantation (HCT) offers potentially curative therapy for chronic myelomonocytic leukemia (CMML). We evaluated HCT outcomes in 85 patients with CMML, 1.0-69.1 (median 51.7) years of age, with follow-up extending to 19 years. CMML was considered de novo in 71 and secondary in 14 patients. Conditioning regimens were of various intensities. Thirty-eight patients had related (34 HLA identical), and 47 (39 HLA matched) unrelated donors. The source of stem cells was marrow in 32 and peripheral blood progenitor cells in 53 patients. Acute graft-versus-host disease (aGVHD) grades II-IV occurred in 72% and chronic GVHD (cGVHD) in 26% of patients. Relapse incidence was 27% at 10 years. Relapse correlated with increasing scores by the MD Anderson prognostic score (P = .01). The major causes of death were relapse and infections ±GVHD. Progression-free survival (PFS) was 38% at 10 years. Mortality was negatively correlated with pre-HCT hematocrit (P = .007), and increased with high-risk cytogenetics (P = .02), higher HCT Comorbidity Index (P = .0008), and increased age (P = .02). WHO classification did not statistically significantly affect outcome. Thus, a proportion of patients with CMML have lasting remissions following allogeneic HCT and appear to be cured of their disease. PMID:20932924

  14. Assessing the Influence of Different Comorbidities Indexes on the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in a Developing Country

    PubMed Central

    Teixeira, Gustavo Machado; Bittencourt, Henrique; Rezende, Suely Meireles

    2015-01-01

    Although the application of Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) has enabled better prediction of transplant-related mortality (TRM) in allogeneic hematopoietic stem cell transplants (AHSCT), data from developing countries are scarce. This study prospectively evaluated the HCT-CI and the Adult Comorbidity Evaluation (ACE-27), in its original and in a modified version, as predictors of post-transplant complications in adults undergoing a first related or unrelated AHSCT in Brazil. Both bone marrow (BM) and peripheral blood stem cells (PBSC) as graft sources were included. We analyzed the cumulative incidence of granulocyte and platelet recovery, sinusoidal obstructive syndrome, acute and chronic graft-versus-host disease, relapse and transplant-related mortality, and rates of event-free survival and overall survival. Ninety-nine patients were assessed. Median age was 38 years (18–65 years); HCT-CI ≥ 3 accounted for only 8% of cases; hematologic malignancies comprised 75.8% of the indications for AHSCT. There was no association between the HCT-CI or the original or modified ACE-27 with TRM or any other studied outcomes after AHSCT. These results show that, in the population studied, none of the comorbidity indexes seem to be associated with AHSCT outcomes. A significantly low frequency of high-risk (HCT-CI ≥ 3) in this Brazilian population might justify these results. PMID:26394228

  15. Does defibrotide prophylaxis decrease the risk of acute graft versus host disease following allogeneic hematopoietic cell transplantation?

    PubMed

    Tekgündüz, Emre; Kaya, Ali Hakan; Bozdağ, Sinem Civriz; Koçubaba, Şerife; Kayıkçı, Ömür; Namdaroğlu, Sinem; Uğur, Bilge; Akpınar, Seval; Batgi, Hikmetullah; Bekdemir, Filiz; Altuntaş, Fevzi

    2016-02-01

    There is some preliminary evidence, that veno-occlusive disease prophylaxis with defibrotide (DF) may also have a role in decreasing risk of acute graft-versus-host disease (aGvHD) by preventing tissue damage. In this study, we aimed to investigate the role of DF prophylaxis on the development of aGvHD at D + 180. One hundred ninety-five consecutive adult patients receiving allogeneic HCT were retrospectively evaluated in 3 groups: no DF, DF/post-HCT (DF D + 1 to D + 14) and DF/pre-HCT (DF for 14 days concurrently with conditioning). The total (p: 0.057) and grades III/IV (p: 0.051) aGvHD rates at D + 180 were 46.5%, 40%, 25.5% and 15.5%, 11.2%, 0% in patients on no DF, DF/post-HCT and DF/pre-HCT. DF may have a role in decreasing incidence and severity of aGvHD, especially if used concurrently with conditioning regimen. PMID:26922995

  16. Allogeneic Hematopoietic Cell Transplantation for Chronic Myelomonocytic Leukemia: Relapse-Free Survival is Determined by Karyotype and Comorbidities

    PubMed Central

    Eissa, Hesham; Gooley, Ted A.; Sorror, Mohamed L.; Nguyen, Franchesca; Scott, Bart L.; Doney, Kristine; Loeb, Keith R.; Martin, Paul J.; Pagel, John M.; Radich, Jerry P.; Sandmaier, Brenda M.; Warren, E. Houston; Storb, Rainer; Appelbaum, Frederick R.; Deeg, H. Joachim

    2011-01-01

    Hematopoietic cell transplantation (HCT) offers potentially curative therapy for Chronic Myelomonocytic Leukemia (CMML). We evaluated HCT outcomes in 85 patients with CMML, 1.0–69.1 (median 51.7) years of age, with follow-up extending to 19 years. CMML was considered de novo in 71 and secondary in 14 patients. Conditioning regimens were of various intensities. Thirty-eight patients had related (34 HLA identical), and 47 (39 HLA matched) unrelated donors. The source of stem cells was marrow in 32 and peripheral blood progenitor cells in 53 patients. Acute GVHD grades II–IV occurred in 72% and chronic GVHD in 26% of patients. Relapse incidence was 27% at 10 years. Relapse correlated with increasing scores by the MD Anderson prognostic score (p=0.01). The major causes of death were relapse and infections ±GVHD. Progression-free survival was 38% at 10 years. Mortality was negatively correlated with pre-HCT hematocrit (p=0.007), and increased with high-risk cytogenetics (p=0.02), higher HCT Comorbidity Index (p=0.0008), and increased age (p=.02). WHO classification did not statistically significantly affect outcome. Thus, a proportion of patients with CMML have lasting remissions following allogeneic HCT and appear to be cured of their disease. PMID:20932924

  17. Brentuximab vedotin enables successful reduced-intensity allogeneic hematopoietic cell transplantation in patients with relapsed or refractory Hodgkin lymphoma.

    PubMed

    Chen, Robert; Palmer, Joycelynne M; Thomas, Sandra H; Tsai, Ni-Chun; Farol, Len; Nademanee, Auayporn; Forman, Stephen J; Gopal, Ajay K

    2012-06-28

    Brentuximab vedotin induces an overall response rate of 75% in patients with relapsed/refractory Hodgkin lymphoma, but its impact on future allogeneic transplantation (allo-HCT) is not known. We retrospectively examined the records of 18 patients with relapsed/refractory Hodgkin lymphoma who were treated on brentuximab vedotin clinical trials to evaluate the efficacy and safety of subsequent reduced-intensity allo-HCT. Seventeen patients had previous autologous transplant; 6 were in complete remission, and 8 were in partial remission before allo-HCT with 12 grafts from unrelated or mismatched donors. The 1-year overall survival was 100%, progression-free survival was 92.3%, and nonrelapse mortality was 0% (median follow-up, 14 months). The incidence of acute GVHD was 27.8% and chronic GVHD was 56.3%. Brentuximab vedotin before reduced-intensity allo-HCT does not appear to adversely affect engraftment, GVHD, or survival and may provide sufficient disease control to enable reduced-intensity allo-HCT. PMID:22611160

  18. Nonmyeloablative allogeneic hematopoietic cell transplantation

    PubMed Central

    Storb, Rainer; Sandmaier, Brenda M.

    2016-01-01

    Most hematological malignancies occur in older patients. Until recently these patients and those with comorbidities were not candidates for treatment with allogeneic hematopoietic transplantation because they were unable to tolerate the heretofore used high-dose conditioning regimens. The finding that many of the cures achieved with allogeneic hematopoietic transplantation were due to graft-versus-tumor effects led to the development of less toxic and well-tolerated reduced intensity and nonmyeloablative regimens. These regimens enabled allogeneic engraftment, thereby setting the stage for graft-versus-tumor effects. This review summarizes the encouraging early results seen with the new regimens and discusses the two hurdles that need to be overcome for achieving even greater success, disease relapse and graft-versus-host disease. PMID:27132278

  19. Transplantation tolerance in primates after total lymphoid irradiation and allogeneic bone marrow injection

    SciTech Connect

    Smit, J.A.; Hill, R.R.H.; Myburgh, J.A.; Browde, S.

    1980-08-01

    After total lymphoid irradiation (TLI), allogeneic bone marrow (BM) injection, and organ transplantation in baboons, there is a prolonged period of reduced lymphocyte proliferative responsiveness to polyclonal mitogens and allogeneic lymphocytes. The effect observed is greater with the use of fractionated TLI than after single doses of irradiation. Suppressor cell activity can be demonstrated in vitro in most animals by inhibition of mixed lymphocyte reactivity (MLR) by mitomycin-treated recipient lymphocytes harvested after TLI, with or without allogeneic BM injection, and organ transplantation. Preliminary data suggest the presence of both donor-specific and nondonor-specific suppression, although other interpretations are possible, and suppressor phenomena may not be responsible for the transplantation tolerance observed.

  20. Association of Distance from Transplantation Center and Place of Residence on Outcomes after Allogeneic Hematopoietic Cell Transplantation.

    PubMed

    Khera, Nandita; Gooley, Ted; Flowers, Mary E D; Sandmaier, Brenda M; Loberiza, Fausto; Lee, Stephanie J; Appelbaum, Frederick

    2016-07-01

    Regionalization of specialized health services can deliver high-quality care but may have an adverse impact on access and outcomes because of distance from the regional centers. In the case of hematopoietic cell transplantation (HCT), the effect of increased distance between the transplantation center and the rural/urban residence is unclear because of conflicting results from the existing studies. We examined the association between distance from primary residence to the transplantation center and rural versus urban residence with clinical outcomes after allogeneic HCT in a large cohort of patients. Overall mortality (OM), nonrelapse mortality (NRM), and relapse in all patients and those who survived for 200 days after HCT were assessed in 2849 patients who received their first allogeneic HCT between 2000 and 2010 at Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance. Median distance from FHCRC was 263 miles (range, 0 to 2740 miles) and 83% of patients were urban residents. The association between distance and the hazard of OM varied according to conditioning intensity: myeloablative (MA) versus nonmyeloablative (NMA). Among MA patients, there was no evidence of an increased risk of mortality with increased distance, but for NMA patients, the results did show a suggestion of increased risk of mortality for some distances, although globally the difference was not statistically significant. In the subgroup of patients who survived 200 days, there was no evidence that the risks of OM, relapse, or NRM were increased with increasing distance. We did not find any association between longer distance from transplantation center and urban/rural residence and outcomes after MA HCT. In patients undergoing NMA transplantations, this relationship and how it is influenced by factors such as age, payers, and comorbidities needs to be further investigated. PMID:27013013

  1. Elevated fluoride levels and periostitis in pediatric hematopoietic stem cell transplant recipients receiving long-term voriconazole.

    PubMed

    Tarlock, Katherine; Johnson, Darren; Cornell, Cathy; Parnell, Shawn; Meshinchi, Soheil; Baker, K Scott; Englund, Janet A

    2015-05-01

    Azole therapy is widely utilized in hematopoietic stem cell transplant (HCT) recipients for the treatment of aspergillus. Complications of voriconazole treatment related to its elevated fluoride content have been described in adults, including reports of symptomatic skeletal fluorosis. We review fluoride levels, clinical, and laboratory data in five pediatric HCT recipients on long-term voriconazole therapy, all found to have elevated serum fluoride levels. Two patients had toxic fluoride levels, one infant had symptoms of significant pain with movement and radiographs confirmed skeletal fluorosis. Monitoring fluoride levels in children, especially with skeletal symptoms, should be considered in patients on long-term voriconazole. PMID:25327935

  2. Resistant herpes simplex virus type 1 infection: an emerging concern after allogeneic stem cell transplantation.

    PubMed

    Chen, Y; Scieux, C; Garrait, V; Socié, G; Rocha, V; Molina, J M; Thouvenot, D; Morfin, F; Hocqueloux, L; Garderet, L; Espérou, H; Sélimi, F; Devergie, A; Leleu, G; Aymard, M; Morinet, F; Gluckman, E; Ribaud, P

    2000-10-01

    Fourteen cases of severe acyclovir-resistant herpes simplex virus type 1 (HSV-1) infection, 7 of which showed resistance to foscarnet, were diagnosed among 196 allogeneic stem cell transplant recipients within a 29-month period. Recipients of unrelated stem cell transplants were at higher risk. All patients received foscarnet; 8 subsequently received cidofovir. Strains were initially foscarnet-resistant in 3 patients and secondarily so in 4 patients. In vitro resistance to acyclovir or foscarnet was associated with clinical failure of these drugs; however, in vitro susceptibility to foscarnet was associated with complete response in only 5 of 7 patients. No strain from any of the 7 patients was resistant in vitro to cidofovir; however, only 3 of 7 patients achieved complete response. Therefore, acyclovir- and/or foscarnet-resistant HSV-1 infections after allogeneic stem cell transplantation have become a concern; current strategies need to be reassessed and new strategies must be evaluated in this setting. PMID:11049772

  3. Specially modified stromal and immune microenvironment in injected bone marrow following intrabone transplantation facilitates allogeneic hematopoietic stem cell engraftment.

    PubMed

    Chen, Chen; Su, Yingjun; Chen, Jianwu; Song, Yajuan; Zhuang, Ran; Xiao, Bo; Guo, Shuzhong

    2016-07-01

    For allogeneic hematopoietic stem cell transplantation (HSCT), the first key step is the engraftment of hematopoietic stem cells (HSCs) across the major histocompatibility complex (MHC) barrier. Intrabone bone marrow transplantation (IBBMT) could replace more recipient stromal cells with donor cells and facilitate allogeneic organ transplantation compared with the conventional intravenous approach. However, it remains unknown whether and how IBBMT reconstructs the immune microenvironment for allogeneic HSCs. We explored where the BM microenvironment changes by determining BM stromal cell chimerism and measuring the change in CXCL-12 expression and regulatory T cells in recipient BM. We found that most stromal cells were replaced by allogeneic cells in the injected BM, with higher expression of immune regulatory cytokines (interleukin-10) compared with the contralateral BM and the intravenous group BM. This difference was independent of injury caused by intrabone injection. Consistent with the microenvironment modification, the allogeneic the engraftment rate and reconstitution capacity of HSCs were enhanced in the injected BM compared with the contralateral BM and intravenous group BM. Surgical removal of the injected bone at 7 days rather than 21 days reduced the levels of allogeneic granulocytes and HSCs in the peripheral blood. In conclusion, IBBMT specially modifies stromal cells in the injected BM which provide immune protective cues that improve the engraftment of allogeneic HSCs in an early period. PMID:27090963

  4. Prognostic Importance of Pretransplant Functional Capacity After Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Devlin, Sean M.; Maloy, Molly A.; Wood, William A.; Tuohy, Sharlynn; Espiritu, Noel; Aquino, Jennifer; Kendig, Tiffany; Michalski, Meghan G.; Gyurkocza, Boglarka; Schaffer, Wendy L.; Ali, Benzar; Giralt, Sergio; Jakubowski, Ann A.

    2015-01-01

    Background. The purpose of this study was to investigate the prognostic importance of functional capacity in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for hematological malignancies. Patients and Methods. Using a retrospective design, 407 patients completed a 6-minute walk distance (6MWD) test to assess functional capacity before HCT; 193 (47%) completed a 6MWD test after hospital discharge. Cox proportional hazards regression was used to estimate the risk of nonrelapse mortality (NRM) and overall survival (OS) according to the 6MWD category (<400 m vs. ≥400 m) and the change in 6MWD (before HCT to discharge) with or without adjustment for Karnofsky performance status (KPS), age, and other prognostic markers. Results. Compared with <400 m, the unadjusted hazard ratio for NRM was 0.65 (95% confidence interval, 0.44–0.96) for a 6MWD ≥400 m. A 6MWD of ≥400 m provided incremental information on the prediction of NRM with adjustment for age (p = .032) but not KPS alone (p = .062) or adjustment for other prognostic markers (p = .099). A significant association was found between the 6MWD and OS (p = .027). A 6MWD of ≥400 m provided incremental information on the prediction of OS with adjustment for age (p = .032) but not for other prognostic markers (p > .05 for all). Patients presenting with a pre-HCT 6MWD of <400 m and experiencing a decline in 6MWD had the highest risk of NRM. Conclusion. The 6MWD is a significant univariate predictor of clinical outcomes but did not provide prognostic information beyond that of traditional prognostic markers in HCT. Implications for Practice: The pretransplant 6-minute walk test is a significant univariate predictor of clinical outcomes in hematological patients beyond age but not beyond that of performance status. On this basis, 6-minute walk distance testing should not be considered part of the standard battery of assessments for risk stratification before hematopoietic cell transplantation

  5. Human herpesvirus-6 viremia is not associated with poor clinical outcomes in children following allogeneic hematopoietic cell transplantation.

    PubMed

    Violago, Leah; Jin, Zhezhen; Bhatia, Monica; Rustia, Evelyn; Kung, Andrew L; Foca, Marc D; George, Diane; Garvin, James H; Sosna, Jean; Robinson, Chalitha; Karamehmet, Esra; Satwani, Prakash

    2015-11-01

    HHV-6 is an evolving pathogen in the field of AlloHCT. However, the impact of HHV-6 on AlloHCT outcomes remains to be elucidated. We studied the incidence and clinical impact of HHV-6 viremia in children following AlloHCT. One hundred consecutive children were monitored weekly by plasma PCR for the first 180 days following AlloHCT for HHV-6, CMV, EBV, and ADV. HHV-6 viremia was defined as plasma PCR >1000 viral copies/mL. The median age was nine yr. Following AlloHCT, 19% (95% CI 11.3-26.7%) of patients had HHV-6 viremia, with the highest incidence of reactivation (14/19, 73%) occurring during day +15-day +98. The proportion of platelet engraftment by day +180 was lower in patients with HHV-6 viremia (58%) than in those without HHV-6 viremia (82%), p = 0.028. Delay in neutrophil and platelet engraftment was not associated with HHV-6 viremia in multivariate analysis. Similarly, HHV-6 viremia was not associated with TRM in multivariate analysis (p = 0.15). In summary, HHV-6 viremia is prevalent in pediatric AlloHCT recipients. Based on our study results, we recommend that HHV-6 PCR should only be performed on clinical suspicion. PMID:26329541

  6. Herpes simplex virus (HSV) colitis in a bone marrow transplant recipient.

    PubMed

    Naik, H R; Chandrasekar, P H

    1996-02-01

    Herpes simplex virus (HSV) infections are common in bone marrow transplantation patients. Unusual sites may be involved, however colonic disease with HSV is rare. We report a successfully treated case of colitis due to HSV, cytomegalovirus, Clostridium difficile and graft-versus-host disease in an allogeneic marrow recipient. PMID:8640181

  7. Sequential myeloablative autologous stem cell transplantation and reduced intensity allogeneic hematopoietic cell transplantation is safe and feasible in children, adolescents and young adults with poor-risk refractory or recurrent Hodgkin and non-Hodgkin lymphoma.

    PubMed

    Satwani, P; Jin, Z; Martin, P L; Bhatia, M; Garvin, J H; George, D; Chaudhury, S; Talano, J; Morris, E; Harrison, L; Sosna, J; Peterson, M; Militano, O; Foley, S; Kurtzberg, J; Cairo, M S

    2015-02-01

    The outcome of children, adolescents and young adults (CAYA) with poor-risk recurrent/refractory lymphoma is dismal (⩽30%). To overcome this poor prognosis, we designed an approach to maximize an allogeneic graft vs lymphoma effect in the setting of low disease burden. We conducted a multi-center prospective study of myeloablative conditioning (MAC) and autologous stem cell transplantation (AutoSCT), followed by a reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (AlloHCT) in CAYA, with poor-risk refractory or recurrent lymphoma. Conditioning for MAC AutoSCT consisted of carmustine/etoposide/cyclophosphamide, RIC consisted of busulfan/fludarabine. Thirty patients, 16 Hodgkin lymphoma (HL) and 14 non-Hodgkin lymphoma (NHL), with a median age of 16 years and median follow-up of 5years, were enrolled. Twenty-three patients completed both MAC AutoSCT and RIC AlloHCT. Allogeneic donor sources included unrelated cord blood (n=9), unrelated donor (n=8) and matched siblings (n=6). The incidence of transplant-related mortality following RIC AlloHCT was only 12%. In patients with HL and NHL, 10 year EFS was 59.8% and 70% (P=0.613), respectively. In summary, this approach is safe, and long-term EFS with this approach is encouraging considering the poor-risk patient characteristics and the use of unrelated donors for RIC AlloHCT in the majority of cases. PMID:24938649

  8. Impact of Pretransplantation (18)F-fluorodeoxy Glucose-Positron Emission Tomography Status on Outcomes after Allogeneic Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma.

    PubMed

    Bachanova, Veronika; Burns, Linda J; Ahn, Kwang Woo; Laport, Ginna G; Akpek, Görgün; Kharfan-Dabaja, Mohamed A; Nishihori, Taiga; Agura, Edward; Armand, Philippe; Jaglowski, Samantha M; Cairo, Mitchell S; Cashen, Amanda F; Cohen, Jonathon B; D'Souza, Anita; Freytes, César O; Gale, Robert Peter; Ganguly, Siddhartha; Ghosh, Nilanjan; Holmberg, Leona A; Inwards, David J; Kanate, Abraham S; Lazarus, Hillard M; Malone, Adriana K; Munker, Reinhold; Mussetti, Alberto; Norkin, Maxim; Prestidge, Tim D; Rowe, Jacob M; Satwani, Prakash; Siddiqi, Tanya; Stiff, Patrick J; William, Basem M; Wirk, Baldeep; Maloney, David G; Smith, Sonali M; Sureda, Anna M; Carreras, Jeanette; Hamadani, Mehdi

    2015-09-01

    Assessment with (18)F-fluorodeoxy glucose (FDG)-positron emission tomography (PET) before hematopoietic cell transplantation (HCT) for lymphoma may be prognostic for outcomes. Patients with chemotherapy-sensitive non-Hodgkin lymphoma (NHL) undergoing allogeneic HCT reported to the Center of International Blood and Marrow Transplantation Registry between 2007 and 2012 were included. Pre-HCT PET status (positive versus negative) was determined by the reporting transplantation centers. We analyzed 336 patients; median age was 55 years and 60% were males. Follicular lymphoma (n = 104) was more common than large cell (n = 85), mantle cell (n = 69), and mature natural killer or T cell lymphoma (n = 78); two thirds of the cohort received reduced-intensity conditioning; one half had unrelated donor grafts. Patients underwent PET scanning a median of 1 month (range, .07 to 2.83 months) before HCT; 159 were PET positive and 177 were PET negative. At 3 years, relapse/progression, progression-free survival (PFS), and overall survival (OS) in PET-positive versus PET-negative groups were 40% versus 26%; P = .007; 43% versus 47%; P = .47; and 58% versus 60%; P = .73, respectively. On multivariate analysis, a positive pretransplantation PET was associated with an increased risk of relapse/progression (risk ratio [RR], 1.86; P = .001) but was not associated with increased mortality (RR, 1.29, 95% confidence interval [CI], .96 to 1.7; P = .08), therapy failure (RR, 1.32; 95% CI, .95 to 1.84; P = .10), or nonrelapse mortality (RR, .75; 95% CI, .48 to 1.18; P = .22). PET status conferred no influence on graft-versus-host disease. A positive PET scan before HCT is associated with increased relapse risk but should not be interpreted as a barrier to a successful allograft. PET status does not appear to predict survival after allogeneic HCT for NHL. PMID:25983043

  9. Impact of Pretransplantation 18F-fluorodeoxy Glucose—Positron Emission Tomography Status on Outcomes after Allogeneic Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma

    PubMed Central

    Bachanova, Veronika; Burns, Linda J.; Ahn, Kwang Woo; Laport, Ginna G.; Akpek, Görgün; Kharfan-Dabaja, Mohamed A.; Nishihori, Taiga; Agura, Edward; Armand, Philippe; Jaglowski, Samantha M.; Cairo, Mitchell S.; Cashen, Amanda F.; Cohen, Jonathon B.; D'Souza, Anita; Freytes, César O.; Gale, Robert Peter; Ganguly, Siddhartha; Ghosh, Nilanjan; Holmberg, Leona A.; Inward, David J.; Kanate, Abraham S.; Lazarus, Hillard M.; Malone, Adriana K.; Munker, Reinhold; Mussetti, Alberto; Norkin, Maxim; Prestidge, Tim D.; Rowe, Jacob M.; Satwani, Prakash; Siddiqi, Tanya; Stiff, Patrick J.; William, Basem M.; Wirk, Baldeep; Maloney, David G.; Smith, Sonali M.; Sureda, Anna M.; Carreras, Jeanette; Hamadani, Mehdi

    2015-01-01

    Assessment with 18F-fluorodeoxy glucose (FDG)—positron emission tomography (PET) before hematopoietic cell transplantation (HCT) for lymphoma may be prognostic for outcomes. Patients with chemotherapy-sensitive non—Hodgkin lymphoma (NHL) undergoing allogeneic HCT reported to the Center of International Blood and Marrow Transplantation Registry between 2007 and 2012 were included. Pre-HCT PET status (positive versus negative) was determined by the reporting transplantation centers. We analyzed 336 patients; median age was 55 years and 60% were males. Follicular lymphoma (n = 104) was more common than large cell (n = 85), mantle cell (n = 69), and mature natural killer or T cell lymphoma (n = 78); two thirds of the cohort received reduced-intensity conditioning; one half had unrelated donor grafts. Patients underwent PET scanning a median of 1 month (range, .07 to 2.83 months) before HCT; 159 were PET positive and 177 were PET negative. At 3 years, relapse/progression, progression-free survival (PFS), and overall survival (OS) in PET-positive versus PET-negative groups were 40% versus 26%; P = .007; 43% versus 47%; P = .47; and 58% versus 60%; P = .73, respectively. On multivariate analysis, a positive pretransplantation PET was associated with an increased risk of relapse/progression (risk ratio [RR], 1.86; P = .001) but was not associated with worse OS (RR, 1.29, 95% confidence interval [CI], .96 to 1.7; P = .08), PFS (RR, 1.32; 95% CI, .95 to 1.84; P = .10), or nonrelapse mortality (RR, .75; 95% CI, .48 to 1.18; P = .22). PET status conferred no influence on graft-versus-host disease. A positive PET scan before HCT is associated with increased relapse risk but should not be interpreted as a barrier to a successful allograft. PET status does not appear to predict survival after allogeneic HCT for NHL. PMID:25983043

  10. Hematopoietic Cell Transplantation–Specific Comorbidity Index Predicts Inpatient Mortality and Survival in Patients Who Received Allogeneic Transplantation Admitted to the Intensive Care Unit

    PubMed Central

    Bayraktar, Ulas D.; Shpall, Elizabeth J.; Liu, Ping; Ciurea, Stefan O.; Rondon, Gabriela; de Lima, Marcos; Cardenas-Turanzas, Marylou; Price, Kristen J.; Champlin, Richard E.; Nates, Joseph L.

    2013-01-01

    Purpose To investigate the prognostic value of the Hematopoietic Cell Transplantation–Specific Comorbidity Index (HCT-CI) in patients who received transplantation admitted to the intensive care unit (ICU). Patients and Methods We investigated the association of HCT-CI with inpatient mortality and overall survival (OS) among 377 patients who were admitted to the ICU within 100 days of allogeneic stem-cell transplantation (ASCT) at our institution. HCT-CI scores were collapsed into four groups and were evaluated in univariate and multivariate analyses using logistic regression and Cox proportional hazards models. Results The most common pretransplantation comorbidities were pulmonary and cardiac diseases, and respiratory failure was the primary reason for ICU admission. We observed a strong trend for higher inpatient mortality and shorter OS among patients with HCT-CI values ≥ 2 compared with patients with values of 0 to 1 in all patient subsets studied. Multivariate analysis showed that patients with HCT-CI values ≥ 2 had significantly higher inpatient mortality than patients with values of 0 to 1 and that HCT-CI values ≥ 4 were significantly associated with shorter OS compared with values of 0 to 1 (hazard ratio, 1.74; 95% CI, 1.23 to 2.47). The factors associated with lower inpatient mortality were ICU admission during the ASCT conditioning phase or the use of reduced-intensity conditioning regimens. The overall inpatient mortality rate was 64%, and the 1-year OS rate was 15%. Among patients with HCT-CI scores of 0 to 1, 2, 3, and ≥ 4, the 1-year OS rates were 22%, 17%, 18%, and 9%, respectively. Conclusion HCT-CI is a valuable predictor of mortality and survival in critically ill patients after ASCT. PMID:24127454

  11. Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients.

    PubMed

    Hogan, William J; Maris, Michael; Storer, Barry; Sandmaier, Brenda M; Maloney, David G; Schoch, H Gary; Woolfrey, Ann E; Shulman, Howard M; Storb, Rainer; McDonald, George B

    2004-01-01

    Liver injury is a frequent, serious complication of allogeneic hematopoietic cell transplantation (HCT) following myeloablative preparative regimens. We sought to determine the frequency and severity of hepatic injury after nonmyeloablative conditioning and its relationship to outcomes. One hundred ninety-three consecutive patients who received 2 Gy total body irradiation with or without fludarabine were evaluated for end points related to liver injury. Patients with diseases treatable by HCT who were ineligible for conventional myeloablative allogeneic HCT because of advanced age and/or comorbid conditions were included. Fifty-one patients (26%) developed hyperbilirubinemia of 68.4 microM (4 mg/dL) or greater, most commonly resulting from cholestasis due to graft-versus-host disease (GVHD) or sepsis. Pretransplantation factors associated with liver dysfunction were a diagnosis of aggressive malignancy (hazard ratio [HR] 1.9; P =.04) and the inclusion of fludarabine in the conditioning regimen (HR 1.8; P =.07). Overall survival at 1 year was superior for patients who had maximal serum bilirubin levels in the normal (78%) or minimally elevated (22.23-66.69 microM [1.3-3.9 mg/dL]) ranges (69%) compared with those in the 68.4 to 117.99 microM (4-6.9 mg/dL; 20%), 119.7 to 169.29 microM (7.0-9.9 mg/dL; 17%), and 171.0 microM (10 mg/dL; 19%) or greater groups. In summary, significant jaundice occurred in 26% of patients and was predominantly due to cholestasis resulting from GVHD and/or sepsis. Aggressive malignancies (mainly advanced disease) and later development of jaundice after transplantation predicted inferior survival. PMID:12969980

  12. Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I.

    PubMed

    McCune, Jeannine S; Bemer, Meagan J

    2016-05-01

    Although immunosuppressive treatments and target concentration intervention (TCI) have significantly contributed to the success of allogeneic haematopoietic cell transplantation (alloHCT), there is currently no consensus on the best immunosuppressive strategies. Compared with solid organ transplantation, alloHCT is unique because of the potential for bidirectional reactions (i.e. host-versus-graft and graft-versus-host). Postgraft immunosuppression typically includes a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate after high-dose myeloablative conditioning, or a calcineurin inhibitor and mycophenolate mofetil after reduced-intensity conditioning. There are evolving roles for the antithymyocyte globulins (ATGs) and sirolimus as postgraft immunosuppression. A review of the pharmacokinetics and TCI of the main postgraft immunosuppressants is presented in this two-part review. All immunosuppressants are characterized by large intra- and interindividual pharmacokinetic variability and by narrow therapeutic indices. It is essential to understand immunosuppressants' pharmacokinetic properties and how to use them for individualized treatment incorporating TCI to improve outcomes. TCI, which is mandatory for the calcineurin inhibitors and sirolimus, has become an integral part of postgraft immunosuppression. TCI is usually based on trough concentration monitoring, but other approaches include measurement of the area under the concentration-time curve (AUC) over the dosing interval or limited sampling schedules with maximum a posteriori Bayesian personalization approaches. Interpretation of pharmacodynamic results is hindered by the prevalence of studies enrolling only a small number of patients, variability in the allogeneic graft source and variability in postgraft immunosuppression. Given the curative potential of alloHCT, the pharmacodynamics of these immunosuppressants deserves to be explored in depth. Development of

  13. Prognostic Utility of Routine Chimerism Testing at 2 – 6 Months after Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Mossallam, Ghada I.; Kamel, Azza M.; Storer, Barry; Martin, Paul J.

    2009-01-01

    The utility of routine chimerism analysis as a prognostic indicator of subsequent outcomes after allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning regimens remains controversial. To address this controversy, routine chimerism test results at 2 – 6 months after HCT with myeloablative conditioning regimens were evaluated for association with subsequent risks of chronic graft versus host disease (GVHD), non-relapse mortality (NRM), relapse and overall mortality. Only 70 (5%) of 1304 patients had <95% donor-derived cells in the marrow. Low donor chimerism in the marrow occurred predominantly among patients with low risk disease as compared to higher risk diseases and was significantly associated with a reduced risk of chronic GVHD. Among 673 patients tested, 164 (24%) had <85% donor-derived T cells in the blood. Low donor T cell chimerism occurred predominantly among patients with low risk disease as compared to higher risk diseases, among those who had conditioning with busulfan as compared to TBI, and among those with lower grades of acute GVHD. Low donor T cell chimerism in the blood was significantly associated with a reduced risk of chronic GVHD, but not with the risks of relapse, NRM or overall mortality. Routine testing of chimerism in the marrow and blood at 2 – 6 months after HCT with myeloablative conditioning regimens may be helpful in documenting engraftment in clinical trials but provides only limited prognostic information in clinical practice. PMID:19203726

  14. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation.

    PubMed

    Armand, Philippe; Kim, Haesook T; Logan, Brent R; Wang, Zhiwei; Alyea, Edwin P; Kalaycio, Matt E; Maziarz, Richard T; Antin, Joseph H; Soiffer, Robert J; Weisdorf, Daniel J; Rizzo, J Douglas; Horowitz, Mary M; Saber, Wael

    2014-06-01

    Because the outcome of allogeneic hematopoietic cell transplantation (HCT) is predominantly influenced by disease type and status, it is essential to be able to stratify patients undergoing HCT by disease risk. The Disease Risk Index (DRI) was developed for this purpose. In this study, we analyzed 13,131 patients reported to the Center for International Blood and Marrow Transplant Research who underwent HCT between 2008 and 2010. The DRI stratified patients into 4 groups with 2-year overall survival (OS) ranging from 64% to 24% and was the strongest prognostic factor, regardless of age, conditioning intensity, graft source, or donor type. A randomly selected training subgroup of 9849 patients was used to refine the DRI, using a multivariable regression model for OS. This refined DRI had improved prediction ability for the remaining 3282 patients compared with the original DRI or other existing schemes. This validated and refined DRI can be used as a 4- or 3-group index, depending on the size of the cohort under study, for prognostication; to facilitate the interpretation of single-center, multicenter, or registry studies; to adjust center outcome data; and to stratify patients entering clinical trials that enroll patients across disease categories. PMID:24744269

  15. Process of allogeneic hematopoietic cell transplantation decision making for older adults.

    PubMed

    Randall, J; Keven, K; Atli, T; Ustun, C

    2016-05-01

    Allogeneic hematopoietic cell transplantation (alloHCT) may be the only curative option for some older adults with hematologic malignancies, and its associated risks of significant morbidity and mortality warrant a clear, informed decision-making process. As older adults have not been transplanted routinely until recent years, younger people have been the prototypical group around whom the current process has developed. Yet, this process is applied to older adults who have different considerations than younger patients when making their transplant decision. Older adults do not have the open-ended lives of younger patients and are entitled to consider how to spend their remaining time. They also possess maturity and experience, and with proper knowledge, they can make informed choices rather than moving forward in the transplant process unaware. Notably, older patients face similar problems with the informed decision-making process in nephrology. Strategies such as providing education about alloHCT gradually and repeatedly during induction, presenting recent knowledge from the literature in plain language, and utilizing a team approach to patient education may help older adults make the best decision about transplant in light of their situation and values. Understanding when and how older adults decide on alloHCT is an important first step to further exploring this problem. PMID:26457910

  16. Allogeneic hematopoietic cell transplant for AML: no impact of pre-transplant extramedullary disease on outcome.

    PubMed

    Goyal, S D; Zhang, M-J; Wang, H-L; Akpek, G; Copelan, E A; Freytes, C; Gale, R P; Hamadani, M; Inamoto, Y; Kamble, R T; Lazarus, H M; Marks, D I; Nishihori, T; Olsson, R F; Reshef, R; Ritchie, D S; Saber, W; Savani, B N; Seber, A; Shea, T C; Tallman, M S; Wirk, B; Bunjes, D W; Devine, S M; de Lima, M; Weisdorf, D J; Uy, G L

    2015-08-01

    The impact of extramedullary disease (EMD) in AML on the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) is unknown. Using data from the Center for International Blood and Marrow Transplant Research, we compared the outcomes of patients who had EMD of AML at any time before transplant, with a cohort of AML patients without EMD. We reviewed data from 9797 AML patients including 814 with EMD from 310 reporting centers and 44 different countries, who underwent alloHCT between and 1995 and 2010. The primary outcome was overall survival (OS) after alloHCT. Secondary outcomes included leukemia-free survival (LFS), relapse rate and treatment-related mortality (TRM). In a multivariate analysis, the presence of EMD did not affect either OS (hazard ratio 1.00, 95% confidence interval (CI) 0.91-1.09), LFS (0.98, 0.89-1.09), TRM (relative risk 0.92, 95% CI 0.80-1.16, P=0.23) or relapse (relative risk=1.03, 95% CI, 0.92-1.16; P=0.62). Furthermore, the outcome of patients with EMD was not influenced by the location, timing of EMD, or intensity of conditioning regimen. The presence of EMD in AML does not affect transplant outcomes and should not be viewed as an independent adverse prognostic feature. PMID:25915806

  17. Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Maffini, Enrico; Giaccone, Luisa; Festuccia, Moreno; Brunello, Lucia; Busca, Alessandro; Bruno, Benedetto

    2016-06-01

    Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared complication, still associated with significant morbidity and mortality. Today, first line treatment of CMV infection/reactivation is still based on dated antiviral compounds Ganciclovir (GCV), Foscarnet (FOS) and Cidofovir (CDF) with their burdensome weight of side effects. Maribavir (MBV), Letermovir (LMV) and Brincidofovir (BDF) are three new promising anti-CMV drugs without myelosuppressive properties or renal toxic effects that are under investigation in randomized phase II and III trials. Adoptive T-cell therapy (ATCT) in CMV infection possesses a strong rationale, demonstrated by several proof of concept studies; its feasibility is currently under investigation by clinical trials. ATCT from third-party and naïve donors could meet the needs of HSCT recipients of seronegative donors and cord blood grafts. In selected patients such as recipients of T-cell depleted grafts, ATCT, based on CMV-specific host T-cells reconstitution kinetics, would be of value in the prophylactic and/or preemptive CMV treatment. Vaccine-immunotherapy has the difficult task to reduce the incidence of CMV reactivation/infection in highly immunocompromised HSCT patients. Newer notions on CMV biology may represent the base to flush out the Troll of transplantation. PMID:27043241

  18. Allogeneic hematopoietic cell transplantation in patients 60 to 70 years of age with de novo high-risk MDS or secondary AML – a comparison with patients lacking donors who received azacitidine

    PubMed Central

    Platzbecker, Uwe; Schetelig, Johannes; Finke, Jürgen; Trenschel, Rudolf; Scott, Bart L.; Kobbe, Guido; Schaefer-Eckart, Kerstin; Bornhäuser, Martin; Itzykson, Raphael; Germing, Ulrich; Beelen, Dietrich; Ehninger, Gerhard; Fenaux, Pierre; Deeg, H.-Joachim; Adès, Lionel

    2015-01-01

    Standard first-line therapy for older patients with high-risk MDS consists of hypomethylating agents such as azacitidine (AZA). However, the only approach with curative potential remains allogeneic hematopoietic cell transplantation (HCT). So far no direct comparison of both strategies has been carried out. The outcomes of two well balanced cohorts of high-risk MDS patients defined by age (60–70 years), performance status (ECOG ≤2) and donor availability (yes/no) were compared including 103 patients undergoing HCT and 75 patients without this option who received AZA. The estimated 2-year overall survival (OS) after the start of treatment was 39% (95% CI, 30% to 50%) for the HCT patients and 23% (95% CI, 14 to 40%) for the AZA patients. In a multivariate Cox regression analysis of all (n=178) patients ECOG score (0 vs. 1 vs. 2, HR: 2.9/3.9, p<0.001), cytogenetics (good vs. intermediate vs. poor, HR: 1.2/1.7, p=0.026) and type of treatment (HCT vs. AZA, HR: 0.3, p=0.007) were associated with OS. This retrospective cohort analysis suggests a survival advantage with allogeneic HCT compared to treatment with AZA in medically fit high-risk MDS patients 60 to 70 years of age, Prospective controlled studies are warranted. PMID:22579634

  19. Risk factors for vancomycin-resistant enterococcus bacteremia and its influence on survival after allogeneic hematopoietic cell transplantation.

    PubMed

    Tavadze, M; Rybicki, L; Mossad, S; Avery, R; Yurch, M; Pohlman, B; Duong, H; Dean, R; Hill, B; Andresen, S; Hanna, R; Majhail, N; Copelan, E; Bolwell, B; Kalaycio, M; Sobecks, R

    2014-10-01

    Vancomycin-resistant enterococcus (VRE) is a well-known infectious complication among immunocompromised patients. We performed a retrospective analysis to identify risk factors for the development of VRE bacteremia (VRE-B) within 15 months after allogeneic hematopoietic cell transplantation (alloHCT) and to determine its prognostic importance for other post-transplant outcomes. Eight hundred consecutive adult patients who underwent alloHCT for hematologic diseases from 1997 to 2011 were included. Seventy-six (10%) developed VRE-B at a median of 46 days post transplant. Year of transplant, higher HCT comorbidity score, a diagnosis of ALL, unrelated donor and umbilical cord blood donor were all significant risk factors on multivariable analysis for the development of VRE-B. Sixty-seven (88%) died within a median of 1.1 months after VRE-B, but only four (6%) of these deaths were attributable to VRE. VRE-B was significantly associated with worse OS (hazard ratio 4.28, 95% confidence interval 3.23-5.66, P<0.001) in multivariable analysis. We conclude that the incidence of VRE-B after alloHCT has increased over time and is highly associated with mortality, although not usually attributable to VRE infection. Rather than being the cause, this may be a marker for a complicated post-transplant course. Strategies to further enhance immune reconstitution post transplant and strict adherence to infection prevention measures are warranted. PMID:25111516

  20. The origin of IgG production and homogeneous IgG components after allogeneic bone marrow transplantation.

    PubMed

    van Tol, M J; Gerritsen, E J; de Lange, G G; van Leeuwen, A M; Jol-van der Zijde, C M; Oudeman-Gruber, N J; de Vries, E; Radl, J; Vossen, J M

    1996-01-15

    Pediatric recipients (n = 25) of an allogeneic bone marrow (BM) graft were selected on the basis of informative IgG allotype (Gm) differences between the BM donor and the recipient. To investigate the kinetics of the appearance of IgG of donor origin and the disappearance of IgG of recipient origin, G1m and G2m allotype levels were quantified in sera obtained at regular intervals between 3 months and 5 years after BM transplantation (BMT). For this quantification, a dot immunobinding assay (DIBA) has been developed. In 19 of 22 informative recipients, the Gm allotype distribution had reached the range of values expected on the basis of the Gm phenotype of the donor within 6 months after BMT. Remarkably, IgG of recipient origin persisted in 15 of 18 informative recipients until last follow up, ie, for several years after BMT. In addition to the origin of total IgG production, the origin of homogeneous IgG components (H-IgG) appearing after BMT was investigated. H-IgG of donor origin could be detected as early as 3 weeks after BMT, but also H-IgG of recipient origin were present in 8 of 13 informative recipients for a period of up to 1 year after BMT. We conclude that host-type IgG-producing cells were not eradicated by the (myeloablative) conditioning regimen and persisted in a high number of graft recipients. It is our hypothesis that lack of graft-versus-host disease (GVHD) in the majority of these recipients results in the persistence of IgG-producing cells of host origin. These observations may be relevant for the evaluation of patients who received allogeneic BMT for the treatment of multiple myeloma. PMID:8555508

  1. Image Guided Total Marrow Irradiation (TMI) Using Helical TomoTherapy in Patients with Multiple Myeloma and Acute Leukemia Undergoing Hematopoietic Cell Transplantation (HCT)

    PubMed Central

    Wong, Jeffrey Y. C.; Rosenthal, Joseph; Liu, An; Schultheiss, Timothy; Forman, Stephen; Somlo, George

    2013-01-01

    Purpose TBI plays an important role in patients undergoing HCT, but is associated with significant toxicities. Targeted TBI using helical tomotherapy (HT) results in reduced doses to normal organs, which predict for reduced toxicities compared to standard TBI. Methods and Materials Thirteen patients with multiple myeloma (MM) were treated on an autologous tandem transplant Phase I trial with high dose melphalan, followed 6 weeks later by TMI to skeletal bone. Doses levels were 10, 12, 14, and 16 Gy at 2 Gy QD/BID. On a separate allogeneic HCT trial, 8 patients (5 AML, 1 ALL, 1 NHL, 1 MM) were treated with TMI+TLI + splenic RT to 12 Gy (1.5 Gy BID) combined with fludarabine/melphalan. Results For the 13 patients on the tandem autoHCT trial, median age was 54 (42–66). Median organ doses were 15–65% that of the GTV dose. Grade 1–2 acute toxicities were primarily observed. Six reported no vomiting, 9 no mucositis, 6 no fatigue, and 8 no diarrhea. For the 8 patients on the alloHCT trial, the median age was 52 (24–61). Grade 2–3 nausea, vomiting, mucositis and diarrhea were observed. On both trials no grade 4 non-hematologic toxicity was observed and all patients engrafted successfully. Conclusions This study demonstrates that TMI using HT is clinically feasible. Reduced acute toxicities observed compare favorably to those seen with standard TBI. Initial results are encouraging and warrant further evaluation as a method to dose escalate with acceptable toxicity or to offer TBI containing regimens to patients unable to tolerate standard approaches. PMID:18786784

  2. 21 CFR 1271.265 - Receipt, predistribution shipment, and distribution of an HCT/P.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... distribution of an HCT/P. 1271.265 Section 1271.265 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Practice § 1271.265 Receipt, predistribution shipment, and distribution of an HCT/P. (a) Receipt. You must evaluate each incoming HCT/P for the presence and significance of microorganisms and inspect for damage...

  3. 21 CFR 1271.265 - Receipt, predistribution shipment, and distribution of an HCT/P.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... distribution of an HCT/P. 1271.265 Section 1271.265 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Practice § 1271.265 Receipt, predistribution shipment, and distribution of an HCT/P. (a) Receipt. You must evaluate each incoming HCT/P for the presence and significance of microorganisms and inspect for damage...

  4. Specific allogeneic unresponsiveness in the adult host: present-day experimental models

    SciTech Connect

    Rapaport, F.T.; Bachvaroff, R.J.; Cronkite, E.; Chanana, A.; Sato, T.; Asari, H.; Waltzer, W.C.

    1982-01-01

    As part of a long-term intensive effort to apply the induction of adult allogensic unresponsiveness to the transplantation problem, two techniques to control the variability in the persistence of immunologically competent postthymic cells iin the treated host and/or the inoculum of autologous marrow returned to the host after irradiation are described. The first consisted of exposing the peripheral blood of prospective recipients to a 5-week course of extra-corporeal irradiation (ECIB), the other of exposing the stored autologous marrow scheduled to repopulate a given recipient to methyl-prednisolone (MPd) and DNase prior to renifusion into the recipient. Serial analysis of bone marrow cell samples at various intervals before and after treatment was undertaken. The significance of the disappearance of a particular population of nonnuclear cells from the samples, and the association of such disappearance with increased success in the induction of allogeneic unresponsiveness is discussed. (ACR)

  5. On Modeling Human Leukocyte Antigen-Identical Sibling Match Probability for Allogeneic Hematopoietic Cell Transplantation: Estimating the Need for an Unrelated Donor Source.

    PubMed

    Besse, Kelsey; Maiers, Martin; Confer, Dennis; Albrecht, Mark

    2016-03-01

    Prior studies of allogeneic hematopoietic cell transplantation (HCT) therapy for the treatment of malignant or nonmalignant blood disorders assume a 30% likelihood that a patient will find a match among siblings and, therefore, a 70% likelihood of needing an unrelated donor source. This study utilizes birth data and statistical modeling to assess the adequacy of these estimates to describe the probability among US population cohorts segmented by race/ethnicity and age, including ages of greatest HCT utilization. Considerable variation in the likelihood of an HLA-identical sibling was found, ranging from 13% to 51%, depending upon patient age and race/ethnicity. Low sibling match probability, compounded with increased genetic diversity and lower availability among unrelated donors, put the youngest minority patients at the greatest risk for not finding a suitable related or unrelated HCT donor. Furthermore, the present 40-year decline in birth rates is expected to lead to 1.5-fold decrease in access to a matched sibling for today's young adults (18 to 44 years of age) when they reach peak HCT utilization years (near age 61 years) versus their contemporary adult counterparts (44 to 64 years). Understanding the sibling match probability by race/ethnicity and age cohort leads to forecasting the demand for unrelated HCT sources. PMID:26403513

  6. Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT.

    PubMed

    Marsh, Rebecca A; Lane, Adam; Mehta, Parinda A; Neumeier, Lisa; Jodele, Sonata; Davies, Stella M; Filipovich, Alexandra H

    2016-01-28

    Reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) with alemtuzumab, fludarabine, and melphalan is an effective approach for patients with nonmalignant disorders. Mixed chimerism and graft-versus-host-disease (GVHD) remain limitations on success. We hypothesized that higher levels of alemtuzumab at day 0 would result in a low risk of acute GVHD, a higher risk of mixed chimerism, and delayed early lymphocyte recovery and that alemtuzumab level thresholds for increased risks of these outcomes would be definable. We collected data from 105 patients to examine the influence of peritransplant alemtuzumab levels on acute GVHD, mixed chimerism, and lymphocyte recovery. The cumulative incidences of initial grades I-IV, II-IV, and III-IV acute GVHD in patients with alemtuzumab levels ≤0.15 vs ≥0.16 μg/mL were 68% vs 18% (P < .0001), 47% vs 13% (P = .0002), and 32% vs 8%, respectively (P = .005). The cumulative incidence of mixed chimerism in patients with an alemtuzumab level ≤0.15 μg/mL was 21%, vs 42% with levels of 0.16 to 4.35 μg/mL, and 100% with levels >4.35 μg/mL (P = .003). Patients with alemtuzumab levels ≤0.15 or 0.16 to 0.56 μg/mL had higher lymphocyte counts at day +30 and higher T-cell counts at day +100 compared with patients with levels ≥0.57 μg/mL (all P < .05). We conclude that peritransplant alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following RIC HCT with alemtuzumab, fludarabine, and melphalan. Precision dosing trials are warranted. We recommend a day 0 therapeutic range of 0.2 to 0.4 μg/mL. PMID:26644451

  7. [Alternatives to allogenous blood transfusion].

    PubMed

    Cernea, Daniela; Vlădoianu, Alice; Stoica, Maria; Novac, M; Berteanu, Cristina

    2009-01-01

    Blood transfusion is usually meant to lower morbidity and mortality rates. Allogenous blood transfusion implies certain risks that can be avoided by autologous blood transfusions techniques including: preoperatory autologous blood donation, acute normovolemic hemodilution, intraoperatory and postoperatory blood salvage. Preoperatory blood donation and acute normovolemic hemodilution are used for planned interventions with an estimated blood loss higher than 20% of blood volume. These methods imply Erythropoietin and iron treatment. Intraoperatory and postoperatory blood salvage is performed by personnel trained in blood donation, handling and storage. Autologous blood transfusions are used for certain surgical procedures that commonly require transfusions: orthopedic surgery, radical prostatectomy, cardiovascular surgery, organ transplantation. An alternative to allogenous blood transfusion is the use of artificial oxygen transporters: human or animal hemoglobin solutions or pefluorocarbonate solutions. These solutions do not require cross reactions, do not carry diseases and are generally well tolerated and easily stored in the operating room, ambulance and other transport means. They have however a slight degree of toxicity. PMID:21495338

  8. A Pilot Pharmacologic Biomarker Study in HLA-Haploidentical Hematopoietic Cell Transplant Recipients

    PubMed Central

    Bemer, Meagan J.; Sorror, Mohamed; Sandmaier, Brenda M.; O’Donnell, Paul V.; McCune, Jeannine S.

    2013-01-01

    PURPOSE Eleven patients diagnosed with various hematologic malignancies receiving an HLA-haploidentical hematopoietic cell transplant (HCT) participated in an ancillary biomarker trial. The goal of the trial was to evaluate potential pharmacologic biomarkers pertinent to the conditioning regimen (fludarabine monophosphate (fludarabine) and cyclophosphamide (CY)) or postgrafting immunosuppression (CY and mycophenolate mofetil (MMF)) in these patients. METHODS We characterized the interpatient variability of nine pharmacologic biomarkers. The biomarkers evaluated were relevant to fludarabine (i.e., area under the curve (AUC) of 2-fluoro-ara-A or F-ara-A); CY (i.e., AUCs of CY and four of its metabolites); and MMF (i.e., total mycophenolic acid (MPA) AUC, unbound MPA AUC, and inosine monophosphate dehydrogenase (IMPDH) activity). RESULTS Interpatient variability in the pharmacologic biomarkers was high. Among those related to HCT conditioning, the interpatient variability ranged from 1.5-fold (CY AUC) to 4.0-fold (AUC of carboxyethlphosphoramide mustard, a metabolite of CY). Among biomarkers evaluated as part of postgrafting immunosuppression, the interpatient variability ranged from 1.7-fold (CY AUC) to 4.9-fold (IMPDH area under the effect curve). There was a moderate correlation (R2=0.441) of within-patient 4-hydroxycyclophosphamide formation clearance. CONCLUSIONS Considerable interpatient variability exists in the pharmacokinetic and drug-specific biomarkers potentially relevant to clinical outcomes in HLA-haploidentical HCT recipients. Pharmacodynamic studies are warranted to optimize the conditioning regimen and postgrafting immunosuppression administered to HLA-haploidentical HCT recipients. PMID:23907443

  9. Sibling versus Unrelated Donor Allogeneic Hematopoietic Cell Transplantation for CML: Refined HLA-matching shows more GVHD but not less relapse

    PubMed Central

    Weisdorf, Daniel J.; Nelson, Gene; Lee, Stephanie J; Haagenson, Michael; Spellman, Stephen; Antin, Joseph H; Bolwell, Brian; Cahn, Jean-Yves; Cervantes, Francisco; Copelan, Edward; Gale, Robert; Gratwohl, Alois; Khoury, H. Jean; McCarthy, Philip; Marks, David I; Szer, Jeff; Woolfrey, Ann; Cortes-Franco, Jorge; Horowitz, Mary M; Arora, Mukta

    2010-01-01

    Purpose Unrelated donor (URD) hematopoietic cell transplantation (HCT) can eradicate chronic myelogenous leukemia (CML). It has been postulated that greater donor:recipient-histoincompatibility can augment the graft vs. leukemia (GvL) effect. We previously reported similar, but not equivalent outcomes of URD vs. sibling donor HCT for CML using an older, less precise classification of HLA-matching. Methods Our recently refined HLA-matching classification, suitable for interpretation when complete allele-level typing is unavailable was used to reanalyze outcomes of previous HCT for CML. Results We observed that new matching criteria identifies substantially more frequent mismatch than older, less precise “6 of 6 antigen” matched URD-HCT. Only 37% of those previously called “HLA-matched” were HLA-well-matched in new classification and 44% were partially-matched. The refined matching classification confirmed that partially matched or mismatched URD:recipient pairs have significantly greater risks of graft failure compared to either sibling or well-matched URD-HCT. Acute and chronic GVHD are significantly more frequent with all levels of recategorized URD HLA-matching. Importantly, survival and leukemia-free survival remain significantly worse following URD-HCT at any matching level. No augmented GvL effect accompanied URD HLA-mismatch. Compared to sibling donor transplants, we observed marginally increased, but not significantly different risks of relapse in either well-matched, partially-matched or mismatched URD-HCT. Conclusions These data confirm the utility of our revised HLA-matching schema as applicable for analysis of retrospective data sets when fully informative, allele level-typing is unavailable. In this analysis, greater histoincompatibility can augment GVHD but does not improve protection against relapse thus the best donor is still the most closely matched. PMID:19822308

  10. Radiolabeled antibodies directed at CD45 for conditioning prior to allogeneic transplantation in acute myeloid leukemia and myelodysplastic syndrome

    PubMed Central

    Orozco, Johnnie J.; Zeller, Jill

    2012-01-01

    While allogeneic hematopoietic cell transplantation (HCT) may offer the best chance of cure for patients suffering from aggressive hematological malignancies such as acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome, successful outcomes for the subgroup of patients with high-risk disease remain disappointing and lag behind those of lower-risk patients. Because relatively high rates of relapse are an important contributor to these poor outcomes, efforts have explored approaches to increase the cytotoxic effects of treatment. Relapse rates have been shown to improve with the addition of increased doses of total body irradiation (TBI) and/or the introduction of additional chemotherapy to a HCT conditioning regimen. However, the increase in TBI dose and/or additional chemotherapy has also been associated with a significant increase in life-threatening toxicities, resulting in no change in overall survival. Radioimmunotherapy (RIT) has been employed as an adjunct to HCT where targeted delivery of radiation may allow for further escalation of therapy to reduce relapse with minimal toxicity. In this review we describe these efforts, including the benefits of escalating the dose of radiation to sites of hematologic disease prior to HCT, the various cellular targets for antibody-mediated delivery of radiation, as well as the rationale for incorporation of various radionuclides such as alpha emitters and beta emitters into the preparative regimen prior to HCT. Lastly, newer novel approaches such as pretargeted RIT (PRIT) are described as a method to further increase delivery of targeted radiation to hematological tissues while sparing noninvolved organs. PMID:23556108

  11. How do I manage hyperglycemia/post-transplant diabetes mellitus after allogeneic HSCT.

    PubMed

    Fuji, S; Rovó, A; Ohashi, K; Griffith, M; Einsele, H; Kapp, M; Mohty, M; Majhail, N S; Engelhardt, B G; Tichelli, A; Savani, B N

    2016-08-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients frequently develop glucose intolerance and post-transplant diabetes mellitus (PTDM). The clinical importance of PTDM and its detrimental impact on HSCT outcomes are under-recognized. After allo-HSCT, various mechanisms can contribute to the development of PTDM. Here we review information about hyperglycemia and PTDM after allo-HSCT as well as PTDM after solid organ transplantation and describe ways to manage hyperglycemia/PTDM after allogeneic HSCT. Taking into consideration a lack of well-established evidence in the field of allo-HSCT, more studies should be conducted in the future, which will require closer multidisciplinary collaboration between hematologists, endocrinologists and nutritionists. PMID:27042848

  12. Immune responses to an encapsulated allogeneic islet {beta}-cell line in diabetic NOD mice

    SciTech Connect

    Black, Sasha P. . E-mail: Sasha.Black@ca.crl.com; Constantinidis, Ioannis; Cui, Hong; Tucker-Burden, Carol; Weber, Collin J.; Safley, Susan A.

    2006-02-03

    Our goal is to develop effective islet grafts for treating type 1 diabetes. Since human islets are scarce, we evaluated the efficacy of a microencapsulated insulin-secreting conditionally transformed allogeneic {beta}-cell line ({beta}TC-tet) in non-obese diabetic mice treated with tetracycline to inhibit cell growth. Relatively low serum levels of tetracycline controlled proliferation of {beta}TC-tet cells without inhibiting effective control of hyperglycemia in recipients. There was no significant host cellular reaction to the allografts or host cell adherence to microcapsules, and host cytokine levels were similar to those of sham-operated controls. We conclude that encapsulated allogeneic {beta}-cell lines may be clinically relevant, because they effectively restore euglycemia and do not elicit a strong cellular immune response following transplantation. To our knowledge, this is First extensive characterization of the kinetics of host cellular and cytokine responses to an encapsulated islet cell line in an animal model of type 1 diabetes.

  13. Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors

    PubMed Central

    Zakrzewski, Johannes L; Suh, David; Markley, John C; Smith, Odette M; King, Christopher; Goldberg, Gabrielle L; Jenq, Robert; Holland, Amanda M; Grubin, Jeremy; Cabrera-Perez, Javier; Brentjens, Renier J; Lu, Sydney X; Rizzuto, Gabrielle; Sant’Angelo, Derek B; Riviere, Isabelle; Sadelain, Michel; Heller, Glenn; Zúñiga-Pflücker, Juan Carlos; Lu, Chen; van den Brink, Marcel R M

    2009-01-01

    We present a strategy for adoptive immunotherapy using T-lineage committed lymphoid precursor cells generated by Notch1-based culture. We found that allogeneic T-cell precursors can be transferred to irradiated individuals irrespective of major histocompatibility complex (MHC) disparities and give rise to host-MHC restricted and host-tolerant functional allogeneic T cells, improving survival in irradiated recipients as well as enhancing anti-tumor responses. T-cell precursors transduced to express a chimeric receptor targeting hCD19 resulted in significant additional anti-tumor activity, demonstrating the feasibility of genetic engineering of these cells. We conclude that ex vivo generated MHC-disparate T-cell precursors from any donor can be used universally for ‘off-the-shelf’ immunotherapy, and can be further enhanced by genetic engineering for targeted immunotherapy. PMID:18376399

  14. Allogeneic anorectal transplantation in rats: technical considerations and preliminary results.

    PubMed

    Galvão, Flavio H F; Waisberg, Daniel R; Seid, Victor E; Costa, Anderson C L; Chaib, Eleazar; Baptista, Rachel Rossini; Capelozzi, Vera Luiza; Lanchotte, Cinthia; Cruz, Ruy J; Araki, Jun; D'Albuquerque, Luiz Carneiro

    2016-01-01

    Fecal incontinence is a challenging condition with numerous available treatment modalities. Success rates vary across these modalities, and permanent colostomy is often indicated when they fail. For these cases, a novel potential therapeutic strategy is anorectal transplantation (ATx). We performed four isogeneic (Lewis-to-Lewis) and seven allogeneic (Wistar-to-Lewis) ATx procedures. The anorectum was retrieved with a vascular pedicle containing the aorta in continuity with the inferior mesenteric artery and portal vein in continuity with the inferior mesenteric vein. In the recipient, the native anorectal segment was removed and the graft was transplanted by end-to-side aorta-aorta and porto-cava anastomoses and end-to-end colorectal anastomosis. Recipients were sacrificed at the experimental endpoint on postoperative day 30. Surviving animals resumed normal body weight gain and clinical performance within 5 days of surgery. Isografts and 42.9% of allografts achieved normal clinical evolution up to the experimental endpoint. In 57.1% of allografts, signs of immunological rejection (abdominal distention, diarrhea, and anal mucosa inflammation) were observed three weeks after transplantation. Histology revealed moderate to severe rejection in allografts and no signs of rejection in isografts. We describe a feasible model of ATx in rats, which may allow further physiological and immunologic studies. PMID:27488366

  15. Allogeneic anorectal transplantation in rats: technical considerations and preliminary results

    PubMed Central

    Galvão, Flavio H. F.; Waisberg, Daniel R.; Seid, Victor E.; Costa, Anderson C. L.; Chaib, Eleazar; Baptista, Rachel Rossini; Capelozzi, Vera Luiza; Lanchotte, Cinthia; Cruz, Ruy J.; Araki, Jun; D’Albuquerque, Luiz Carneiro

    2016-01-01

    Fecal incontinence is a challenging condition with numerous available treatment modalities. Success rates vary across these modalities, and permanent colostomy is often indicated when they fail. For these cases, a novel potential therapeutic strategy is anorectal transplantation (ATx). We performed four isogeneic (Lewis-to-Lewis) and seven allogeneic (Wistar-to-Lewis) ATx procedures. The anorectum was retrieved with a vascular pedicle containing the aorta in continuity with the inferior mesenteric artery and portal vein in continuity with the inferior mesenteric vein. In the recipient, the native anorectal segment was removed and the graft was transplanted by end-to-side aorta-aorta and porto-cava anastomoses and end-to-end colorectal anastomosis. Recipients were sacrificed at the experimental endpoint on postoperative day 30. Surviving animals resumed normal body weight gain and clinical performance within 5 days of surgery. Isografts and 42.9% of allografts achieved normal clinical evolution up to the experimental endpoint. In 57.1% of allografts, signs of immunological rejection (abdominal distention, diarrhea, and anal mucosa inflammation) were observed three weeks after transplantation. Histology revealed moderate to severe rejection in allografts and no signs of rejection in isografts. We describe a feasible model of ATx in rats, which may allow further physiological and immunologic studies. PMID:27488366

  16. A potential role for B cells in suppressed immune responses in cord blood transplant recipients

    PubMed Central

    Beaudette-Zlatanova, Britte C.; Le, Phong T.; Knight, Katherine L.; Zhang, Shubin; Zakrzewski, Sandra; Parthasarathy, Mala; Stiff, Patrick J.

    2014-01-01

    We evaluated immune reconstitution in 58 adults who received hematopoietic stem cell transplants from allogeneic siblings (allosib), matched unrelated donors (MUD), or cord blood (CB) at 90-day intervals for one year post-transplant. CB recipients had a higher incidence of infections in the first 100 days compared to allosib and MUD recipients. The number of circulating T cells was lower in CB recipients compared to MUD recipients at 90 days and compared to allosib recipients at 180 days. Spectratype analysis of the TCR Vβ complementarity determining region 3 (CDR3) of patient lymphocytes revealed that the TCR repertoire remained poorly diversified even at 360 days in nearly all patients. In contrast, the number of circulating B cells was significantly elevated in CB recipients compared to allosib recipients throughout the first year post-transplant and compared to MUD recipients at 9-12 months. Spectratype analysis of the B cell receptor VH CDR3 showed that the B cell repertoire was diversified in most patients by 90 days. CD5pos B cells from assayed CB recipients expressed intracellular IL-10 early post-transplant. Our data suggest that B cells, in addition to T cells, may play a role in impaired immune responses in CB transplant patients. PMID:22732699

  17. Multicenter biologic assignment trial comparing reduced-intensity allogeneic hematopoietic cell transplant to hypomethylating therapy or best supportive care in patients aged 50 to 75 with intermediate-2 and high-risk myelodysplastic syndrome: Blood and Marrow Transplant Clinical Trials Network #1102 study rationale, design, and methods.

    PubMed

    Saber, Wael; Le Rademacher, Jennifer; Sekeres, Mikkael; Logan, Brent; Lewis, Moira; Mendizabal, Adam; Leifer, Eric; Appelbaum, Frederick R; Horowitz, Mary M; Nakamura, Ryotaro; Cutler, Corey S

    2014-10-01

    The introduction of reduced-intensity conditioning (RIC) regimens made it possible to offer allogeneic hematopoietic cell transplantation (alloHCT) to older patients with myelodysplastic syndromes (MDS). However, the relative risks and benefits of alloHCT compared with novel nontransplant therapies continue to be the source of considerable uncertainty. We will perform a prospective biologic assignment trial to compare RIC alloHCT with nontransplant therapies based on donor availability. Primary outcome is 3-year overall survival. Secondary outcomes include leukemia-free survival, quality of life, and cost-effectiveness. Four hundred patients will be enrolled over roughly 3 years. Planned subgroup analyses will evaluate key biologic questions, such as the impact of age and response to hypomethylating agents on treatment effects. Findings from this study potentially may set a new standard of care for older MDS patients who are considered candidates for alloHCT. PMID:24972249

  18. Safety and Efficacy of Transplantation with Allogeneic Skin Tumors to Treat Chemically-Induced Skin Tumors in Mice.

    PubMed

    Zhang, Zhiwei; Sun, Hua; Zhang, Jianhua; Ge, Chunlei; Dong, Suwei; Li, Zhen; Li, Ruilei; Chen, Xiaodan; Li, Mei; Chen, Yun; Zou, Yingying; Qian, Zhongyi; Yang, Lei; Yang, Jinyan; Zhu, Zhitao; Liu, Zhimin; Song, Xin

    2016-01-01

    BACKGROUND Transplantation with allogeneic cells has become a promising modality for cancer therapy, which can induce graft-versus-tumor (GVT) effect. This study was aimed at assessing the safety, efficacy, and tissue type GVT (tGVT) response of transplantation with allogeneic skin tumors to treat chemically-induced skin tumors in mice. MATERIAL AND METHODS FVB/N and ICR mice were exposed topically to chemicals to induce skin tumors. Healthy ICR mice were transplanted with allogeneic skin tumors from FVB/N mice to test the safety. The tumor-bearing ICR mice were transplanted with, or without, allogeneic skin tumors to test the efficacy. The body weights (BW), body condition scores (BCS), tumor volumes in situ, metastasis tumors, overall survival, and serum cytokines were measured longitudinally. RESULTS Transplantation with no more than 0.03 g allogeneic skin tumors from FVB/N mice to healthy ICR mice was safe. After transplantation with allogeneic skin tumors to treat tumor-bearing mice, it inhibited the growth of tumors slightly at early stage, accompanied by fewer metastatic tumors at 24 days after transplantation (21.05% vs. 47.37%), while there were no statistically significant differences in the values of BW, BCS, tumor volumes in situ, metastasis tumors, and overall survival between the transplanted and non-transplanted groups. The levels of serum interleukin (IL)-2 were significantly reduced in the controls (P<0.05), but not in the recipients, which may be associated with the tGVT response. CONCLUSIONS Our results suggest that transplantation with allogeneic skin tumors is a safe treatment in mice, which can induce short-term tGVT response mediated by IL-2. PMID:27587310

  19. Relationship between age of allogeneic thymus donor and immunological restoration of athymic ('nude") mice.

    PubMed

    Radov, L A; Sussdorf, D H; McCann, R L

    1975-12-01

    In nude mice back-crossed a minimum of five times to BALB/c, solid thymus grafts from C57Bl donors 3 days of age or younger restored both the humoral immune response against sheep erythrocytes and cellular immunity as tested by rejection of CBA skin grafts. Donor thymus placed under the renal capsule at a dose of 0-5 mg/g of recipient resulted in normal humoral immunity, while a minimum dose of 1-5 mg/g was required to reconstitute cellular competence. None of the various amounts of allogeneic thymus tissue transplanted affected the immunological status of nude recipients when grafts were obtained from donors 4 days of age or older. Histological findings correlated with the humoral and cellular responses observed. In nudes grafted with neonatal tissue, the thymus implant proliferated and developed normal architecture. The density of lymphocytes in thymus-dependent regions of peripheral lymphoid organs was near normal. On the other hand, most grafts from older (3-week-old) donors were resorbed by 90 days after implantation. In a number of cases, however, Russell bodies and numerous blast and plasma cells were seen in the graft site. Our observations suggest a possible cytotoxic rejection of implants from older allogeneic donors, while the survival and restorative capacity of transplants from 3-day-old or younger donors may have been due to a tolerogenic effect of the graft on the nude recipient. PMID:1193689

  20. Relationship between neurocognitive functioning and medication management ability over the first 6 months following allogeneic stem cell transplantation.

    PubMed

    Mayo, S; Messner, H A; Rourke, S B; Howell, D; Victor, J C; Kuruvilla, J; Lipton, J H; Gupta, V; Kim, D D; Piescic, C; Breen, D; Lambie, A; Loach, D; Michelis, F V; Alam, N; Uhm, J; McGillis, L; Metcalfe, K

    2016-06-01

    Although neurocognitive impairment has been established as a major issue among cancer survivors, the real-world consequences of this impairment are unclear. This study investigated the relationship between neurocognitive functioning and medication management ability over time among 58 patients treated with allogeneic hematopoietic stem cell transplantation (HCT). Participants completed a neuropsychological test battery and a simulated medication management task at three time points: pre-transplant (T0), Day 100 (T1) and 6 months post transplant (T2). Neurocognitively impaired participants performed worse on the medication management task than neurocognitively normal participants at each time point, and were more likely to score in the impaired range of medication management ability post transplant (72% vs 20%, P<0.001 at T1; 67% vs 23%, P=0.013 at T2). In multivariate analyses, worse performance in executive functioning/working memory consistently predicted impaired medication management ability, even when controlling for sociodemographic and clinical confounders (odds ratio=0.89, 95% confidence interval (0.80, 0.98), P=0.023). Lower physical symptom distress also predicted impaired medication management ability, but this effect decreased over time. Self-reported cognitive problems were not correlated with medication management ability at any time point. Findings suggest that poor neurocognitive functioning, particularly in the domain of executive functioning/working memory, is associated with worse medication management ability within the first 6 months after allogeneic HCT. PMID:26926230

  1. Early vancomycin-resistant enterococcus (VRE) bacteremia after allogeneic bone marrow transplantation is associated with a rapidly deteriorating clinical course.

    PubMed

    Avery, R; Kalaycio, M; Pohlman, B; Sobecks, R; Kuczkowski, E; Andresen, S; Mossad, S; Shamp, J; Curtis, J; Kosar, J; Sands, K; Serafin, M; Bolwell, B

    2005-03-01

    Vancomycin-resistant enterococcal (VRE) infection is a growing threat. We studied the incidence, risk factors, and clinical course of early-onset VRE bacteremia in allogeneic hematopoietic stem cell transplant recipients. We carried out a chart review of 281 allogeneic hematopoietic stem cell transplant recipients from 1997-2003, including preparative regimen, diagnosis, status of disease, graft-versus-host disease prophylaxis, antimicrobial therapy, and survival. VRE bacteremia developed in 12/281 (4.3%) recipients; 10 (3.6%) were within 21 days of transplant. Diagnoses were acute leukemia (7), NHL (2), and MDS (1). In all, 70% had refractory/relapsed disease; 30% were in remission. In total, 50% had circulating blasts. Nine of 10 had matched unrelated donors (7/9 with CD8+ T-cell depletion). The average time to positive VRE cultures was 15 days; average WBC was 0.05, and 80% had concomitant infections. Despite treatment, all patients died within 73 days of VRE bacteremia. Intra-abdominal complications were common. Causes of death included bacterial or fungal infection, multiorgan failure, VOD, ARDS, and relapse. A total of 60% of patients engrafted neutrophils, but none engrafted platelets. Early VRE bacteremia after allogeneic bone marrow transplant is associated with a rapidly deteriorating clinical course, although not always directly due to VRE. Early VRE may be a marker for the critical condition of these high-risk patients at the time of transplant. PMID:15640812

  2. Production of donor-derived offspring by allogeneic transplantation of spermatogonia in the yellowtail (Seriola quinqueradiata).

    PubMed

    Morita, Tetsuro; Kumakura, Naoki; Morishima, Kagayaki; Mitsuboshi, Toru; Ishida, Masashi; Hara, Takashi; Kudo, Satomi; Miwa, Misako; Ihara, Shoko; Higuchi, Kentaro; Takeuchi, Yutaka; Yoshizaki, Goro

    2012-06-01

    Although the yellowtail (Seriola quinqueradiata) is the fish most commonly farmed in Japan, breeding of this species has not yet started. This is primarily due to the lack of sufficiently sophisticated methods for manipulating gametogenesis, which makes it difficult to collect gametes from specific dams and sires. If it were possible to produce large numbers of surrogate fish by transplanting germ cells isolated from donor individuals harboring desirable genetic traits, then the probability of acquiring gametes carrying the donor-derived haplotype would increase, and breeding programs involving this species might increase as a result. As a first step, we established a method for the allogeneic transplantation of yellowtail spermatogonia and the production of donor-derived offspring. Donor cells were collected from immature (10-month-old) yellowtail males with testes containing abundant type A spermatogonia, labeled with PKH26 fluorescent dye, and transferred into the peritoneal cavities of 8-day-old larvae. Fluorescence observation at 28 days post-transplantation revealed that PKH26-labeled cells were incorporated into recipients' gonads. To assess whether donor-derived spermatogonia could differentiate into functional gametes in the allogeneic recipient gonads, gametes collected from nine male and four female adult recipients were fertilized with wild-type eggs and milt. Analysis of microsatellite DNA markers confirmed that some of the first filial (F(1)) offspring were derived from donor fish, with the average contribution of donor-derived F(1) offspring being 66% and the maximum reaching 99%. These findings confirmed that our method was effective for transplanting yellowtail spermatogonia into allogeneic larvae to produce donor-derived offspring. PMID:22460666

  3. Oral Complications in Hematopoietic Stem Cell Recipients: The Role of Inflammation

    PubMed Central

    Haverman, T. M.; Raber-Durlacher, J. E.; Rademacher, W. M. H.; Vokurka, S.; Epstein, J. B.; Huisman, C.; Hazenberg, M. D.; de Soet, J. J.; de Lange, J.; Rozema, F. R.

    2014-01-01

    Hematopoietic stem cell transplantation (HSCT) is widely used as a potentially curative treatment for patients with various hematological malignancies, bone marrow failure syndromes, and congenital immune deficiencies. The prevalence of oral complications in both autologous and allogeneic HSCT recipients remains high, despite advances in transplant medicine and in supportive care. Frequently encountered oral complications include mucositis, infections, oral dryness, taste changes, and graft versus host disease in allogeneic HSCT. Oral complications are associated with substantial morbidity and in some cases with increased mortality and may significantly affect quality of life, even many years after HSCT. Inflammatory processes are key in the pathobiology of most oral complications in HSCT recipients. This review article will discuss frequently encountered oral complications associated with HSCT focusing on the inflammatory pathways and inflammatory mediators involved in their pathogenesis. PMID:24817792

  4. TLR5 stop codon polymorphism is associated with invasive aspergillosis after allogeneic stem cell transplantation.

    PubMed

    Grube, Matthias; Loeffler, Juergen; Mezger, Markus; Krüger, Bernd; Echtenacher, Bernd; Hoffmann, Petra; Edinger, Matthias; Einsele, Hermann; Andreesen, Reinhard; Holler, Ernst

    2013-11-01

    Single nucleotide polymorphisms (SNPs) have been associated with an increased incidence of invasive aspergillosis (IA) after allogeneic stem cell transplantation (allo-SCT). We analyzed 41 patients with proven/probable IA after allo-SCT for an association of SNPs, within the TLR2, TLR4, TLR5, TLR9, and NOD2/CARD15 genes, with susceptibility to IA. The control group consisted of 130 patients who had allo-SCT but did not develop IA. While no association was found for donor SNPs and the recipients' risk of IA, analysis of recipient SNPs showed a significant association between the presence of recipient TLR5-Stop SNP (1174C> T) and the incidence of IA (P = 0.004). Multivariate analysis demonstrated that the recipient TLR5-Stop SNP appeared as an independent risk factor for IA after allo-SCT. Our study suggests that TLR5 is involved in host defense against Aspergillus fumigatus, and that the recipient TLR5-Stop SNP represents a risk factor for the development of IA after allo-SCT. PMID:23862689

  5. [Cytomegalovirus reactivation after allogeneic stem cell transplantation reduces the risk of relapse in patients with acute myeloid leukemia].

    PubMed

    Takenaka, Katsuto

    2015-07-01

    Cytomegalovirus (CMV) infection is still a major infectious complication after allogeneic hematopoietic cell transplantation (HCT). Recently, CMV reactivation was reported to be associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). We herein retrospectively evaluated the impact of early CMV reactivation on the incidence of disease relapse after allo-HCT using the database of the Transplant Registry Unified Management Program (TRUMP) at the JSHCT. Patients who underwent their first allo-HCT from HLA-matched related or unrelated donors between 2000 and 2009, and who survived without disease relapse until day 100 after transplantation, were analyzed. CMV reactivation was associated with a decreased cumulative incidence of relapse among patients with AML, but not in patients with other hematological malignancies in our study. However, this benefit was nullified by the increased rate of non-relapse mortality. The underlying mechanism is unclear, but the immunological reaction against CMV reactivation plays an essential role in this association. Thus, immune augmentation treatment options including vaccination and adoptive T-cell transfer might be useful for taking advantage of the efficacy of CMV reactivation while minimizing the increase in non-relapse mortality. PMID:26251145

  6. Allogeneic hematopoietic cell transplantation for peripheral T-cell NHL results in long-term disease control

    PubMed Central

    Zain, Jasmine; Palmer, Joycelynne M.; Delioukina, Maria; Thomas, Sandra; Tsai, Ni-Chun; Nademanee, Auayporn; Popplewell, Leslie; Gaal, Karl; Senitzer, David; Kogut, Neil; O'Donnell, Margaret; Forman, Stephen J.

    2012-01-01

    The study analyzed outcomes of a consecutive case series of 37 patients with peripheral T-cell non-Hodgkin lymphoma, from related and unrelated donors, using allogeneic hematopoietic cell transplantation (allo-HCT), between the years 2000 and 2007. All patients were pretreated; the majority had either relapsed or progressive disease (n=25, 68%), 13 had cutaneous histologies (CTCL), and all were ineligible for autologous transplant. Fully ablative conditioning regimens were used in 13 patients while 24 patients underwent reduced intensity conditioning (RIC). At five years the overall survival (OS) and progression-free survival (PFS) probabilities were 52.2% and 46.5%, respectively. At the time of analysis, 9 (24.3%) patients had either relapsed (n=6) or progressed (n=3) post allo-HCT. The cumulative incidences of relapse/progression and non-relapse mortality at 5 years were 24.3% and 28.9%. No statistically significant variables for survival or relapse were discovered by univariate Cox-regression analysis of disease and patient characteristics; differences between CTCL and other histologies were not significant. The median follow-up of 64.0 months (range: 16.4–100.4) indicates a mature data-set with probable cure in the survivors. The relapse/progression curves reached and maintained plateaus after 1 year post-transplant, demonstrating that long-term disease control is possible after allo-HCT in PTCL patients with advanced disease. PMID:21699453

  7. Allogeneic Hematopoietic Cell Transplant for Acute Myeloid Leukemia: No Impact of Pre-transplant Extramedullary Disease on Outcome

    PubMed Central

    Goyal, Sagun D.; Zhang, Mei-Jie; Wang, Hai-Lin; Akpek, Görgün; Copelan, Edward A.; Freytes, César; Gale, Robert Peter; Hamadani, Mehdi; Inamoto, Yoshihiro; Kamble, Rammurti T.; Lazarus, Hillard M.; Marks, David I.; Nishihori, Taiga; Olsson, Richard F.; Reshef, Ran; Ritchie, David S.; Saber, Wael; Savani, Bipin N.; Seber, Adriana; Shea, Thomas C.; Tallman, Martin S.; Wirk, Baldeep; Bunjes, Donald W.; Devine, Steven M.; de Lima, Marcos; Weisdorf, Daniel J.; Uy, Geoffrey L.

    2015-01-01

    The impact of extramedullary disease (EMD) in AML on the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) is unknown. Using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) we compared the outcomes of patients who had EMD of AML at any time prior to transplant to a cohort of AML patients without EMD. We reviewed data AML from 9,797 patients including 814 with EMD from 310 reporting centers and 44 different countries who underwent alloHCT between and 1995–2010. The primary outcome was overall survival (OS) after alloHCT. Secondary outcomes included leukemia-free survival (LFS), relapse rate, and treatment-related mortality (TRM). In a multivariate analysis, the presence of EMD did not affect either OS (HR 1.00, 95% CI 0.91–1.09), LFS (0.98, 0.89–1.09), TRM (RR 0.92, 95% CI 0.80–1.16, p=0.23) or relapse (RR =1.03, 95% CI, 0.92–1.16; p=0.62). Furthermore, the outcome of patients with EMD was not influenced by the location, timing of EMD, or intensity of conditioning regimen. The presence of EMD in AML does not affect transplant outcomes and should not be viewed as an independent adverse prognostic feature. PMID:25915806

  8. Nephrotic syndrome: an under-recognised immune-mediated complication of non-myeloablative allogeneic haematopoietic cell transplantation.

    PubMed

    Srinivasan, R; Balow, J E; Sabnis, S; Lundqvist, A; Igarashi, T; Takahashi, Y; Austin, H; Tisdale, J; Barrett, J; Geller, N; Childs, R

    2005-10-01

    Nephrotic syndrome (NS) is an extremely rare complication of myeloablative allogeneic haematopoietic cell transplantation (HCT) that usually occurs in association with chronic graft-versus-host disease (C-GVHD). We observed an unexpectedly high incidence of NS in a cohort of 163 consecutive patients undergoing non-myeloablative HCT from a related human leucocyte antigen-compatible donor. Seven patients developed NS at a median 318 d post-transplant (range 119-1203 d; cumulative incidence 6.1%). The median age at onset of NS was 46 years (range 33-59 years); three of the seven patients had no evidence of C-GVHD while four had accompanying limited C-GVHD. At diagnosis, median proteinuria was 16.5 g/24 h (range 3-24 g/24 h). Renal biopsy was performed in four cases and revealed membranous nephropathy. NS was not always associated with other symptoms of C-GVHD, and in contrast to previous reports, usually did not improve with the re-initiation of aggressive immunosuppression, resulting in progressive renal failure necessitating dialysis in three of seven cases. Membranous nephropathy resulting in NS is a previously unrecognised and clinically significant complication of non-myeloablative HCT. PMID:16173966

  9. Treosulfan, cyclophosphamide and antithymocyte globulin for allogeneic hematopoietic cell transplantation in acquired severe aplastic anemia.

    PubMed

    Giebel, Sebastian; Wojnar, Jerzy; Krawczyk-Kulis, Malgorzata; Markiewicz, Miroslaw; Wylezoł, Iwona; Seweryn, Marek; Holowiecka-Goral, Aleksandra; Holowiecki, Jerzy

    2006-01-01

    To reduce the risk of graft rejection after allogeneic hematopoietic cell transplantation (alloHCT) for patients with acquired severe aplastic anemia (SAA), we introduced an intensified preparative regimen consisting of treosulfan 10 g/m2/d on days -7, -6, cyclophosphamide 40 mg/kg/d on days -5, -4, -3, -2 and anti-thymocyte globulin 2 mg/kg/d on days -3, -2, -1. Six patients with the history of multiple transfusions were treated with alloHCT from either HLA-identical sibling (n=3) or an unrelated volunteer (n=3). Each, bone marrow and peripheral blood was used as a source of stem cells in three cases. All patients engrafted and achieved complete donor chimerism. None of the patients experienced severe organ toxicity. No severe acute graft-versus-host-disease (GVHD) was observed; two patients experienced extensive chronic GVHD. At the median follow-up of 14.5 (13-27) months all patients remained alive and disease-free. Our observation indicates that treosulfan + cyclophosphamide + antithymocyte globulin conditioning is well-tolerated and allows stable engraftment in acquired SAA. PMID:17494286

  10. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors.

    PubMed

    Shanavas, Mohamed; Popat, Uday; Michaelis, Laura C; Fauble, Veena; McLornan, Donal; Klisovic, Rebecca; Mascarenhas, John; Tamari, Roni; Arcasoy, Murat O; Davies, James; Gergis, Usama; Ukaegbu, Oluchi C; Kamble, Rammurti T; Storring, John M; Majhail, Navneet S; Romee, Rizwan; Verstovsek, Srdan; Pagliuca, Antonio; Vasu, Sumithira; Ernst, Brenda; Atenafu, Eshetu G; Hanif, Ahmad; Champlin, Richard; Hari, Paremeswaran; Gupta, Vikas

    2016-03-01

    The impact of Janus kinase (JAK) 1/2 inhibitor therapy before allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into 5 groups: (1) clinical improvement (n = 23), (2) stable disease (n = 31), (3) new cytopenia/increasing blasts/intolerance (n = 15), (4) progressive disease: splenomegaly (n = 18), and (5) progressive disease: leukemic transformation (LT) (n = 13). Overall survival (OS) at 2 years was 61% (95% confidence interval [CI], 49% to 71%). OS was 91% (95% CI, 69% to 98%) for those who experienced clinical improvement and 32% (95% CI, 8% to 59%) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (P = .03), dynamic international prognostic scoring system score (P = .003), and donor type (P = .006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, 2 patients developed serious adverse events necessitating delay of HCT and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days before conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplantation outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy before HCT were particularly encouraging, and need further prospective validation. PMID:26493563

  11. Allogeneic Hematopoietic Cell Transplantation for Patients with Mixed Phenotype Acute Leukemia.

    PubMed

    Munker, Reinhold; Brazauskas, Ruta; Wang, Hai Lin; de Lima, Marcos; Khoury, Hanna J; Gale, Robert Peter; Maziarz, Richard T; Sandmaier, Brenda M; Weisdorf, Daniel; Saber, Wael

    2016-06-01

    Acute biphenotypic leukemias or mixed phenotype acute leukemias (MPAL) are rare and considered high risk. The optimal treatment and the role of allogeneic hematopoietic stem cell transplantation (alloHCT) are unclear. Most prior case series include only modest numbers of patients who underwent transplantation. We analyzed the outcome of 95 carefully characterized alloHCT patients with MPAL reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2012. The median age was 20 years (range, 1 to 68). Among the 95 patients, 78 were in first complete remission (CR1) and 17 were in second complete remission (CR2). Three-year overall survival (OS) of 67% (95% confidence interval [CI], 57 to 76), leukemia-free survival of 56% (95% CI, 46 to 66), relapse incidence of 29% (95% CI, 20 to 38), and nonrelapse mortality of 15% (95% CI, 9 to 23) were encouraging. OS was best in younger patients (<20 years), but no significant differences were observed between those 20 to 40 years of age and those who were 40 years or older. A matched-pair analysis showed similar outcomes comparing MPAL cases to 375 acute myelogenous leukemia or 359 acute lymphoblastic leukemia cases. MPAL patients had more acute and a trend for more chronic graft-versus-host disease. No difference was observed between patients who underwent transplantation in CR1 versus those who underwent transplantation in CR2. AlloHCT is a promising treatment option for pediatric and adult patients with MPAL with encouraging long-term survival. PMID:26903380

  12. Anti-thymocyte globulin-induced hyperbilirubinemia in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation.

    PubMed

    Ecsedi, Matyas; Schmohl, Jörg; Zeiser, Robert; Drexler, Beatrice; Halter, Jörg; Medinger, Michael; Duyster, Justus; Kanz, Lothar; Passweg, Jakob; Finke, Jürgen; Bethge, Wolfgang; Lengerke, Claudia

    2016-10-01

    Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment option for myelofibrosis (MF) despite the emergence of novel targeted therapies. To reduce graft rejection and graft-versus-host disease (GvHD), current allo-HCT protocols often include in vivo T lymphocyte depletion using polyclonal anti-thymocyte globulin (ATG). Shortly after ATG administration, an immediate inflammatory response with fever, chills, and laboratory alterations such as cytopenias, elevation of serum C-reactive protein, bilirubin, and transaminases can develop. Here, we explore whether MF patients, who commonly exhibit extramedullary hematopoiesis in the liver, might be particularly susceptible to ATG-induced liver toxicity. To test this hypothesis, we analyzed 130 control and 94 MF patients from three transplant centers treated with or without ATG during the allo-HCT conditioning regimen. Indeed, hyperbilirubinemia was found in nearly every MF patient treated with ATG (MF-ATG 54/60 = 90 %) as compared to non-ATG treated MF (MF-noATG 15/34 = 44.1 %, p < 0.001) and respectively ATG-treated non-MF patients of the control group (control-ATG, 43/77 = 56 %, p < 0.001). In contrast, transaminases were only inconsistently elevated. Hyperbilirubinemia was in most cases self-limiting and not predictive of increased incidence of non-relapse mortality, hepatic sinusoidal obstruction syndrome (SOS) or liver GvHD. In sum, awareness of this stereotypic bilirubin elevation in MF patients treated with ATG provides a relatively benign explanation for hyperbilirubinemia occurring in these patients during the early transplant. However, attention to drug levels of biliary excreted drugs is warranted, since altered bile flow may influence their clearance and enhance toxicity (e.g., busulfan, antifungal agents). PMID:27480090

  13. Pregnancy After Hematopoietic-cell Transplantation: A Report From the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR)

    PubMed Central

    Loren, Alison W.; Chow, Eric; Jacobsohn, David A.; Gilleece, Maria; Halter, Joerg; Joshi, Sarita; Wang, Zhiwei; Gupta, Vikas; Hale, Gregory A.; Marks, David I.; Stadtmauer, Edward A; Apperley, Jane; Cahn, Jean-Yves; Schouten, Harry C.; Lazarus, Hillard M.; Savani, Bipin; McCarthy, Philip L.; Jakubowski, Ann A.; Kamani, Naynesh R.; Hayes-Lattin, Brandon; Maziarz, Richard T.; Warwick, Anne B.; Sorror, Mohamed L.; Bolwell, Brian J.; Socié, Gerard; Wingard, John R.; Rizzo, J Douglas; Majhail, Navneet S.

    2010-01-01

    Preservation of fertility after hematopoietic-cell transplantation (HCT) can have a significant influence on the quality of life of transplant survivors. We describe 178 pregnancies in HCT recipients that were reported to the CIBMTR between 2002 and 2007. There were 83 pregnancies in female HCT recipients and 95 pregnancies in female partners of male HCT recipients. Indications for transplantation included hematologic and other malignancies (N=99) and non-malignant disorders (N=79, of which 75 patients had severe aplastic anemia). The cohort included recipients of autologous HCT (20 women, 13 men), myeloablative allogeneic HCT (12 women, 50 men) and non-myeloablative allogeneic HCT (2 women, 2 men). Age at HCT was <20 years for 50% of women and 19% of men. Conditioning regimens included total body irradiation (TBI) in 16% of women and 19% of men; doses were myeloablative in 10% of women and in 16% of men. Live births were reported in 86% of pregnancies in partners of male transplant patients and 85% of pregnancies in female transplant patients, with most pregnancies occurring 5-10 years after HCT. We conclude that some HCT recipients can retain fertility, including patients who have received TBI and/or myeloablative conditioning. Young patients undergoing HCT should be counseled both before and after HCT about potential loss of fertility, methods for preserving fertility and planning for future pregnancy. Fertility and outcomes of pregnancy after HCT need prospective evaluation in large transplant cohorts. PMID:20659574

  14. Allogeneic hematopoietic cell transplantation in HIV-positive patients with hematological disorders: A report from the Center for International Blood and Marrow Transplant Research (CIBMTR)

    PubMed Central

    Gupta, Vikas; Tomblyn, Marcie; Pedersen, Tanya L.; Atkins, Harry L.; Battiwalla, Minoo; Gress, Ronald E.; Pollack, Marilyn S.; Storek, Jan; Thompson, Jill C.; Tiberghien, Pierre; Young, Jo-Anne H.; Ribaud, Patricia; Horowitz, Mary; Keating, Armand

    2010-01-01

    The role of allogeneic hematopoietic cell transplantation (alloHCT) in HIV-positive patients is not known. Using the CIBMTR database, we retrospectively evaluated 23 HIV-positive patients undergoing matched sibling (n=19) or unrelated (n=4) donor transplants between 1987 and 2003. The median age at alloHCT was 32 years. Indications for alloHCT were diverse and included malignant (n=21) and non-malignant (n=2) hematologic disorders. Nine patients (39%) were transplanted after 1996, the approximate year highly active anti-retroviral therapy became standard. The median time to neutrophil engraftment was 16 days (range 7–30) and the cumulative incidences of grades II – IV acute graft-versus-host disease (GVHD) at 100 days, chronic GVHD and survival at 2 years were 30% (95% C.I. 14-50), 28% (95% C.I. 12-48) and 30% (95% C.I. 14-50), respectively. At a median follow-up of 59 months, 6 patients are alive. Survival appears better among the patients transplanted after 1996: 4 of 9 patients transplanted after 1996 survive compared to 2 of 14 patients transplanted prior to 1996. These data suggest that alloHCT is feasible for selected HIV-positive patients with malignant and non-malignant disorders. Prospective studies are needed in these patients to evaluate the safety and efficacy of this modality in specific diseases. PMID:19539219

  15. Generation of a cord blood-derived Wilms Tumor 1 dendritic cell vaccine for AML patients treated with allogeneic cord blood transplantation

    PubMed Central

    de Haar, Colin; Plantinga, Maud; Blokland, Nina JG; van Til, Niek P; Flinsenberg, Thijs WH; Van Tendeloo, Viggo F; Smits, Evelien L; Boon, Louis; Spel, Lotte; Boes, Marianne; Boelens, Jaap Jan; Nierkens, Stefan

    2015-01-01

    The poor survival rates of refractory/relapsed acute myeloid leukemia (AML) patients after haematopoietic cell transplantation (HCT) requires the development of additional immune therapeutic strategies. As the elicitation of tumor-antigen specific cytotoxic T lymphocytes (CTLs) is associated with reduced relapses and enhanced survival, enhanced priming of these CTLs using an anti-AML vaccine may result in long-term immunity against AML. Cord blood (CB), as allogeneic HCT source, may provide a unique setting for such post-HCT vaccination, considering its enhanced graft-versus-leukemia (GvL) effects and population of highly responsive naïve T cells. It is our goal to develop a powerful and safe immune therapeutic strategy composed of CB-HCT followed by vaccination with CB CD34+-derived dendritic cells (DCs) presenting the oncoprotein Wilms Tumor-1 (WT1), which is expressed in AML-blasts in the majority of patients. Here, we describe the optimization of a clinically applicable DC culture protocol. This two-step protocol consisting of an expansion phase followed by the differentiation toward DCs, enables us to generate sufficient cord blood-derived DCs (CBDCs) in the clinical setting. At the end of the culture, the CBDCs exhibit a mature surface phenotype, are able to migrate, express tumor antigen (WT1) after electroporation with mRNA encoding the full-length WT1 protein, and stimulate WT1-specific T cells. PMID:26451309

  16. Lung function score including a parameter of small airway disease as a highly predictive indicator of survival after allogeneic hematopoietic cell transplantation.

    PubMed

    Nakamae, Mika; Yamashita, Mariko; Koh, Hideo; Nishimoto, Mitsutaka; Hayashi, Yoshiki; Nakane, Takahiko; Nakashima, Yasuhiro; Hirose, Asao; Hino, Masayuki; Nakamae, Hirohisa

    2016-06-01

    Some studies on the predictive value of determining pulmonary function prior to allogeneic hematopoietic cell transplantation (allo-HCT) have shown a significant association between pulmonary function test (PFT) parameters and pulmonary complications, and mortality. However, the percentage of patients showing abnormalities in pretransplant PFT parameters is low. We comprehensively evaluated the effect of pretransplant PFT parameters, including a marker of small airway disease (ratio of the airflow rate of 50% vital capacity to the airflow rate of 25% vital capacity (V˙50/V˙25), on outcomes in 206 evaluable patients who underwent allo-HCT at our institute. Notable among the significant parameters in a univariable analysis, V˙50/V˙25 was the most powerful indicator of survival following allo-HCT (delta-Akaike information criterion [∆AIC] = 12.47, ∆χ(2)  = 14.47; P = 0.0001). Additionally, a pretransplant lung function score (pLFS) established by applying three parameters with superior predictive values including V˙50/V˙25 represented a better discriminating variable for the prediction of survival. Our data demonstrate that a pLFS incorporating a parameter of small airway disease, rather than the parameters of central airway obstruction, may be useful for predicting patient survival following allo-HCT. PMID:27018997

  17. Effects of T cell depletion in radiation bone marrow chimeras. I. Evidence for a donor cell population which increases allogeneic chimerism but which lacks the potential to produce GVHD

    SciTech Connect

    Sykes, M.; Sheard, M.; Sachs, D.H.

    1988-10-01

    The opposing problems of graft-vs-host disease (GVHD) and failure of alloengraftment present major obstacles to the application of bone marrow transplantation (BMT) across complete MHC barriers. The addition of syngeneic T-cell-depleted (TCD) bone marrow (BM) to untreated fully allogeneic marrow inocula in lethally irradiated mice has been previously shown to provide protection from GVHD. We have used this model to study the effects of allogeneic T cells on levels of chimerism in recipients of mixed marrow inocula. The results indicate that T cells in allogeneic BM inocula eliminate both coadministered recipient-strain and radioresistant host hematopoietic elements to produce complete allogeneic chimerism without clinical GVHD. To determine the role of GVH reactivity in this phenomenon, we performed similar studies in an F1 into parent combination, in which the genetic potential for GVHD is lacking. The presence of T cells in F1 marrow inocula led to predominant repopulation with F1 lymphocytes in such chimeras, even when coadministered with TCD-recipient-strain BM. These results imply that the ability of allogeneic BM cells removed by T cell depletion to increase levels of allochimerism may be mediated by a population which is distinct from that which produces GVHD. These results may have implications for clinical BM transplantation.

  18. Expression of SOCS1 and SOCS3 genes in human graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Lee, Tae Hyang; Lee, Ji Yoon; Park, Sohye; Shin, Seung Hwan; Yahng, Seung-Ah; Yoon, Jae-Ho; Lee, Sung-Eun; Cho, Byung-Sik; Kim, Yoo-Jin; Lee, Seok; Min, Chang-Ki; Kim, Dong-Wook; Lee, Jong-Wook; Min, Woo-Sung; Park, Chong-Won

    2013-01-01

    Background Suppressor of cytokine signaling genes (SOCS) are regarded as pivotal negative feedback regulators of cytokine signals, including the interferon-gamma (IFN-γ), granulocyte-colony stimulating factor, and interleukin families, released by T cells. A detailed understanding of the involvement of SOCS genes in graft-versus-host disease (GVHD) is critical to effectively manage GVHD, yet their expression patterns among recipients remain largely unexplored. Methods Expression levels of SOCS1 and SOCS3 were determined by real-time quantitative reverse transcription PCR (qRT-PCR) in patients with acute GVHD (aGVHD) and chronic GVHD (cGVHD), in a severity-dependent manner, after allogeneic hematopoietic stem cell transplantation (HSCT). A total of 71 recipients with AML (N=40), ALL (N=12), myelodysplastic syndromes (MDS; N=10), chronic myelogenous leukemia (CML; N=2), severe aplastic anemia (SAA; N=5), or others (N=2), who received allogeneic HSCT from human leukocyte antigen-identical siblings or unrelated donors between 2009 and 2011, were included in the present study. Results Overall, the expression levels of SOCS1 decreased in recipients with grade II to IV aGVHD and cGVHD when compared to normal donors and non-GVHD recipients. Interestingly, the expressions of SOCS1 decreased significantly more in cGVHD than in aGVHD recipients (P=0.0091). In contrast, SOCS3 expressions were similarly reduced in all the recipients. Conclusion This is the first study to show that SOCS1 and SOCS3 are differentially expressed in recipients following allogeneic HSCT, suggesting a prognostic correlation between SOCS genes and the development of GVHD. This result provides a new platform to study GVHD immunobiology and potential diagnostic and therapeutic targets for GVHD. PMID:23589790

  19. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Children and Young Adults with Chronic Myeloid Leukemia: A CIBMTR Cohort Analysis.

    PubMed

    Chaudhury, Sonali; Sparapani, Rodney; Hu, Zhen-Huan; Nishihori, Taiga; Abdel-Azim, Hisham; Malone, Adriana; Olsson, Richard; Hamadani, Mehdi; Daly, Andrew; Bacher, Ulrike; Wirk, Baldeep M; Kamble, Rammurti T; Gale, Robert P; Wood, William A; Hale, Gregory; Wiernik, Peter H; Hashmi, Shahrukh K; Marks, David; Ustun, Celalettin; Munker, Reinhold; Savani, Bipin N; Alyea, Edwin; Popat, Uday; Sobecks, Ronald; Kalaycio, Matt; Maziarz, Richard; Hijiya, Nobuko; Saber, Wael

    2016-06-01

    Chronic myeloid leukemia (CML) in children and young adults is uncommon. Young patients have long life expectancies and low morbidity with hematopoietic cell transplantation (HCT). Prolonged tyrosine kinase inhibitor (TKI) use may cause significant morbidity. In addition, indication for HCT in patients in the first chronic phase is not established. We hence retrospectively evaluated outcomes in 449 CML patients with early disease receiving myeloablative HCT reported to the CIBMTR. We analyzed various factors affecting outcome, specifically the effect of age and pre-HCT TKI in pediatric patients (age < 18 years, n = 177) and young adults (age 18 to 29 years, n = 272) with the goal of identifying prognostic factors. Post-HCT probability rates of 5-year overall survival (OS) and leukemia-free survival (LFS) were 75% and 59%, respectively. Rates of OS and LFS were 76% and 57% in <18-year and 74% and 60% in 18- to 29-year group, respectively, by univariate analysis (P = .1 and = .6). Five-year rates of OS for HLA matched sibling donor (MSD) and bone marrow (BM) stem cell source were 83% and 80%, respectively. In multivariate analysis there was no effect of age (<18 versus 18 to 29) or pre-HCT TKI therapy on OS, LFS, transplant related mortality, or relapse. Favorable factors for OS were MSD (P < .001) and recent HCT (2003 to 2010; P = .04). LFS was superior with MSD (P < .001), BM as graft source (P = .001), and performance scores > 90 (P = .03) compared with unrelated or mismatched peripheral blood stem cells donors and recipients with lower performance scores. Older age was associated with increased incidence of chronic graft-versus-host disease (P = .0002). In the current era, HCT outcomes are similar in young patients and children with early CML, and best outcomes are achieved with BM grafts and MSD. PMID:26964698

  20. MODIFYING LIGNIN IN CONIFERS: THE ROLE OF HCT DURING TRACHEARY ELEMENT FORMATION IN PINUS RADIATA

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The enzyme hydroxycinnamoyl-CoA: shikimate hydroxycinnamoyltransferase (HCT) is involved in the production of methoxylated monolignols that are precursors to guaiacyl and syringyl lignin in angiosperm species. We identified and cloned a putative HCT gene from Pinus radiata, a coniferous gymnosperm, ...

  1. Assuring Quality in Promoting Generic Skills in the Higher College of Technology (HCT), Muscat: Challenges & Realities

    ERIC Educational Resources Information Center

    Ali, Holi Ibrahim Holi

    2012-01-01

    This paper explores EFL teachers' perceptions in relation to the pedagogical and conceptual challenges that they face in promoting generic skills in the Higher College of Technology (HCT), Muscat, in the context of post foundation level provision. A questionnaire was administered to 17 EFL teachers at HCT, at post foundation levels to investigate…

  2. Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis

    PubMed Central

    Kumar, Shaji; Zhang, Mei-Jie; Li, Peigang; Dispenzieri, Angela; Milone, Gustavo A.; Lonial, Sagar; Krishnan, Amrita; Maiolino, Angelo; Wirk, Baldeep; Weiss, Brendan; Freytes, César O.; Vogl, Dan T.; Vesole, David H.; Lazarus, Hillard M.; Meehan, Kenneth R.; Hamadani, Mehdi; Lill, Michael; Callander, Natalie S.; Majhail, Navneet S.; Wiernik, Peter H.; Nath, Rajneesh; Kamble, Rammurti T.; Vij, Ravi; Kyle, Robert A.; Gale, Robert Peter

    2011-01-01

    Allogeneic hematopoietic cell transplantation in multiple myeloma is limited by prior reports of high treatment-related mortality. We analyzed outcomes after allogeneic hematopoietic cell transplantation for multiple myeloma in 1207 recipients in 3 cohorts based on the year of transplantation: 1989-1994 (n = 343), 1995-2000 (n = 376), and 2001-2005 (n = 488). The most recent cohort was significantly older (53% > 50 years) and had more recipients after prior autotransplantation. Use of unrelated donors, reduced-intensity conditioning and the blood cell grafts increased over time. Rates of acute graft-versus-host (GVHD) were similar, but chronic GVHD rates were highest in the most recent cohort. Overall survival (OS) at 1-year increased over time, reflecting a decrease in treatment-related mortality, but 5-year relapse rates increased from 39% (95% confidence interval [CI], 33%-44%) in 1989-1994 to 58% (95% CI, 51%-64%; P < .001) in the 2001-2005 cohort. Projected 5-year progression-free survival and OS are 14% (95% CI, 9%-20%) and 29% (95% CI, 23%-35%), respectively, in the latest cohort. Increasing age, longer interval from diagnosis to transplantation, and unrelated donor grafts adversely affected OS in multivariate analysis. Survival at 5 years for subjects with none, 1, 2, or 3 of these risk factors were 41% (range, 36%-47%), 32% (range, 27%-37%), 25% (range, 19%-31%), and 3% (range, 0%-11%), respectively (P < .0001). PMID:21690560

  3. Facilitation of allogeneic bone marrow transplantation by a T cell-specific immunotoxin containing daunomycin

    SciTech Connect

    Xie, S.S.; Inazawa, M.; Sinha, N.; Sawada, S.; Vergidis, R.; Diener, E.

    1987-12-01

    Daunomycin coupled via an acid-sensitive spacer to monoclonal Thy-1.2-specific antibody was used to purge T lymphocytes from a 1:1 mixture of murine C57BL/6J bone marrow and spleen cells prior to engraftment in fully allogeneic, irradiated BALB/c recipients. Treatment of bone marrow with the immunotoxin at a concentration used for purging had no effect on the viability of committed hematopoietic progenitor or multipotent stem cells. All of the recipients of purged bone marrow were at least 80% chimeric for donor peripheral blood cells and none developed graft-versus-host disease. Out of 50 chimeras, 49 were still alive more than 200 days posttransplantation. The chimeras were shown to be tolerant to donor tissue as tested by mixed lymphocyte reactivity, cell-mediated cytotoxicity, and skin grafting. The same tests revealed full immunocompetence of chimeras to third-party alloantigens. In vivo IgM and IgG antibody responses to sheep red blood cells were similar in magnitude in allogeneically and syngeneically reconstituted mice.

  4. Donor CD4 T Cell Diversity Determines Virus Reactivation in Patients After HLA-Matched Allogeneic Stem Cell Transplantation

    PubMed Central

    Ritter, J; Seitz, V; Balzer, H; Gary, R; Lenze, D; Moi, S; Pasemann, S; Seegebarth, A; Wurdack, M; Hennig, S; Gerbitz, A; Hummel, M

    2015-01-01

    Delayed reconstitution of the T cell compartment in recipients of allogeneic stem cell grafts is associated with an increase of reactivation of latent viruses. Thereby, the transplanted T cell repertoire appears to be one of the factors that affect T cell reconstitution. Therefore, we studied the T cell receptor beta (TCRβ) gene rearrangements of flow cytometry–sorted CD4+ and CD8+ T cells from the peripheral blood of 23 allogeneic donors before G-CSF administration and on the day of apheresis. For this purpose, TCRβ rearrangements were amplified by multiplex PCR followed by high-throughput amplicon sequencing. Overall, CD4+ T cells displayed a significantly higher TCRβ diversity compared to CD8+ T cells irrespective of G-CSF administration. In line, no significant impact of G-CSF treatment on the TCR Vβ repertoire usage was found. However, correlation of the donor T cell repertoire with clinical outcomes of the recipient revealed that a higher CD4+ TCRβ diversity after G-CSF treatment is associated with lower reactivation of cytomegalovirus and Epstein–Barr virus. By contrast, no protecting correlation was observed for CD8+ T cells. In essence, our deep TCRβ analysis identifies the importance of the CD4+ T cell compartment for the control of latent viruses after allogeneic stem cell transplantation. PMID:25873100

  5. Control of Immune Response to Allogeneic Embryonic Stem Cells by CD3 Antibody-Mediated Operational Tolerance Induction.

    PubMed

    Calderon, D; Prot, M; You, S; Marquet, C; Bellamy, V; Bruneval, P; Valette, F; de Almeida, P; Wu, J C; Pucéat, M; Menasché, P; Chatenoud, L

    2016-02-01

    Implantation of embryonic stem cells (ESCs) and their differentiated derivatives into allogeneic hosts triggers an immune response that represents a hurdle to clinical application. We established in autoimmunity and in transplantation that CD3 antibody therapy induces a state of immune tolerance. Promising results have been obtained with CD3 antibodies in the clinic. In this study, we tested whether this strategy can prolong the survival of undifferentiated ESCs and their differentiated derivatives in histoincompatible hosts. Recipients of either mouse ESC-derived embryoid bodies (EBs) or cardiac progenitors received a single short tolerogenic regimen of CD3 antibody. In immunocompetent mice, allogeneic EBs and cardiac progenitors were rejected within 20-25 days. Recipients treated with CD3 antibody showed long-term survival of implanted cardiac progenitors or EBs. In due course, EBs became teratomas, the growth of which was self-limited. Regulatory CD4(+)FoxP3(+) T cells and signaling through the PD1/PDL1 pathway played key roles in the CD3 antibody therapeutic effect. Gene profiling emphasized the importance of TGF-β and the inhibitory T cell coreceptor Tim3 to the observed effect. These results demonstrate that CD3 antibody administered alone promotes prolonged survival of allogeneic ESC derivatives and thus could prove useful for enhancing cell engraftment in the absence of chronic immunosuppression. PMID:26492394

  6. Nocardiosis in Heart Transplant Recipients.

    PubMed

    Koerner, Michael M; El-Banayosy, Aly; Schulz, Uwe; Zeriouh, Mohamad; Koerfer, Reiner; Tenderich, Gero; Ghodsizad, Ali

    2015-01-01

    Nocardia has emerged as an important opportunistic pathogen, especially in organ transplant recipients. Heart transplant (HT) recipients initially had an especially high rate of Nocardia infection, but this could be reduced by the routine use of cyclosporine. Our objective was to clarify the prevalence and presentation of Nocardiosis in HT recipients in a retrospective cross-sectional analysis. PMID:26726715

  7. Donor cell leukemia after allogeneic peripheral blood stem cell transplantation: a case report and literature review.

    PubMed

    Murata, Makoto; Ishikawa, Yuichi; Ohashi, Haruhiko; Terakura, Seitaro; Ozeki, Kazutaka; Kiyoi, Hitoshi; Naoe, Tomoki

    2008-07-01

    A 49-year-old male developed recurrent acute myeloid leukemia 27 months after allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical brother. The immunophenotype of the blastic cell population was incompatible with that of the pre-transplant blast cells; a mutation in C/EBPA gene was found in the pre-transplant blast cells that was not present in the post-transplant blast cells, and short tandem repeat analysis of marrow cells, which included 71% blasts, showed complete donor chimera. Thus, this recipient developed donor cell leukemia (DCL). The donor was healthy when DCL developed in the recipient as well as before donation of the peripheral blood stem cells. Only five cases of DCL after PBSCT have been reported in the literature. As a mechanism for the development of DCL, a vigorous proliferative demand on the donor cells, which often correlates with a higher likelihood of replication error or mutation, has been proposed. Peripheral blood stem cells might have an advantage in that they are associated with a low incidence of DCL development because PBSCT recipients receive a higher total cell dose than recipients of bone marrow or cord blood cells. PMID:18470599

  8. Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation

    PubMed Central

    Jenq, Robert R.; King, Christopher G.; Volk, Christine; Suh, David; Smith, Odette M.; Rao, Uttam K.; Yim, Nury L.; Holland, Amanda M.; Lu, Sydney X.; Zakrzewski, Johannes L.; Goldberg, Gabrielle L.; Diab, Adi; Alpdogan, Onder; Penack, Olaf; Na, Il-Kang; Kappel, Lucy W.; Wolchok, Jedd D.; Houghton, Alan N.; Perales, Miguel-Angel

    2009-01-01

    Keratinocyte growth factor (KGF), which is given exogenously to allogeneic bone marrow transplantation (allo-BMT) recipients, supports thymic epithelial cells and increases thymic output of naive T cells. Here, we demonstrate that this improved T-cell reconstitution leads to enhanced responses to DNA plasmid tumor vaccination. Tumor-bearing mice treated with KGF and DNA vaccination have improved long-term survival and decreased tumor burden after allo-BMT. When assayed before vaccination, KGF-treated allo-BMT recipients have increased numbers of peripheral T cells, including CD8+ T cells with vaccine-recognition potential. In response to vaccination, KGF-treated allo-BMT recipients, compared with control subjects, generate increased numbers of tumor-specific CD8+ cells, as well as increased numbers of CD8+ cells producing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). We also found unanticipated benefits to antitumor immunity with the administration of KGF. KGF-treated allo-BMT recipients have an improved ratio of T effector cells to regulatory T cells, a larger fraction of effector cells that display a central memory phenotype, and effector cells that are derived from a broader T-cell–receptor repertoire. In conclusion, our data suggest that KGF can function as a potent vaccine adjuvant after allo-BMT through its effects on posttransplantation T-cell reconstitution. PMID:19011222

  9. Donor-Specific Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Morin-Zorman, Sarah; Loiseau, Pascale; Taupin, Jean-Luc; Caillat-Zucman, Sophie

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative treatment for a wide variety of hematological diseases. In 30% of the cases, a geno-identical donor is available. Any other situation displays some level of human leukocyte antigen (HLA) incompatibility between donor and recipient. Deleterious effects of anti-HLA immunization have long been recognized in solid organ transplant recipients. More recently, anti-HLA immunization was shown to increase the risk of primary graft failure (PGF), a severe complication of AHSCT that occurs in 3–4% of matched unrelated donor transplantation and up to 15% in cord blood transplantation and T-cell depleted haplo-identical stem cell transplantation. Rates of PGF in patients with DSA were reported to be between 24 and 83% with the highest rates in haplo-identical and cord blood transplantation recipients. This led to the recommendation of anti-HLA antibody screening to detect donor-specific antibodies (DSA) in recipients prior to AHSCT. In this review, we highlight the role of anti-HLA antibodies in AHSCT and the mechanisms that may lead to PGF in patients with DSA, and discuss current issues in the field. PMID:27570526

  10. Donor-Specific Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Morin-Zorman, Sarah; Loiseau, Pascale; Taupin, Jean-Luc; Caillat-Zucman, Sophie

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative treatment for a wide variety of hematological diseases. In 30% of the cases, a geno-identical donor is available. Any other situation displays some level of human leukocyte antigen (HLA) incompatibility between donor and recipient. Deleterious effects of anti-HLA immunization have long been recognized in solid organ transplant recipients. More recently, anti-HLA immunization was shown to increase the risk of primary graft failure (PGF), a severe complication of AHSCT that occurs in 3-4% of matched unrelated donor transplantation and up to 15% in cord blood transplantation and T-cell depleted haplo-identical stem cell transplantation. Rates of PGF in patients with DSA were reported to be between 24 and 83% with the highest rates in haplo-identical and cord blood transplantation recipients. This led to the recommendation of anti-HLA antibody screening to detect donor-specific antibodies (DSA) in recipients prior to AHSCT. In this review, we highlight the role of anti-HLA antibodies in AHSCT and the mechanisms that may lead to PGF in patients with DSA, and discuss current issues in the field. PMID:27570526

  11. Origin and Biology of the Allogeneic Response

    PubMed Central

    Lakkis, Fadi G.; Lechler, Robert I.

    2013-01-01

    The recognition by the immune system of nonself determinants on cells, tissues, or organs transplanted between genetically disparate members of the same species can lead to a potent allogeneic response that is responsible for rejection. We review here fundamental concepts that underlie the origins and biology of allorecognition in the mammalian immune system. We examine why and how T cells are alloreactive and discuss emerging evidence of allorecognition by innate immune cells. The nature of T cells (naïve vs. memory) and the alloantigen presentation pathways (direct, indirect, and semidirect) that initiate the allogeneic response are outlined. PMID:23906882

  12. Early Lung Computed Tomography Scan after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Cornetto, Marie Alice; Chevret, Sylvie; Abbes, Sarah; de Margerie-Mellon, Constance; Hussenet, Claire; Sicre de Fontbrune, Flore; Tazi, Abdellatif; Ribaud, Patricia; Bergeron, Anne

    2016-08-01

    A lung computed tomography (CT) scan is essential for diagnosing lung diseases in hematopoietic stem cell transplantation (HSCT) recipients. As a result, lung CT scans are increasingly prescribed in the early phase after allogeneic HSCT, with no assessment of the added value for global patient management. Among 250 patients who underwent allogeneic HSCT in our center over a 2-year period, we evaluated 68 patients who had at least 1 lung CT scan within the first 30 days post-transplantation. The median interval between allogeneic HSCT and lung CT scan was 8.5 days. Patients who underwent an early lung CT scan were more immunocompromised and had a more severe course. Fever was the main indication for the CT scan (78%). The lung CT scan was abnormal in 52 patients, including 17 patients who had an abnormal pre-HSCT CT scan. A therapeutic change was noted in 37 patients (54%) within 24 hours after the lung CT scan. The main changes included the introduction of corticosteroids (n = 23; 62%), especially in patients with a normal CT scan (89%). In univariate models, we found that a normal pretransplantation CT scan (P = .002), the absence of either dyspnea (P = .029) or hypoxemia (P = .015), and a serum C-reactive protein level <10 mg/L (P = .004) were associated with a normal post-HSCT lung CT scan. We found that the association of these variables could predict the normality of early post-HSCT lung CT scans. Pretransplantation lung CT scans are useful for the interpretation of subsequent lung CT scans following allogeneic HSCT, which are frequently abnormal. Early post-HSCT lung CT scans are helpful in patient management, but prescriptions could be more targeted. PMID:27189110

  13. Avascular necrosis of bone after allogeneic bone marrow transplantation: clinical findings, incidence and risk factors.

    PubMed

    Socié, G; Sélimi, F; Sedel, L; Frija, J; Devergie, A; Esperou Bourdeau, H; Ribaud, P; Gluckman, E

    1994-03-01

    In the present study we describe the incidence, clinical course, and management of avascular necrosis of bone following allogeneic bone marrow transplantation, and identify risk factors related to its development. All patients developing avascular necrosis of bone after allogeneic bone marrow transplantation between January 1974 and September 1992 were included in the analysis and were studied using the Hôpital Saint Louis Bone Marrow Transplant Database and hospital records. 27/727 allogeneic transplant recipients developed avascular necrosis leading to an 8.1% incidence at 5 years, by product limit estimate, ranging from 5% to 11.2%. Symptoms developed 119-1747 d (median 398 d) after transplantation. In these 27 patients a total of 52 joints were affected (mean 1.92 per patient, range 1-7). The hip joint was most often affected (69% of patients). All patients had joint pain that led to diagnosis by means of standard radiographs with or without the help of technetium-99 scans and/or magnetic resonance imaging. All but three patients received steroid therapy for acute graft-versus-host disease. Among 10 factors tested, three were shown to be significantly linked to an increased risk for developing avascular necrosis by multivariate analysis: male gender (relative risk (RR) 4.72, P = 0.002), age older than 16 (RR = 3.87, P = 0.004), and acute graft-versus-host disease requiring steroid therapy (RR = 6.30, P = 0.0002). 10 patients (37%) required joint replacement within 19 months (range 2-42) following diagnosis of avascular necrosis. In conclusion, avascular necrosis of bone is a frequent late complication of allogeneic bone marrow transplantation causing significant morbidity and requiring replacement surgery in one-third of affected patients. In this 18-year single-centre survey, older age, male gender and steroid therapy given for acute graft-versus-host disease were shown to independently increase the risk of avascular necrosis of bone. PMID:8043445

  14. High Resolution SPectrometer for HCT, Hanle: an update

    NASA Astrophysics Data System (ADS)

    Sunetra, Giridhar; Sivarani, T.; Anantha, Ch.; Jayashree, Roy; Anand, M. N.; Anupama, G. C.; Mahesh, P. K.; Parihar, P. S.; Prabhu, T. P.; Singhal, A. K.; Sriram, S.; Sundararajan, M. S.

    A high resolution spectrometer for the 2m Himalayan Chandra Telescope (HCT) at Indian Astronomical Observatory (IAO) Hanle, is being built to meet the observational requirement of many advanced areas in astronomy requiring high spectral resolution. This instrument is based upon a modern design using a white pupil concept which has been adopted in several contemporary high resolution spectrometers. This design is known to reduce light losses due to vignetting and also provides the full spectral coverage (350nm-1000nm) in a single CCD frame. This design also incorporates additional features like image-slicer which would result in very high light efficiency. A peak throughput of 20% in visual range and throughput of 8% is expected at extreme blue and red wavelengths. The spectrometer would give resolutions of 60,000 and 30,000 in two resolution modes. In this contribution we describe the instrument and its environment and give an update on its development and science programs we propose to undertake.

  15. Characterization of sphere-forming HCT116 clones by whole RNA sequencing

    PubMed Central

    Chung, Eunkyung; Oh, Inkyung

    2016-01-01

    Purpose To determine CD133+ cells defined as cancer stem cells (CSCs) in colon cancer, we examined whether CD133+ clones in HCT116 demonstrate known features of CSCs like sphere-forming ability, chemodrug-resistance, and metastatic potential. Methods Magnetic cell isolation and cell separation demonstrated that <1% of HCT116 cells expressed CD133, with the remaining cells being CD133- clones. In colon cancer cells, radioresistance is also considered a CSC characteristic. We performed clonogenic assay using 0.4 Gy γ-irradiation. Results Interestingly, there were no differences between HCT116 parental and HCT116 CD133+ clones when the cells comprised 0.5% of the total cells, and CD133- clone demonstrated radiosensitive changes compared with parental and CD133+ clones. Comparing gene expression profiles between sphere-forming and nonforming culture conditions of HCT116 subclones by whole RNA sequencing failed to obtain specific genes expressed in CD133+ clones. Conclusion Despite no differences of gene expression profiles in monolayer attached culture conditions of each clone, sphere-forming conditions of whole HCT116 subclones, parental, CD133+, and CD133- increased 1,761 coding genes and downregulated 1,384 genes related to CSCs self-renewal and survival. Thus, spheroid cultures of HCT116 cells could be useful to expand colorectal CSCs rather than clonal expansion depending on CD133 expressions. PMID:27073788

  16. 21 CFR 1271.25 - What information is required for establishment registration and HCT/P listing?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... registration and HCT/P listing? 1271.25 Section 1271.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... HCT/P listing? (a) Your establishment registration Form FDA 3356 must include: (1) The legal name(s... registration and HCT/P listing form is true and accurate, to the best of his or her knowledge. (b) Your...

  17. 21 CFR 1271.21 - When do I register, submit an HCT/P list, and submit updates?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false When do I register, submit an HCT/P list, and... Listing § 1271.21 When do I register, submit an HCT/P list, and submit updates? (a) You must register and submit a list of every HCT/P that your establishment manufactures within 5 days after...

  18. 21 CFR 1271.21 - When do I register, submit an HCT/P list, and submit updates?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false When do I register, submit an HCT/P list, and... Listing § 1271.21 When do I register, submit an HCT/P list, and submit updates? (a) You must register and submit a list of every HCT/P that your establishment manufactures within 5 days after...

  19. 21 CFR 1271.25 - What information is required for establishment registration and HCT/P listing?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... registration and HCT/P listing? 1271.25 Section 1271.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... HCT/P listing? (a) Your establishment registration Form FDA 3356 must include: (1) The legal name(s... registration and HCT/P listing form is true and accurate, to the best of his or her knowledge. (b) Your...

  20. 21 CFR 1271.21 - When do I register, submit an HCT/P list, and submit updates?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false When do I register, submit an HCT/P list, and... Listing § 1271.21 When do I register, submit an HCT/P list, and submit updates? (a) You must register and submit a list of every HCT/P that your establishment manufactures within 5 days after...

  1. 21 CFR 1271.25 - What information is required for establishment registration and HCT/P listing?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... registration and HCT/P listing? 1271.25 Section 1271.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... HCT/P listing? (a) Your establishment registration Form FDA 3356 must include: (1) The legal name(s... registration and HCT/P listing form is true and accurate, to the best of his or her knowledge. (b) Your...

  2. A limited sampling schedule to estimate mycophenolic Acid area under the concentration-time curve in hematopoietic cell transplantation recipients.

    PubMed

    Li, Hong; Mager, Donald E; Bemer, Meagan J; Salinger, David H; Vicini, Paolo; Sandmaier, Brenda M; Nash, Richard; McCune, Jeannine S

    2012-11-01

    Mycophenolate mofetil (MMF) is a key component of postgrafting immunosuppression in hematopoietic cell transplant (HCT) recipients. The plasma area under the curve (AUC) of its active metabolite, mycophenolic acid (MPA), is associated with MMF efficacy and toxicity. This study developed a population pharmacokinetic model of MPA in HCT recipients and created limited sampling schedules (LSSs) to enable individualized pharmacotherapy. A retrospective evaluation of MPA concentration-time data following a 2-hour MMF intravenous (IV) infusion was conducted in 77 HCT recipients. The final model consisted of 1 and 2 compartments for MMF and MPA pharmacokinetics, respectively. The mean estimated values (coefficient of variation, %) for total systemic clearance, distributional clearance, and central and peripheral compartment volumes of MPA were 36.9 L/h (34.5%), 15.3 L/h (80.4%), 11.9 L (71.7%), and 182 L (127%), respectively. No covariates significantly explained variability among individuals. Optimal LSSs were derived using a simulation approach based on the scaled mean squared error. A 5-sample schedule of 2, 2.5, 3, 5, and 6 hours from the start of the infusion precisely estimated MPA AUC(0-12 h) for Q12-hour IV MMF. A comparable schedule (2, 2.5, 3, 4, and 6 hours) similarly estimated MPA AUC(0-8) (h) for Q8-hour dosing. PMID:22174435

  3. A Limited Sampling Schedule to Estimate Mycophenolic Acid Area Under the Concentration-Time Curve in Hematopoietic Cell Transplantation Recipients

    PubMed Central

    Li, Hong; Mager, Donald E.; Bemer, Meagan J.; Salinger, David H.; Vicini, Paolo; Sandmaier, Brenda M.; Nash, Richard; McCune, Jeannine S.

    2011-01-01

    Mycophenolate mofetil (MMF) is a key component of post-grafting immunosuppression in hematopoietic cell transplant (HCT) recipients. The plasma area under the curve (AUC) of its active metabolite, mycophenolic acid (MPA), is associated with MMF efficacy and toxicity. This study developed a population pharmacokinetic model of MPA in HCT recipients and created limited sampling schedules (LSS) to enable individualized pharmacotherapy. A retrospective evaluation of MPA concentration-time data following a 2 hr MMF intravenous (IV) infusion was conducted in 77 HCT recipients. The final model consisted of one and two compartments for MMF and MPA pharmacokinetics, respectively. The mean estimated values (coefficient of variation, %) for total systemic clearance, distributional clearance, and central and peripheral compartment volumes of MPA were 36.9 L/h (34.5%), 15.3 L/h (80.4%), 11.9 L (71.7%), and 182 L (127%), respectively. No covariates significantly explained variability among individuals. Optimal LSS were derived using a simulation approach based on the scaled mean squared error. A five-sample schedule of 2, 2.5, 3, 5, and 6 hr from the start of the infusion precisely estimated MPA AUC0–12 hr for Q12 hr IV MMF. A comparable schedule (2, 2.5, 3, 4 and 6 hr) similarly estimated MPA AUC0–8hr for Q8 hr dosing. PMID:22174435

  4. Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil.

    PubMed

    Li, Hong; Mager, Donald E; Sandmaier, Brenda M; Storer, Barry E; Boeckh, Michael J; Bemer, Meagan J; Phillips, Brian R; Risler, Linda J; McCune, Jeannine S

    2014-08-01

    A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplantation (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNCs) at 5 time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic-dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory maximum effect model with an IC50 of 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, nonrelapse mortality, and overall mortality. In conclusion, a pharmacokinetic-dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker. PMID:24727337

  5. Five-Year Follow-Up of Patients With Advanced Chronic Lymphocytic Leukemia Treated With Allogeneic Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning

    PubMed Central

    Sorror, Mohamed L.; Storer, Barry E.; Sandmaier, Brenda M.; Maris, Michael; Shizuru, Judith; Maziarz, Richard; Agura, Edward; Chauncey, Thomas R.; Pulsipher, Michael A.; McSweeney, Peter A.; Wade, James C.; Bruno, Benedetto; Langston, Amelia; Radich, Jerald; Niederwieser, Dietger; Blume, Karl G.; Storb, Rainer; Maloney, David G.

    2008-01-01

    Purpose We reported encouraging early results of allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning in 64 patients who had advanced chronic lymphocytic leukemia (CLL). Here, we have extended the follow-up to a median of 5 years and have included data on an additional 18 patients. Patients and Methods Eighty-two patients, age 42 to 72 years, who had fludarabine-refractory CLL were conditioned with 2 Gy total-body irradiation alone or combined with fludarabine followed by HCT from related (n = 52) or unrelated (n = 30) donors. Results Complete remission (CR) and partial remission were achieved in 55% and 15% of patients, respectively. Higher CR rates were noted after unrelated HCT (67% v 48%). The 5-year incidences of nonrelapse mortality (NRM), progression/relapse, overall survival, and progression-free survival were 23%, 38%, 50%, and 39%, respectively. Among 25 patients initially reported in CR, 8% relapsed and 8% died as a result of NRM, whereas 84% have remained alive and in CR. Among 14 responding patients who were tested and who had molecular eradication of their disease, two died as a result of NRM, two relapsed, and 10 have remained negative. At 5 years, 76% of living patients were entirely well, whereas 24% continued to receive immunosuppression for chronic graft-versus-host disease; the median performance status in each group was 100% and 90%, respectively. Lymphadenopathy ≥ 5 cm, but not cytogenetic abnormalities at HCT, predicted relapse. In a risk-stratification model, patients who had lymphadenopathy less than 5 cm and no comorbidities had a 5-year OS of 71%. Conclusion Nonmyeloablative HCT resulted in a median survival of 5 years for patients who had fludarabine-refractory CLL with sustained remissions and in the continued resolution of chronic graft-versus-host disease in surviving patients. PMID:18794548

  6. IMPACT OF PRETRANSPLANT CONDITIONING REGIMENS ON OUTCOMES OF ALLOGENEIC TRANSPLANTATION FOR CHEMOTHERAPY-UNRESPONSISVE DIFFUSE LARGE B-CELL LYMPHOMA AND GRADE-III FOLLICULAR LYMPHOMA

    PubMed Central

    Hamadani, Mehdi; Saber, Wael; Ahn, Kwang Woo; Carreras, Jeanette; Cairo, Mitchell S.; Fenske, Timothy S.; Gale, Robert Peter; Gibson, John; Hale, Gregory A.; Hari, Parameswaran N.; Hsu, Jack W.; Inwards, David J.; Kamble, Rammurti T.; Klein, Anderas; Maharaj, Dipnarine; Marks, David I.; Rizzieri, David A.; Savani, Bipin N.; Schouten, Harry C.; Waller, Edmund K.; Wirk, Baldeep; Laport, Ginna G.; Montoto, Silvia; Maloney, David G.; Lazarus, Hillard M.

    2013-01-01

    Patients with chemorefractory non-Hodgkin lymphomas (NHL) generally have a poor prognosis. We used the observational database of the CIBMTR to study the outcome of 533 patients with refractory diffuse large B-cell lymphoma (DLBCL) or grade-III follicular lymphoma (FL-III) who underwent allogeneic transplantation (allo-HCT) using either myeloablative (MA; N=307) or reduced intensity/non-myeloablative conditioning (RIC/NST; N=226), between 1998-2010. We analyzed non-relapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Only 45% of the patients at transplant had a Karnofsky performance score of ≥90%. Median follow-up of surviving patients after MA and RIC/NST allo-HCT is 35 months and 30 months, respectively. At 3years, MA allo-HCT was associated with a higher NRM compared to RIC/NST (53% vs. 42%; p=0.03), similar PFS (19% vs. 23%; p=0.40), and lower OS (19% vs. 28%; p=0.02), respectively. On multivariate analysis, FL-III histology was associated with lower NRM (relative-risk [RR]=0.52), reduced risk of relapse/progression (RR=0.42), superior PFS (RR=0.51) and OS (RR=0.53), while MA conditioning was associated with reduced risk of relapse/progression (RR=0.66). Despite a refractory state, a small subset of DLBCL and FL-III patients can attain durable remissions after allo-HCT. Conditioning regimen intensity was not associated with PFS and OS despite a higher risk of relapse/progression with RIC/NST allo-HCT. PMID:23380340

  7. Cytology and histology of haemopoietic cell transplantation under the influence of ALS in mice. II. The effect of marrow from donors pretreated with antilymphocyte serum (ALS) on the recipient

    PubMed Central

    Thierfelder, S.; Rodriguez-Paradisi, E.; Mempel, W.; Beil, E.

    1971-01-01

    Cytology and histology of recipients of allogeneic bone marrow were studied 13. 20, 24, 30 and 34 days after transplantation. The developing chronic secondary disease was characterized by increased numbers of myeloid cells, by lymphopenia and by erythroblastopenia in the bone marrow and the spleen. Erythroblastopenia together with lymphopenia and augmented myeloid cells also occurred in irradiated F1-hybrids suffering from a chronic homologous disease. The latter model eliminated the following as a cause of erythroblastopenia in secondary disease: (1) host-versus-graft reaction against donor-type erythroblasts for immunogenetical reasons, and (2) graft-versus-host reaction against recipient-type erythroblasts since they had already been destroyed by irradiation. Treatment of the donor with ALS resulted in a suppression of homologous disease in F1-hybrids with a cytology resembling that of recipients of syngeneic spleen cells. The same treatment only delayed the onset of chronic secondary disease in recipients of allogeneic bone marrow. These allogeneic recipients, in contrast to the F1-hybrid recipients, died with the typical morphology of a chronic secondary disease. In recipients of syngeneic bone marrow from donors treated with ALS, repopulation with lymphocytes was somewhat delayed and transient erythroblastosis in the spleen occurred 20 days after transplantation. PMID:4395674

  8. Invasive Pulmonary Aspergillosis in a Haematopoietic Stem Cell Transplant Recipient with Sickle Cell Disease: a Successful Treatment

    PubMed Central

    Paciaroni, Katia; De Angelis, Gioia; Gallucci, Cristiano; Alfieri, Cecilia; Ribersani, Michela; Roveda, Andrea; Isgrò, Antonella; Marziali, Marco; Aloi, Ivan Pietro; Inserra, Alessandro; Gaziev, Javid; Sodani, Pietro; Lucarelli, Guido

    2015-01-01

    Sickle Cell Anaemia (SCA) is the most common inherited blood disorder and is associated with severe morbidity and decreased survival. Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) is the only curative approach. Nevertheless the decision to perform a bone marrow transplant includes the risk of major complications and transplant-related mortality. Infections represent the leading cause of death in SCA patients undergoing HSCT. Invasive Pulmonary Aspergillosis (IPA) is a devastating opportunistic infection and remains a significant cause of morbidity and mortality in HSCT recipients. Data regarding IPA in the setting of SCA are lacking. In the present report, we describe a patient with SCA, who developed IPA after allogeneic bone marrow transplant. The fungal infection was treated by systemic antifungal therapy in addition to surgery, despite mild chronic graft versus host disease (GVHD) and continuing immunosuppressive therapy. This case shows that IPA occurring in bone marrow recipients with SCA can be successfully treated. PMID:25574365

  9. Invasive pulmonary aspergillosis in a haematopoietic stem cell transplant recipient with sickle cell disease: a successful treatment.

    PubMed

    Paciaroni, Katia; De Angelis, Gioia; Gallucci, Cristiano; Alfieri, Cecilia; Ribersani, Michela; Roveda, Andrea; Isgrò, Antonella; Marziali, Marco; Aloi, Ivan Pietro; Inserra, Alessandro; Gaziev, Javid; Sodani, Pietro; Lucarelli, Guido

    2015-01-01

    Sickle Cell Anaemia (SCA) is the most common inherited blood disorder and is associated with severe morbidity and decreased survival. Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) is the only curative approach. Nevertheless the decision to perform a bone marrow transplant includes the risk of major complications and transplant-related mortality. Infections represent the leading cause of death in SCA patients undergoing HSCT. Invasive Pulmonary Aspergillosis (IPA) is a devastating opportunistic infection and remains a significant cause of morbidity and mortality in HSCT recipients. Data regarding IPA in the setting of SCA are lacking. In the present report, we describe a patient with SCA, who developed IPA after allogeneic bone marrow transplant. The fungal infection was treated by systemic antifungal therapy in addition to surgery, despite mild chronic graft versus host disease (GVHD) and continuing immunosuppressive therapy. This case shows that IPA occurring in bone marrow recipients with SCA can be successfully treated. PMID:25574365

  10. DNA profiling in peripheral blood, buccal swabs, hair follicles and semen from a patient following allogeneic hematopoietic stem cells transplantation.

    PubMed

    Li, Ya-Ting; Xie, Ming-Kun; Wu, Jin

    2014-11-01

    Allogeneic peripheral blood stem cells transplantation (allo-PBSCT) or allogeneic bone marrow transplantation (allo-BMT) have been widely used to treat patients exhibiting certain severe illnesses. However, previous studies have shown that the biological materials of allo-PBSCT or allo-BMT recipients may not constitute credible materials for personal identification. In the present study, four types of commonly used samples were collected from a male individual following gender-matched allo-BMT. Autosomal short tandem repeat (STR) and Y-STR markers analysis, based on polymerase chain reaction, were used to evaluate the chimerism status. The results showed that the blood sample were all donor type, the buccal swab sample were mixed chimerism, and the sperm and hair follicle samples maintained a recipient origin of 100%. In conclusion, identical results were obtained by the two methods and it was confirmed that DNA extracted from hair follicles and sperm can be used as a reference for the pre-transplant genotype DNA profile of the recipient in the gender-match allo-BMT or -PBSCT. PMID:25279149

  11. DNA profiling in peripheral blood, buccal swabs, hair follicles and semen from a patient following allogeneic hematopoietic stem cells transplantation

    PubMed Central

    LI, YA-TING; XIE, MING-KUN; WU, JIN

    2014-01-01

    Allogeneic peripheral blood stem cells transplantation (allo-PBSCT) or allogeneic bone marrow transplantation (allo-BMT) have been widely used to treat patients exhibiting certain severe illnesses. However, previous studies have shown that the biological materials of allo-PBSCT or allo-BMT recipients may not constitute credible materials for personal identification. In the present study, four types of commonly used samples were collected from a male individual following gender-matched allo-BMT. Autosomal short tandem repeat (STR) and Y-STR markers analysis, based on polymerase chain reaction, were used to evaluate the chimerism status. The results showed that the blood sample were all donor type, the buccal swab sample were mixed chimerism, and the sperm and hair follicle samples maintained a recipient origin of 100%. In conclusion, identical results were obtained by the two methods and it was confirmed that DNA extracted from hair follicles and sperm can be used as a reference for the pre-transplant genotype DNA profile of the recipient in the gender-match allo-BMT or -PBSCT. PMID:25279149

  12. Impact of graft-versus-host disease on outcomes after allogeneic hematopoietic cell transplantation for adult T-cell leukemia: a retrospective cohort study.

    PubMed

    Kanda, Junya; Hishizawa, Masakatsu; Utsunomiya, Atae; Taniguchi, Shuichi; Eto, Tetsuya; Moriuchi, Yukiyoshi; Tanosaki, Ryuji; Kawano, Fumio; Miyazaki, Yasushi; Masuda, Masato; Nagafuji, Koji; Hara, Masamichi; Takanashi, Minoko; Kai, Shunro; Atsuta, Yoshiko; Suzuki, Ritsuro; Kawase, Takakazu; Matsuo, Keitaro; Nagamura-Inoue, Tokiko; Kato, Shunichi; Sakamaki, Hisashi; Morishima, Yasuo; Okamura, Jun; Ichinohe, Tatsuo; Uchiyama, Takashi

    2012-03-01

    Allogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus-leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P = .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment-related mortality (HR, 3.50; P < .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL. PMID:22234682

  13. Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation

    PubMed Central

    Fowler, Daniel H.; Mossoba, Miriam E.; Steinberg, Seth M.; Halverson, David C.; Stroncek, David; Khuu, Hahn M.; Hakim, Frances T.; Castiello, Luciano; Sabatino, Marianna; Leitman, Susan F.; Mariotti, Jacopo; Gea-Banacloche, Juan C.; Sportes, Claude; Hardy, Nancy M.; Hickstein, Dennis D.; Pavletic, Steven Z.; Rowley, Scott; Goy, Andre; Donato, Michele; Korngold, Robert; Pecora, Andrew; Levine, Bruce L.; June, Carl H.; Gress, Ronald E.; Bishop, Michael R.

    2013-01-01

    In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4+ T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4+ Th2 and Th1 cells relative to regulatory T cells and CD8+ T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens. This trial was registered at www.cancer.gov/clinicaltrials as #NCT 00077480. PMID:23426943

  14. Protective effect of CMV reactivation on relapse after allogeneic hematopoietic cell transplantation in AML patients is influenced by their conditioning regimen

    PubMed Central

    Manjappa, Shivaprasad; Bhamidipati, Pavan Kumar; Stokerl-Goldstein, Keith E.; DiPersio, John F.; Uy, Geoffrey L.; Westervelt, Peter; Liu, Jingxia; Schroeder, Mark A.; Vij, Ravi; Abboud, Camille N.; Fehniger, Todd A; Cashen, Amanda F.; Pusic, Iskra; Jacoby, Meagan; Meera, Srinidhi J.; Romee, Rizwan

    2014-01-01

    Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (allo-HCT) has been associated with reduced risk of relapse in patients with acute myeloid leukemia (AML). However the influence of the conditioning regimen on this protective effect of CMV reactivation after allo-HCT is relatively unexplored. To address this, we evaluated the risk of relapse in 264 AML patients who received T cell replete, 6/6 HLA matched sibling or 10/10 HLA matched unrelated donor transplantation at a single institution between 2006 and 2011. Out of these 264 patients, 206 received myeloablative (MA) and 58 received reduced intensity conditioning (RIC) regimens. CMV reactivation was observed in 88 patients with MA conditioning and 37 patients with RIC. At a median follow up of 299 days, CMV reactivation was associated with significantly lower risk of relapse in patients who received MA conditioning both in univariate (P= .01) and multivariate analyses (hazard ratio of 0.5246, P= .006), however CMV reactivation did not significantly affect the risk of relapse in our RIC cohort. These results confirm the protective effect of CMV reactivation on relapse in AML patients after allo-HCT reported by previous studies, however they suggest that this protective effect of CMV reactivation on relapse is influenced by the conditioning regimen used with the transplant. PMID:24120526

  15. Protective effect of cytomegalovirus reactivation on relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients is influenced by conditioning regimen.

    PubMed

    Manjappa, Shivaprasad; Bhamidipati, Pavan Kumar; Stokerl-Goldstein, Keith E; DiPersio, John F; Uy, Geoffrey L; Westervelt, Peter; Liu, Jingxia; Schroeder, Mark A; Vij, Ravi; Abboud, Camille N; Fehniger, Todd A; Cashen, Amanda F; Pusic, Iskra; Jacoby, Meagan; Meera, Srinidhi J; Romee, Rizwan

    2014-01-01

    Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (allo-HCT) has been associated with a reduced risk of relapse in patients with acute myeloid leukemia (AML). However, the influence of the conditioning regimen on this protective effect of CMV reactivation after allo-HCT is relatively unexplored. To address this, we evaluated the risk of relapse in 264 AML patients who received T cell-replete, 6/6 HLA matched sibling or 10/10 HLA matched unrelated donor transplantation at a single institution between 2006 and 2011. Of these 264 patients, 206 received myeloablative (MA) and 58 received reduced-intensity conditioning (RIC) regimens. CMV reactivation was observed in 88 patients with MA conditioning and 37 patients with RIC. At a median follow-up of 299 days, CMV reactivation was associated with significantly lower risk of relapse in patients who received MA conditioning both in univariate (P = .01) and multivariate analyses (hazard ratio, .5246; P = .006); however, CMV reactivation did not significantly affect the risk of relapse in our RIC cohort. These results confirm the protective effect of CMV reactivation on relapse in AML patients after allo-HCT reported by previous studies but suggest this protective effect of CMV reactivation on relapse is influenced by the conditioning regimen used with the transplant. PMID:24120526

  16. Comparison of Outcomes after Peripheral Blood Haploidentical versus Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia: A Retrospective Single-Center Review.

    PubMed

    Rashidi, Armin; DiPersio, John F; Westervelt, Peter; Vij, Ravi; Schroeder, Mark A; Cashen, Amanda F; Fehniger, Todd A; Romee, Rizwan

    2016-09-01

    Recent studies comparing allogeneic hematopoietic cell transplantation (HCT) using HLA-matched unrelated donors (MUD) versus HLA-haploidentical donors in patients with acute myeloid leukemia (AML) have suggested equivalent outcomes. The graft source used in most studies of haploidentical transplants has been bone marrow. Similar comparisons between MUD and haplo-HCT using peripheral blood as a graft source have not been adequately performed. We reviewed the records of all 52 AML patients who underwent haplo-HCT (using peripheral blood and post-transplantation high-dose cyclophosphamide) between January 2010 and August 2015 at our institution and compared their outcomes with 88 patients who had a MUD transplant in the same time frame and were frequency matched (preanalysis) to the haploidentical group for conditioning intensity. Multivariate analysis found no difference in outcomes between the 2 groups with the exception of slower count recovery after haploidentical allografts (HR, .48; 95% CI, .32 to .74 for platelets, and HR, .47; 95% CI, .32 to .71 for neutrophils; P < .001 for both comparisons). Our retrospective analysis, although limited by the small sample size, suggests largely similar outcomes with peripheral blood haploidentical versus MUD transplants for AML. PMID:27223108

  17. Subacute hepatic necrosis mimicking veno-occlusive disease in a patient with HFE H63D homozygosity after allogeneic hematopoietic cell transplantation with busulfan conditioning.

    PubMed

    Chen, Sylvia; Osborn, James Dane; Chen, Xinjian; Boyer, Michael W; McDonald, George B; Hildebrandt, Gerhard Carl

    2015-12-01

    Busulfan is a commonly used chemotherapeutic agent in myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). It has been associated with sinusoidal-obstructive syndrome(SOS) as a life-threatening complication of myeloablative allo-HCT, yet it has not been found to cause severe hepatocellular injury, even in cases of significant accidental overdose.We report the case of a 31-year-old male with a history of high-risk myelodysplastic syndrome transitioning to acute myeloid leukemia, who in complete remission underwent allo-HCT using myeloablative busulfan–fludarabine conditioning, and who developed hepatic failure. While he met clinical criteria for SOS and was treated with defibrotide,liver biopsy demonstrated severe subacute hepatic necrosis and lacked characteristics of SOS. Further evaluation revealed that the patient was homozygous for the HFE H63D gene mutation, associated with hereditary hemochromatosis.Both Busulfan and iron overload related to HFE H63D homozygosity can cause oxidative stress resulting in cellular injury, and the cumulative effects of these risk factors are possibly responsible for the severe hepatocellular injury in this case, making our patient the first-known case of subacute hepatic necrosis related to busulfan administration. PMID:26497867

  18. Cyclophosphamide followed by intravenous targeted busulfan for allogeneic hematopoietic cell transplantation: pharmacokinetics and clinical outcomes

    PubMed Central

    Rezvani, Andrew R.; McCune, Jeannine S.; Storer, Barry E.; Batchelder, Ami; Kida, Aiko; Deeg, H. Joachim; McDonald, George B.

    2013-01-01

    Targeted busulfan/cyclophosphamide (TBU/CY) for allogeneic hematopoietic cell transplantation (HCT) carries a high risk of sinusoidal obstruction syndrome (SOS) in patients transplanted for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from TBU/CY to CY/TBU) will reduce SOS and day +100 non-relapse mortality (NRM). We enrolled 51 patients with myelofibrosis (n=20), acute myeloid leukemia (AML, n=20), or myelodysplastic syndrome (MDS, n=11) in a prospective trial of CY/TBU conditioning for HCT. Cyclophosphamide 60 mg/kg/day IV for two days was followed by daily IV BU for four days, targeted to a concentration at steady state (Css) of 800–900 ng/mL. CY/TBU-conditioned patients had higher exposure to CY (p<0.0001) and lower exposure to 4-hydroxyCY (p<0.0001) compared to TBU/CY-conditioned patients. Clinical outcomes were compared with controls (n=271) conditioned with TBU/CY for the same indications. In patients with myelofibrosis, CY/TBU conditioning was associated with a significantly reduced incidence of SOS (0% vs. 30% after TBU/CY, p=0.006), while SOS incidence was low in both cohorts with AML/MDS. Day +100 mortality was significantly lower in the CY/TBU cohort (2% vs. 13%, p=0.01). CY/TBU conditioning markedly impacted CY pharmacokinetics and was associated with significantly lower incidences of SOS and day +100 mortality, suggesting that CY/TBU is superior to TBU/CY as conditioning for patients with myelofibrosis. PMID:23583825

  19. Polymorphism in the Interleukin-7 Receptor-alpha and Outcome after Allogeneic Hematopoietic Cell Transplantation with Matched Unrelated Donor

    PubMed Central

    Shamim, Zaiba; Spellman, Stephen; Haagenson, Michael; Wang, Tao; Lee, Stephanie J.; Ryder, Lars P.; Müller, Klaus

    2014-01-01

    Interleukin-7 (IL-7) is essential for T cell development in the thymus and maintenance of peripheral T cells. The α-chain of the IL-7R is polymorphic with the existence of SNPs that give rise to nonsynonymous amino acid substitutions. We previously found an association between donor genotypes and increased treatment related mortality (TRM) (rs1494555G) and acute graft versus host disease (aGvHD) (rs1494555G and rs1494558T) after hematopoietic cell transplantation (HCT). Some studies have confirmed an association between rs6897932C and multiple sclerosis. In the present study we evaluated the prognostic significance of IL-7Rα SNP genotypes in 590-recipient/donor pairs that received HLA matched unrelated donor HCT for hematological malignancies. Consistent with the primary studies, the rs1494555GG and rs1494558TT genotypes of the donor were associated with aGvHD and chronic GvHD in the univariate analysis. The T allele of rs6897932 was suggestive of an association with increased frequency of relapse by univariate analysis (p=0.017) and multivariate analysis (p=0.015). In conclusion, this study provides further evidence of a role of the IL-7 pathway and IL-7Rα SNPs in HCT. PMID:23692589

  20. Practice patterns for evaluation, consent, and care of related donors and recipients at hematopoietic cell transplantation centers in the United States

    PubMed Central

    Pedersen, Tanya L.; Confer, Dennis L.; Rizzo, J. Douglas; Pulsipher, Michael A.; Stroncek, David; Leitman, Susan; Anderlini, Paolo

    2010-01-01

    Conflict of interest may arise when 1 physician serves 2 persons whose medical care is interdependent. In hematopoietic cell transplantation (HCT) from unrelated donors and in the setting of solid organ transplantation from living donors, the standard of care is for donors and recipients to be managed by separate physicians to provide unbiased care. However, the practice patterns of evaluation and care of related donors and recipients are not well described. A survey of HCT centers in the United States was conducted by the Donor Health and Safety Working Committee of the Center for International Blood and Marrow Transplant Research to determine the type of provider involved in medical clearance, informed consent, and medical management of hematopoietic cell collection and the relationship of that provider to the HC transplant recipient. The response rate was 40%. In greater than 70% of centers, transplantation physicians were involved or potentially involved in overlapping care of the HC transplant donor and the recipient. These patterns were similar between transplantation teams caring for adult or pediatric donors and recipients. Among responding centers, medical management of recipients and their related donors by the same provider is common, a practice that has the potential for conflict of interest. PMID:20228276

  1. Allogeneic hematopoietic stem cell transplantation in Tunisia.

    PubMed

    Ben Othman, T; Torjemane, L; Abdelkefi, A; Lakhal, A; Ladeb, S; Ben Hamed, L; Slama, H; Ben Abdeladhim, A

    2008-08-01

    In 1998, the Tunisian team of the 'Centre National de Greffe de Moelle Osseuse' initiated allogeneic hematopoietic SCT (AHSCT) in Tunisia. As of June 2007, information was collected about 299 patients with a first AHSCT and 12 additional retransplants. The median age was 19 years (range 2-49 years). The main indications were aplastic anemia (n=106, 36%), leukemia and nonmalignant disorders (n=153, 51%), Fanconi anemia (n=26, 9%) and other nonmalignant disorders (n=14, 4%). Preparative regimens depended on indication. All donors were HLA geno-identical. The stem cell sources were BM (87%) and PBSCs (13%). At the time of analysis, 200 patients (67%) were alive after a median follow-up of 42 months (range 3-112 months). The overall TRM rate was 17%. Outcome depended on indication. According to our results, allogeneic HSCT is potentially curative for hematological diseases, but it is a toxic approach for malignant disorders. PMID:18724288

  2. Total Lymphoid Irradiatione—Antithymocyte Globulin Conditioning and Allogeneic Transplantation for Patients with Myelodysplastic Syndromes and Myeloproliferative Neoplasms

    PubMed Central

    Benjamin, Jonathan; Chhabra, Saurabh; Kohrt, Holbrook E.; Lavori, Philip; Laport, Ginna G.; Arai, Sally; Johnston, Laura; Miklos, David B.; Shizuru, Judith A.; Weng, Wen-Kai; Negrin, Robert S.; Lowsky, Robert

    2015-01-01

    Allogeneic hematopoietic cell transplantation (allo HCT) is the only curative therapy for the myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but treatment toxicity has been a barrier to its more widespread use. The nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) permits the establishment of donor hematopoiesis necessary for the graft-versus-malignancy effect and is protective against acute graft-versus-host disease (aGVHD), but it has minimal direct cytotoxicity against myeloid diseases. We explored the use of TLI-ATG conditioning to treat 61 patients with allo HCT for MDS (n = 32), therapy-related myeloid neoplasms (n = 15), MPN (n = 9), and chronic myelomonocytic leukemia (n = 5). The median age of all patients was 63 years (range, 50 to 73). The cumulative incidence of aGVHD grades II to IV was 14% (95% confidence interval [CI], 4% to 23%) and for grades III to IV, 4% (95% CI, 0 to 9%), and it did not differ between patients who received allografts from related or unrelated donors. The cumulative incidence of nonrelapse mortality (NRM) at 100 days, 12 months, and 36 months was 0%, 7%, and 11%. Overall survival and progression-free survival were 41% (95% CI, 29% to 53%) and 35% (95% CI, 23% to 48%), respectively. The safety and tolerability of TLI-ATG, as exemplified by its low NRM, provides a foundation for further risk-adapted or prophylactic interventions to prevent disease progression. PMID:24607552

  3. Maintenance of the stemness in CD44(+) HCT-15 and HCT-116 human colon cancer cells requires miR-203 suppression.

    PubMed

    Ju, Sy-Yeuan; Chiou, Shih-Hwa; Su, Yeu

    2014-01-01

    The purpose of this study was to isolate cancer stem cells (CSCs, also called tumor-initiating cells, TICs) from established human colorectal carcinoma (CRC) cell lines, characterize them extensively and dissect the mechanism for their stemness. Freshly isolated CD44(+) and CD44(-) cells from the HCT-15 human colon cancer cell line were subjected to various analyses. Interestingly, CD44(+) cells exhibited higher soft agar colony-forming ability and in vivo tumorigenicity than CD44(-) cells. In addition, the significant upregulation of the protein Snail and the downregulation of miR-203, a stemness inhibitor, in CD44(+) cells suggested that this population possessed higher invasion/metastasis and differentiation potential than CD44(-) cells. By manipulating the expression of CD44 in HCT-15 and HCT-116 cells, we found that the levels of several EMT activators and miR-203 were positively and negatively correlated with those of CD44, respectively. Further analyses revealed that miR-203 levels were repressed by Snail, which was shown to bind to specific E-box(es) present in the miR-203 promoter. In agreement, silencing miR-203 expression in wild-type HCT-116 human colon cancer cells also resulted in an increase of their stemness. Finally, we discovered that c-Src kinase activity was required for the downregulation of miR-203 in HCT-15 cells, which was stimulated by the interaction between hyaluronan (HA) and CD44. Taken together, CD44 is a critical molecule for modulating stemness in CSCs. More importantly, we show for the first time that the downregulation of miR-203 by HA/CD44 signaling is the main reason for stemness-maintenance in colon cancer cells. PMID:24145190

  4. Fatal human metapneumovirus and influenza B virus coinfection in an allogeneic hematopoietic stem cell transplant recipient.

    PubMed

    Ghattas, C; Mossad, S B

    2012-10-01

    Human metapneumovirus (hMPV) infection can occur in all age groups with significant morbidity and mortality. Coinfection with influenza virus occurs mainly with influenza type A and all reported cases recovered completely. We report the case of a 61-year-old man who had hematopoietic stem cell transplant for myelodysplastic syndrome. He was admitted to hospital for septic shock and neutropenia, and blood culture was positive for Pseudomonas aeruginosa. He rapidly developed respiratory failure and required ventilator support. His respiratory culture grew P. aeruginosa and hMPV. His course was complicated by persistent shock requiring vasopressor support, and repeat nasopharyngeal swab was positive for influenza type B and hMPV. His condition rapidly deteriorated, his family elected comfort care, and the patient died shortly thereafter. Coinfection with hMPV and influenza virus type B may have a poor outcome and can be fatal, especially in immunocompromised patients. PMID:22823898

  5. Time to unrelated donor leukocyte infusion is longer, but incidence of GVHD and overall survival are similar for recipients of unrelated DLI compared to matched sibling DLI.

    PubMed

    Kumar, Anita J; Vassilev, Pavel; Loren, Alison W; Luger, Selina M; Reshef, Ran; Gill, Saar; Smith, Jacqueline; Goldstein, Steven C; Hexner, Elizabeth; Stadtmauer, Edward A; Porter, David; Frey, Noelle V

    2016-06-01

    Donor leukocyte infusion (DLI) is used to treat relapsed leukemia after allogeneic hematopoietic stem cell transplant (HCT). Data comparing outcomes after unrelated DLI (uDLI) to matched sibling DLI (msDLI) are scant. We performed a retrospective analysis to assess differences in time to administer uDLI versus msDLI, and impact on outcomes. Fifty three patients with relapsed acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) after allogeneic HCT received uDLI (n = 18) or msDLI (n = 35) from 2000 to 2011. Median time from relapse to uDLI request was 15 days (range 0-66). Median time from relapse to uDLI was 56 days versus 40 days for msDLI patients (p = 0.034). 35% of msDLI and 44% of uDLI patients developed acute GVHD (p = 0.50). There was no significant difference in Grade C/D GVHD among uDLI and msDLI (28% and 21%, p = 0.58) or median OS after DLI between uDLI and msDLI (95 versus 75 days, p = 0.76). For patients with relapsed acute leukemia and MDS after allogeneic HCT, time from relapse to uDLI was longer than to msDLI, but incidence of GVHD and overall survival were similar. Access to uDLI does not appear to be a barrier to DLI administration. Outcomes unfortunately remain poor regardless of donor source. Am. J. Hematol. 91:426-429, 2016. © 2016 Wiley Periodicals, Inc. PMID:26820493

  6. Career Maturity of Welfare Recipients.

    ERIC Educational Resources Information Center

    Beckman, Carol M.

    To investigate the career maturity of welfare recipients, this thesis examines six independent variables: (1) race; (2) sex; (3) age; (4) level of formal education; (5) general intelligence; and (6) locus of control. Scales taken from the Career Maturity Inventory served as the dependent variables. The sample consisted of 83 welfare recipients who…

  7. Gallic acid induced apoptotic events in HCT-15 colon cancer cells

    PubMed Central

    Subramanian, Aruna Priyadharshni; Jaganathan, Saravana Kumar; Mandal, Mahitosh; Supriyanto, Eko; Muhamad, Ida Idayu

    2016-01-01

    AIM: To investigate the inhibitory action of diet-derived phenolic compound gallic acid (GA) against HCT-15 colon cancer cells. METHODS: The antiproliferative effect of GA against colon cancer cells was determined by performing thiazolyl blue tetrazolium bromide (MTT) assay. The colony forming ability of GA treated colon cancer cells was evaluated using the colony forming assay. The cell cycle changes induced by GA in HCT-15 cells were analyzed by propidium iodide staining. Levels of reactive oxygen species (ROS) and mitochondrial membrane potential of HCT-15 exposed to GA was assessed using 2’,7’-dichlorfluorescein-diacetate and rhodamine-123 respectively, with the help of flow cytometry. Morphological changes caused by GA treatment in the colon cancer cells were identified by scanning electron microscope and photomicrograph examination. Apoptosis was confirmed using flow cytometric analysis of GA treated HCT-15 cells after staining with Yo-Pro-1. RESULTS: MTT assay results illustrated that GA has an inhibitory effect on HCT-15 cells with IC50 value of 740 μmol/L. A time-dependent inhibition of colony formation was evident with GA treatment. Cell cycle arrest was evident from the accumulation of GA treated HCT-15 cells at sub-G1 phase (0.98 ± 1.03 vs 58.01 ± 2.05) with increasing exposure time. Flow cytometric analysis of GA treated HCT-15 cells depicted early events associated with apoptosis like lipid layer breakage and fall in mitochondrial membrane potential apart from an increase in the generation of ROS which were in a time dependent manner. SEM and photomicrograph images of the GA-treated cells displayed membrane blebbing and cell shrinking characteristics of apoptosis. Further apoptosis confirmation by Yo-Pro-1 staining also showed the time-dependent increase of apoptotic cells after treatment. CONCLUSION: These results show that GA induced ROS dependent apoptosis and inhibited the growth of colon cancer cells. PMID:27099438

  8. Permeation and pathways of human calcitonin (hCT) across excised bovine nasal mucosa.

    PubMed

    Lang, S; Rothen-Rutishauser, B; Perriard, J C; Schmidt, M C; Merkle, H P

    1998-01-01

    In vitro permeation of human calcitonin (hCT), salmon calcitonin (sCT), and the somatostatin analog octreotide (SMS) through excised bovine nasal mucosa was studied applying donor/receiver experiments and confocal laser scanning microscopy. Permeabilities of gonadorelin, buserelin, Hoe013, and of thymopoietin fragments TP5 and TP4 were also included. Apparent permeability coefficients (Peff) ranged between 4 x 10(-5) (SMS) and 1.7 x 10(-5) cm s(-1) (TP4). Such Peff are typical for leaky-type airway epithelia. The order of permeabilities was: SMS > hCT, sCT > buserelin, Hoe013 > TP5 > TP4, LHRH. The relatively high permeability of hCT and sCT contrasted to their high molecular weight. At 37 degrees C, the permeability of hCT from mucosal to serosal (m-to-s) was found two-fold higher (p < 0.05) than from serosal to mucosal (s-to-m). Controls using 3H-mannitol showed equal permeabilities in both directions. At 4 degrees C, permeation of hCT was reduced but equal in both directions (m-to-s and s-to-m). As evaluated by confocal laser scanning microscopy, uptake studies with FITC-18-hCT revealed intracellular fluorescence in the epithelial cells, at 10 min/10 microM exposure in the form of fluorescent vesicles. By combination of these findings, an endocytotic pathway is suggested to contribute to the transport of hCT through nasal epithelium. PMID:9533651

  9. Nitronaproxen: AZD 3582, HCT 3012, Naproxen Nitroxybutylester, NO-Naproxen.

    PubMed

    2006-01-01

    Nitronaproxen [AZD 3582, HCT 3012, naproxen nitroxybutylester, NO-naproxen] is a naproxen derivative with similar anti-inflammatory activity to the parent compound, but with less gastrointestinal toxicity. It is the first of a new class of analgesic and anti-inflammatory drugs known as cyclo-oxygenase-inhibiting nitric oxide donators (CINODs), which are under development by NicOx. The better gastrointestinal tolerability of nitronaproxen appears to be due to its release of nitric oxide (NO) and the consequent maintenance of tissue perfusion and integrity. Nitronaproxen is in phase III clinical development for the treatment of osteoarthritis and is available for licensing. AstraZeneca had been a worldwide licensee for nitronaproxen and other CINODs. However, the results of phase II clinical trials of nitronaproxen did not fulfill AstraZeneca's strategic commercial criteria for further investment and NicOx reacquired rights following AstraZeneca's decision to discontinue its involvement in 2003. NicOx was surprised by AstraZeneca's decision, and remained fully convinced of the potential of nitronaproxen. NicOx is seeking new partners for development of compounds of the CINOD class. Nitronaproxen is in a phase III clinical trial for the treatment of osteoarthritis (OA) of the knee. The 13-week trial completed enrolment of 820 patients from 120 clinical sites in the US in May 2006. The study is designed to confirm that nitronaproxen is superior to placebo and is as effective as naproxen in relieving signs and symptoms of OA. The study will also seek to show that nitronaproxen has no adverse effect on blood pressure. An additional trial has begun that is employing ambulatory blood pressure monitoring to provide a description of the blood pressure effect of nitronaproxen over a 24-hour period in hypertensive subjects. This US trial will enrol approximately 120 volunteers with stable essential hypertension. The volunteers will not have osteoarthritis but will be between

  10. 21 CFR 1271.65 - How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are not prohibited? 1271.65 Section 1271.65 Food and Drugs... TISSUE-BASED PRODUCTS Donor Eligibility § 1271.65 How do I store an HCT/P from a donor determined to...

  11. 21 CFR 1271.65 - How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are not prohibited? 1271.65 Section 1271.65 Food and Drugs... TISSUE-BASED PRODUCTS Donor Eligibility § 1271.65 How do I store an HCT/P from a donor determined to...

  12. Effect of selective T cell depletion of host and/or donor bone marrow on lymphopoietic repopulation, tolerance, and graft-vs-host disease in mixed allogeneic chimeras (B10 + B10. D2----B10)

    SciTech Connect

    Ildstad, S.T.; Wren, S.M.; Bluestone, J.A.; Barbieri, S.A.; Stephany, D.; Sachs, D.H.

    1986-01-01

    Reconstitution of lethally irradiated mice with a mixture of T cell-depleted syngeneic plus T cell-depleted allogeneic bone marrow (B10 + B10.D2----B10) leads to the induction of mixed lymphopoietic chimerism, excellent survivals, specific in vivo transplantation tolerance to subsequent donor strain skin grafts, and specific in vitro unresponsiveness to allogeneic donor lymphoid elements as assessed by mixed lymphocyte reaction (MLR) proliferative and cell-mediated lympholysis (CML) cytotoxicity assays. When B10 recipient mice received mixed marrow inocula in which the syngeneic component had not been T cell depleted, whether or not the allogeneic donor marrow was treated, they repopulated exclusively with host-type cells, promptly rejected donor-type skin allografts, and were reactive in vitro to the allogeneic donor by CML and MLR assays. In contrast, T cell depletion of the syngeneic component of the mixed marrow inocula resulted in specific acceptance of allogeneic donor strain skin grafts. Such animals were specifically unreactive to allogeneic donor lymphoid elements in vitro by CML and MLR, but were reactive to third party. When both the syngeneic and allogeneic marrow were T cell depleted, variable percentages of host- and donor-type lymphoid elements were detected in the mixed reconstituted host. When only the syngeneic bone marrow was T cell depleted, animals repopulated exclusively with donor-type cells. Although these animals had detectable in vitro anti-host (B10) reactivity by CML and MLR and reconstituted as fully allogeneic chimeras, they exhibited excellent survival and had no in vivo evidence for graft-vs-host disease. Experiments in which untreated donor spleen cells were added to the inocula in this last group suggest that the presence of T cell-depleted syngeneic bone marrow cells diminishes graft-vs-host disease and the mortality from it.

  13. The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure

    PubMed Central

    Bray, Robert; Rosen-Bronson, Sandra; Haagenson, Michael; Klein, John; Flesch, Susan; Vierra-Green, Cynthia; Anasetti, Claudio

    2010-01-01

    Donor-directed human leukocyte antigen (HLA)–specific allo-antibodies (DSAs) cause graft failure in animal models of hematopoietic stem cell transplantation (HCT). Archived pretransplantation sera from graft failure patients (n = 37) and a matched case-control cohort (n = 78) were tested to evaluate the role of DSAs in unrelated donor HCT. Controls were matched for disease, disease status, graft type, patient age, and transplantation year. Patients had acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome; 98% received myeloablative conditioning regimens 100% received T-replete grafts, 97% received marrow, 95% HLA-mismatched, and 97% received calcineurin-based graft-versus-host disease prophylaxis. Among the 37 failed transplantations, 9 (24%) recipients possessed DSAs against HLA-A, B, and/or DP, compared with only 1 (1%) of 78 controls. Therefore, the presence of DSAs was significantly associated with graft failure (odds ratio = 22.84; 95% confidence interval, 3.57-∞; P < .001). These results indicate that the presence of pretransplantation DSAs in recipients of unrelated donor HCT is associated with failed engraftment and should be considered in HCT donor selection. PMID:20089963

  14. Further progress in the induction of allogeneic unresponsiveness in the adult host

    SciTech Connect

    Rapaport, F.T.; Bachvaroff, R.J.; Waltzer, W.C.; Sato, T.; Asari, H.; Chanana, A.D.; Cronkite, E.P.

    1982-09-01

    At present, the state of allogeneic unresponsiveness produced in adult dogs by total body irradiation (TBI) and autologous bone marrow transplantation (ABMT), followed by host exposure to a renal allograft appears to be specific for the kidney donor; it exhibits a degree of organ specificity and appears to be mediated by the retransplanted marrow stem cells. The successful induction of unresponsiveness requires at least one cycle of cell generation in the microenvironment of the irradiated host. One new approach to boosting unresponsiveness involves the exposure of the circulating blood cells of the recipient to extracorporeal irradiation. Neck vessels of dogs were exposed, through an arterio-venous shunt, to radioactive cesium for a cumulative dose of 22-40 thousand rads over 4-5 weeks. Following TBI, ABMT and renal allograft, bilateral nephrectomy was performed. Eight of ten animals thus treated have remained unresponsive to their renal allografts for more than 250 days. Other approaches are also described. (JMT)

  15. Donor origin of circulating endothelial progenitors after allogeneic bone marrow transplantation.

    PubMed

    Ikpeazu, C; Davidson, M K; Halteman, D; Browning, P J; Brandt, S J

    2000-01-01

    Endothelial cell precursors circulate in blood and express antigens found on hematopoietic stem cells, suggesting that such precursors might be subject to transplantation. To investigate, we obtained adherence-depleted peripheral blood mononuclear cells from 3 individuals who had received a sex-mismatched allogeneic bone marrow transplant (BMT) and cultured the cells on fibronectin-coated plates with endothelial growth factors. The phenotype of the spindle-shaped cells that emerged in culture was characterized by immunofluorescent staining, and the origin of the cells was determined using a polymerase chain reaction (PCR)-based assay for polymorphic short tandem repeats (STRs). The cells manifested a number of endothelial characteristics-such as von Wlllebrand factor, CD31, and Flk-1/KDR expression; Bandeiraea simplicifolia lectin 1 binding; and acetylated low-density lipoprotein uptake-but lacked expression of certain markers of activation or differentiation, including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and the epitope for the anti-endothelial cell antibody P1H12. For each patient and at all time points studied (ranging from 5 to 52 months after transplantation), STR-PCR analysis showed that cultured cells and nucleated blood cells came exclusively from the bone marrow donor. These results demonstrate that circulating endothelial progenitors are both transplantable and capable of long-term repopulation of human allogeneic BMT recipients. PMID:10905767

  16. Venous Thromboembolism after Allogeneic Pediatric Hematopoietic Stem Cell Transplantation: A Single-Center Study

    PubMed Central

    Azık, Fatih; Gürlek Gökçebay, Dilek; Tavil, Betül; Işık, Pamir; Tunç, Bahattin; Uçkan, Duygu

    2015-01-01

    Objective: Venous thromboembolism (VTE) in children who undergo hematopoietic stem cell transplantation (HSCT) has high morbidity. The aim of this study is to assess the incidence of VTE in allogeneic pediatric HSCT recipients and the contribution of pretransplant prothrombotic risk factors to thrombosis. Materials and Methods: We retrospectively evaluated 92 patients between April 2010 and November 2012 undergoing allogeneic HSCT who had completed 100 days post-HSCT. Before HSCT, coagulation profiles; acquired and inherited prothrombotic risk factors including FV G1691A (factor V Leiden), prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations; and serum homocysteine and lipoprotein (a), plasma antithrombin III, protein C, and protein S levels were obtained from all patients. Results: In the screening of thrombophilia, 8 patients (9%) were heterozygous for factor V Leiden, 5 (6%) were homozygous for MTHFR 677TT, 12 (14%) were homozygous for MTHFR 1298CC, and 2 (2%) were heterozygous for prothrombin G20210A mutation. We observed VTE in 5 patients (5.4%); a prothrombotic risk factor was found in 3 out of these 5 patients, while 4 out of 5 patients had central venous catheters. It was determined there was no significant relationship between VTE and inherited prothrombotic risk factors. Conclusion: VTE after HSCT seems to be a low-frequency event that may be due to low-dose, low-molecular-weight heparin prophylaxis, and the role of inherited prothrombotic risk factors cannot be entirely excluded without a prospective study. PMID:25912774

  17. Pristimerin inhibits proliferation, migration and invasion, and induces apoptosis in HCT-116 colorectal cancer cells.

    PubMed

    Yousef, Bashir A; Hassan, Hozeifa M; Guerram, Mounia; Hamdi, Aida M; Wang, Bin; Zhang, Lu-Yong; Jiang, Zhen-Zhou

    2016-04-01

    Colorectal cancer (CRC) is one of the world's most common cancers with a high mortality rate mainly due to metastasis. Our previous study showed that pristimerin had potent antitumor activities against human CRC cells. In the present study, we further evaluated pristimerin anti-tumor and anti-metastatic properties. MTT assay, Hoechst staining, Annexin V/PI double staining, reactive oxygen species (ROS) measurements were used to assess pristimerin cytotoxicity and apoptotic-inducing effects on HCT-116 cells. Wound healing assay and Transwell assay were used to estimate pristimerin anti-migration and anti-invasion activities on CRC cells. Meanwhile, HCT-116 xenograft model applied for investigating in vivo antitumor activities. Our results showed that pristimerin mediated in vitro HCT-116 cell death, through generation of intracellular ROS and apoptosis induction. Tumor volumes and weights measurements, pathological analysis and Tunnel assay proved that pristimerin inhibited in vivo HCT-116 xenografts growth. Pristimerin was also able to limit CRC invasion and metastasis. It caused downregulation of PI3K/AKT/mTOR pathway and its subsequent downstream p70S6K and E4-BP1 proteins. Collectively, pristimerin exerted both in vitro and in vivo cytotoxic and anti-metastatic effects on HCT-116 cells, suggesting that pristimerin has potential as a new anticancer drug for treatment of colon cancer. PMID:27044819

  18. Factors affecting the outcome of related allogeneic hematopoietic cell transplantation in patients with Fanconi Anemia.

    PubMed

    Ayas, Mouhab; Siddiqui, Khawar; Al-Jefri, Abdullah; El-Solh, Hassan; Al-Ahmari, Ali; Khairy, Ashraf; Markiz, Samer; Shahin, Hasan; Al-Musa, Abdulrahman; Al-Seraihy, Amal

    2014-10-01

    Hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi Anemia (FA), and it is generally accepted that these patients should receive low-intensity conditioning because of the underlying DNA repair defect in their cells. Outcomes for recipients of matched related HCT have generally been favorable, but only a few studies have scrutinized the factors that may affect the eventual outcome of these patients. This retrospective analysis of 94 pediatric patients with FA who underwent related HCT at King Faisal Specialist Hospital & Research Center was carried out to attempt to identify factors that may affect outcome. Results showed overall survival (OS) probabilities of 92.5%, 89%, and 86% at 1, 5, and 10 years, respectively. In univariate analysis, use of higher dose cyclophosphamide (CY) (60 mg/kg) conditioning was associated with a better 10-year OS than lower dose CY (20 mg/kg) conditioning (91% versus 82%, respectively; P = .035), and use of radiation-containing regimens was associated with a significantly lower 10-year OS than nonradiation regimens (76% versus 91%, respectively; P = .005). Of the 4 regimens used in this study, the fludarabine-based regimen was associated with the highest survival (95.2%; P = .034). The use of the higher dose CY (60 mg/kg) was associated with a significantly increased incidence of hemorrhagic cystitis (HC) (20% versus 5.6% respectively; P = .049). Three patients (3%) developed squamous cell carcinoma (2 oropharyngeal and 1 genitourinary), at 9.4, 5.4, and 13.3 years after HCT; 2 of them had radiation-containing conditioning. In conclusion, our data suggest that although using a higher dose CY (60 mg/kg) conditioning regimen may be associated with better survival, it is also associated with a significantly increased risk of HC. The addition of fludarabine to the low-dose CY (20 mg/kg) is associated with the best survival. On the other hand, radiation-containing regimens are associated with

  19. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH).

    PubMed

    Koç, O N; Day, J; Nieder, M; Gerson, S L; Lazarus, H M; Krivit, W

    2002-08-01

    Patients with Hurler syndrome (mucopolysaccharidosis type-IH) and metachromatic leukodystrophy (MLD) develop significant skeletal and neurologic defects that limit their survival. Transplantation of allogeneic hematopoietic stem cells results in partial correction of the clinical manifestations. We postulated that some of these defects may be corrected by infusion of allogeneic, multipotential, bone marrow-derived mesenchymal stem cells (MSC). Patients with Hurler syndrome (n = 5) or MLD (n = 6) who previously underwent successful bone marrow transplantation from an HLA-identical sibling were infused with 2-10 x 10(6)/kg MSCs, isolated and expanded from a bone marrow aspirate of the original donor. There was no infusion-related toxicity. In most recipients culture-purified MSCs at 2 days, 30-60 days and 6-24 months after MSC infusion remained of host type. In two patients the bone marrow-derived MSCs contained 0.4 and 2% donor MSCs by FISH 60 days after MSC infusion. In four patients with MLD there were significant improvements in nerve conduction velocities after MSC infusion. The bone mineral density was either maintained or slightly improved in all patients. There was no clinically apparent change in patients' overall health, mental and physical development after MSC infusion. We conclude that donor allogeneic MSC infusion is safe and may be associated with reversal of disease pathophysiology in some tissues. The role of MSCs in the management of Hurler syndrome and MLD should be further evaluated. PMID:12203137

  20. Influence of Previous Inflammatory Bowel Disease on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation: A Matched-Pair Analysis.

    PubMed

    Rabian, Florence; Porcher, Raphael; Sicre de Fontbrune, Flore; Lioure, Bruno; Laplace, Anne; Nguyen, Stephanie; Tabrizi, Reza; Vigouroux, Stephane; Tomowiak, Cécile; Maillard, Nathalie; Suarez, Felipe; Delage, Jeremy; Peffault de Latour, Régis; Socié, Gérard

    2016-09-01

    The idiopathic inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis are associated with increased risk of hematologic malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) could be a curative strategy in this setting, but has been thought to be associated with increased nonrelapse mortality (NRM). We conducted a national French retrospective analysis of patients with IBD who underwent allogeneic HSCT for hematologic malignancies and were matched with 3 controls according to recipient, donor, and transplant characteristics. Between 2004 and 2015, 18 patients with IBD underwent allogeneic HSCT. With a median follow-up of 33 months for the patients with IBD and 57 months for controls, the cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 39% for the patients with IBD and 40% for controls (hazard ratio [HR], 1.10; P = .82). The cumulative incidence of chronic GVHD at 48 months was 52% for the patients with IBD and 43% for controls (HR, 0.92; P = .89). Nonrelapse mortality at 48 months was 19% for the patients with IBD and 11% for controls (HR, 4.93; P = .067). Overall survival at 48 months was 59% for the patients with IBD and 60% for matched controls (HR, 1.35; P = .56). In conclusion, IBD should not be considered a contraindication for transplantation, and its impact on comorbidity indexes should be reduced. PMID:27246370

  1. Graft rejection by cytolytic T cells. Specificity of the effector mechanism in the rejection of allogeneic marrow

    SciTech Connect

    Nakamura, H.; Gress, R.E. )

    1990-02-01

    Cellular effector mechanisms of allograft rejection remain incompletely described. Characterizing the rejection of foreign-marrow allografts rather than solid-organ grafts has the advantage that the cellular composition of the marrow graft, as a single cell suspension, can be altered to include cellular components with differing antigen expression. Rejection of marrow grafts is sensitive to lethal doses of radiation in the mouse but resistant to sublethal levels of radiation. In an effort to identify cells mediating host resistance, lymphocytes were isolated and cloned from spleens of mice 7 days after sublethal TBI (650 cGy) and inoculation with allogeneic marrow. All clones isolated were cytolytic with specificity for MHC encoded gene products of the allogeneic marrow donor. When cloned cells were transferred in vivo into lethally irradiated (1025 cGy) recipients unable to reject allogeneic marrow, results utilizing splenic 125IUdR uptake indicated that these MHC-specific cytotoxic clones could suppress marrow proliferation. In order to characterize the effector mechanism and the ability of the clones to affect final engraftment, double donor chimeras were constructed so that 2 target cell populations differing at the MHC from each other and from the host were present in the same marrow allograft. Results directly demonstrated an ability of CTL of host MHC type to mediate graft rejection and characterized the effector mechanism as one with specificity for MHC gene products.

  2. Low CD34 Dose is Associated with Poor Survival after Reduced Intensity Conditioning Allogeneic Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome

    PubMed Central

    Törlén, Johan; Ringdén, Olle; Le Rademacher, Jennifer; Batiwalla, Minoo; Chen, Junfang; Erkers, Tom; Ho, Vincent; Kebriaei, Partow; Keever-Taylor, Carolyn; Kindwall-Keller, Tamila; Lazarus, Hillard M.; Laughlin, Mary J.; Lill, Michael; O’Brien, Tracey; Perales, Miguel-Angel; Rocha, Vanderson; Savani, Bipin N.; Szwajcer, David; Valcarcel, David; Eapen, Mary

    2014-01-01

    Reduced intensity conditioning/non-myeloablative conditioning regimens are increasingly used in allogeneic hematopoietic cell transplantation (HCT). Reports have shown CD34+ dose to be important for transplant-outcome using myeloablative conditioning. The role of CD34+ dose of peripheral blood progenitor cells (PBPC) has not been previously analyzed in a large population undergoing reduced intensity conditioning/non-myeloablative HCT. We studied 1,054 patients aged 45–75 years, with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) transplanted between 2002 and 2011. Results of multivariate analysis showed that PBPC from HLA-matched siblings containing <4 × 106 CD34+/kg were associated with higher non-relapse mortality (HR 2.03, p=0.001), overall mortality (HR 1.48, p=0.008), and lower neutrophil (OR 0.76, p=0.03) and platelet (OR 0.76, p=0.03) recovery. PBPC from unrelated donors with CD34+ dose <6 × 106 CD34+/kg were also associated with higher non-relapse (HR 1.38, p=0.02) and overall mortality (HR 1.20, p=0.05). In contrast to reports after myeloablative HCT, CD34+ dose did not affect relapse or graft-versus-host disease with either donor type. An upper cell dose limit was not associated with adverse outcomes. These data suggest that PBPC CD34+ dose >4 × 106 CD34+/kg and >6 × 106 CD34+/kg are optimal for HLA-matched sibling and unrelated donor HCT, respectively. PMID:24892261

  3. Thymus and immune reconstitution after allogeneic hematopoietic stem cell transplantation in humans: never say never again.

    PubMed

    Toubert, A; Glauzy, S; Douay, C; Clave, E

    2012-02-01

    Assessment of the host immune status is becoming a key issue in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the long-term follow-up of these patients, severe post-transplant infections, relapse or secondary malignancies may be directly related to persistent immune defects. In allo-HSCT, T-cell differentiation of donor progenitors within the recipient thymus is required to generate naive recent T-cell emigrants (RTE). These cells account for a durable T-cell reconstitution, generating a diverse T-cell receptor (TCR) repertoire and robust response to infections. It is now possible to quantify the production of RTE by measuring thymic T-cell receptor excision circles or 'TREC' which are small circular DNA produced during the recombination of the genomic segments encoding the TCR alpha chain. Here we discuss the role of thymic function in allo-HSCT. The pre-transplant recipient thymic function correlates with clinical outcome in terms of survival and occurrence of severe infections. Post-transplant, TREC analysis showed that the thymus is a sensitive target to the allogeneic acute graft-versus-host disease (GvHD) reaction but is also prone to recovery in young adult patients. In all, thymus is a key player for the quality of immune reconstitution and clinical outcome after allo-HSCT. Thymic tissue is plastic and it is a future challenge to halt or reverse thymic GVHD therapeutically by acting at the level of T-cell progenitors generation, thymic homing and/or epithelial thymic tissue preservation. PMID:22220718

  4. Naive Donor NK Cell Repertoires Associated with Less Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Björklund, Andreas T; Clancy, Trevor; Goodridge, Jodie P; Béziat, Vivien; Schaffer, Marie; Hovig, Eivind; Ljunggren, Hans-Gustaf; Ljungman, Per T; Malmberg, Karl-Johan

    2016-02-01

    Acute and latent human CMV cause profound changes in the NK cell repertoire, with expansion and differentiation of educated NK cells expressing self-specific inhibitory killer cell Ig-like receptors. In this study, we addressed whether such CMV-induced imprints on the donor NK cell repertoire influenced the outcome of allogeneic stem cell transplantation. Hierarchical clustering of high-resolution immunophenotyping data covering key NK cell parameters, including frequencies of CD56(bright), NKG2A(+), NKG2C(+), and CD57(+) NK cell subsets, as well as the size of the educated NK cell subset, was linked to clinical outcomes. Clusters defining naive (NKG2A(+)CD57(-)NKG2C(-)) NK cell repertoires in the donor were associated with decreased risk for relapse in recipients with acute myeloid leukemia and myelodysplastic syndrome (hazard ratio [HR], 0.09; 95% confidence interval [CI]: 0.03-0.27; p < 0.001). Furthermore, recipients with naive repertoires at 9-12 mo after hematopoietic stem cell transplantation had increased disease-free survival (HR, 7.2; 95% CI: 1.6-33; p = 0.01) and increased overall survival (HR, 9.3; 95% CI: 1.1-77, p = 0.04). Conversely, patients with a relative increase in differentiated NK cells at 9-12 mo displayed a higher rate of late relapses (HR, 8.41; 95% CI: 6.7-11; p = 0.02), reduced disease-free survival (HR, 0.12; 95% CI: 0.12-0.74; p = 0.02), and reduced overall survival (HR, 0.07; 95% CI: 0.01-0.69; p = 0.02). Thus, our data suggest that naive donor NK cell repertoires are associated with protection against leukemia relapse after allogeneic HSCT. PMID:26746188

  5. Sleep Disruption in Hematopoietic Cell Transplant Recipients: Prevalence, Severity, and Clinical Management

    PubMed Central

    Jim, Heather S.L.; Evans, Bryan; Jeong, Jiyeon M.; Gonzalez, Brian D.; Johnston, Laura; Nelson, Ashley M.; Kesler, Shelli; Phillips, Kristin M.; Barata, Anna; Pidala, Joseph; Palesh, Oxana

    2014-01-01

    Sleep disruption is common among hematopoietic cell transplant (HCT) recipients, with over 50% of patients experiencing sleep disruption pre-transplant, up to 82% experiencing moderate to severe sleep disruption during hospitalization for transplant, and up to 43% in the post-transplant period. These rates of sleep disruption are substantially higher than the general population. Although sleep disruption can be distressing to patients and contribute to diminished quality of life, it is rarely discussed during clinical visits. The goal of the current review is to draw attention to sleep disruption as a clinical problem in HCT in order to facilitate patient education, intervention, and research. The review opens with a discussion of sleep disruption measurement and clinical diagnosis of sleep disorders. An overview of the prevalence, severity, and chronicity of sleep disruption and disorders in patients receiving HCT follows. Current evidence regarding sociodemographic and clinical predictors of sleep disruption and disorders is summarized. The review concludes with suggestions for behavioral and pharmacologic management of sleep disruption and disorders as well as directions for future research. PMID:24747335

  6. Second solid cancers after allogeneic hematopoietic cell transplantation using reduced intensity conditioning

    PubMed Central

    Ringdén, Olle; Brazauskas, Ruta; Wang, Zhiwei; Ahmed, Ibrahim; Atsuta, Yoshiko; Buchbinder, David; Burns, Linda J.; Cahn, Jean-Yves; Duncan, Christine; Hale, Gregory A.; Halter, Joerg; Hayashi, Robert J.; Hsu, Jack W.; Jacobsohn, David A.; Kamble, Rammurti T.; Kamani, Naynesh R.; Kasow, Kimberly A.; Khera, Nandita; Lazarus, Hillard M.; Loren, Alison W.; Marks, David I.; Myers, Kasiani C.; Ramanathan, Muthalagu; Saber, Wael; Savani, Bipin N.; Schouten, Harry C.; Socie, Gérard; Sorror, Mohamed L.; Steinberg, Amir; Popat, Uday; Wingard, John R.; Mattsson, Jonas; Majhail, Navneet S.

    2014-01-01

    We examined risk of second solid cancers after allogeneic hematopoietic cell transplantation (AHCT) using reduced intensity/non-myeloablative conditioning (RIC/NMC). RIC/NMC recipients with leukemia/myelodysplastic syndrome (MDS) (n=2833) and lymphoma (n=1436) between 1995–2006 were included. In addition, RIC/NMC recipients 40–60 years of age (n=2138) were compared with patients of the same age receiving myeloablative conditioning (MAC, n=6428). The cumulative incidence of solid cancers was 3.35% at 10-years. There was no increase in overall cancer risk compared to the general population (standardized incidence ratio [SIR] 0.99, P=1.00 for leukemia/MDS and 0.92, P=0.75 for lymphoma). However, risks were significantly increased in leukemia/MDS patients for cancers of lip (SIR 14.28), tonsil (SIR 8.66), oropharynx (SIR 46.70), bone (SIR 23.53), soft tissue (SIR 12.92), and vulva (SIR 18.55) and skin melanoma (SIR 3.04). Lymphoma patients had significantly higher risks of oropharyngeal cancer (SIR 67.35) and skin melanoma (SIR 3.52). Among RIC/NMC recipients, age >50 years was the only independent risk factor for solid cancers (hazard ratio [HR] 3.02, P<0.001). Among patients age 40–60 years, when adjusted for other factors, there was no difference in cancer risks between RIC/NMC and MAC in leukemia/MDS patients (HR 0.98, P=0.905). In lymphoma patients, risks were lower after RIC/NMC (HR 0.51, P=0.047). In conclusion, the overall risks of second solid cancers in RIC/NMC recipients are similar to the general population, although there is an increased risk of cancer at some sites. Studies with longer follow-up are needed to realize the complete risks of solid cancers after RIC/NMC AHCT. PMID:25042734

  7. MicroRNAs as biomarkers for graft-versus-host disease following allogeneic stem cell transplantation.

    PubMed

    Tomuleasa, Ciprian; Fuji, Shigeo; Cucuianu, Andrei; Kapp, Markus; Pileczki, Valentina; Petrushev, Bobe; Selicean, Sonia; Tanase, Alina; Dima, Delia; Berindan-Neagoe, Ioana; Irimie, Alexandru; Einsele, Hermann

    2015-07-01

    Allogeneic hematopoietic stem cell transplantation (HCT) is a well-established treatment for many malignant and non-malignant hematological disorders. As frequent complication in up to 50 % of all patients, graft-versus-host disease (GVHD) is still the main cause for morbidity and non-relapse mortality. Diagnosis of GVHD is usually done clinically, even though confirmation by pathology is often used to support the clinical findings. Effective treatment requires intensified immunosuppression as early as possible. Although several promising biomarkers have been proposed for an early diagnosis, no internationally recognized consensus has yet been established. Here, microRNAs (miRs) represent an interesting tool since miRs have been recently reported to be an important regulator of various cells, including immune cells such as T cells. Therefore, we could assume that miRs play a key role in the pathogenesis of acute GVHD, and their detection might be an interesting possibility in the early diagnosis and monitoring of acute GVHD. Recent studies additionally demonstrated the implication of miRs in the pathogenesis of acute GVHD. In this review, we aim to summarize the previous reports of miRs, focusing on the pathogenesis of acute GVHD and possible implications in diagnostic approaches. PMID:25900787

  8. Carnosine inhibits KRAS-mediated HCT116 proliferation by affecting ATP and ROS production.

    PubMed

    Iovine, Barbara; Iannella, Maria Luigia; Nocella, Francesca; Pricolo, Maria Rosaria; Bevilacqua, Maria Assunta

    2012-02-28

    Carnosine is a natural dipeptide that has generated particular interest for its antioxidant, anti-aging and especially for its antiproliferative properties. In this study, we demonstrate that carnosine inhibits the proliferation of human HCT116 colon cancer cells. In this cell line, the activating KRAS mutation induces mitochondrial ROS, the signaling molecules for cell proliferation. We observed that 50-100 mM carnosine decreases ATP and ROS concentration and induces cell cycle arrest in G1 phase. In HCT116 cells these effects are related to decreased ERK1/2 phosphorylation and increased p21waf1 protein. Our findings support the concept that carnosine could inhibit HCT116 cell growth via its antioxidant activity and its ability to affect glycolysis. PMID:22137144

  9. The Prevalence of Antifungal Agents Administration in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Study

    PubMed Central

    Kargar, Mona; Ahmadvand, Alireza; Ahmadvand, Milad; Hadjibabaie, Molouk; Gholami, Kheirollah; Khoee, Seyed Hamid; Javadi, Mohammad Reza; Ghavamzadeh, Ardeshir

    2013-01-01

    Background Invasive fungal infections (IFIs) are chief infectious complications in patients undergoing hematopoietic stem cell transplantation (HSCT). However, the diagnosis of fungal infections is difficult, and often empiric treatment initiates. Since there is no data available on the prevalence of antifungal drugs administration in allogeneic HSCT recipients in Iran, we decided to conduct this study. Methods This study was a retrospective review of records of patients who received allogeneic HSCT in the Hematology-Oncology, Bone Marrow Transplantation center at Shariati Hospital in Tehran, between August 2009 and August 2010. Results Sixty (73.1%) patients consist of 41 men (68.3%) with mean age of 26.3 (± 1.2) years received allogeneic HSCT. Patients received prophylaxis with fulconazole however; in 28 patients (46.7%) it was switched to low dose amphotericin B. Fifteen patients (25%) received treatment with antifungal agents. Amphotericin B was the empiric agent administered. In 3 patients treatment was switched to voriconazole. Neither positive culture nor direct microscopic evidence was available from the obtained specimen. Only in one patient the result of serum galactomannan assay was positive. There were no significant differences in neutropenia duration (P value: 0.54), length of hospital stay (P value: 0.27) and number of patients developed graft versus host disease (P value: 0.07) between patients received antifungal agents with those who did not receive treatment. Conclusion In this study HSCT recipients received antifungal agents for prophylaxis. Twenty five percent of patients received treatment with antifungal agents empirically. Improvement in diagnosis of these infections can be helpful and lead to targeted therapy. We suggest larger prospective trials for better assessment of antifungal agent administration. PMID:24505528

  10. Programming of donor T cells using allogeneic δ-like ligand 4-positive dendritic cells to reduce GVHD in mice.

    PubMed

    Mochizuki, Kazuhiro; Meng, Lijun; Mochizuki, Izumi; Tong, Qing; He, Shan; Liu, Yongnian; Purushe, Janaki; Fung, Henry; Zaidi, M Raza; Zhang, Yanyun; Reshef, Ran; Blazar, Bruce R; Yagita, Hideo; Mineishi, Shin; Zhang, Yi

    2016-06-23

    Alloreactive T cells play a critical role in eliminating hematopoietic malignant cells but are also the mediators of graft-versus-host disease (GVHD), a major complication that subverts the success of allogeneic hematopoietic stem cell transplantation (HSCT). However, induction of alloreactive T cells does not necessarily lead to GVHD. Here we report the development of a cellular programming approach to render alloreactive T cells incapable of causing severe GVHD in both major histocompatibility complex (MHC)-mismatched and MHC-identical but minor histocompatibility antigen-mismatched mouse models. We established a novel platform that produced δ-like ligand 4-positive dendritic cells (Dll4(hi)DCs) from murine bone marrow using Flt3 ligand and Toll-like receptor agonists. Upon allogeneic Dll4(hi)DC stimulation, CD4(+) naïve T cells underwent effector differentiation and produced high levels of interferon γ (IFN-γ) and interleukin-17 in vitro, depending on Dll4 activation of Notch signaling. Following transfer, allogeneic Dll4(hi)DC-induced T cells were unable to mediate severe GVHD but preserved antileukemic activity, significantly improving the survival of leukemic mice undergoing allogeneic HSCT. This effect of Dll4(hi)DC-induced T cells was associated with their impaired expansion in GVHD target tissues. IFN-γ was important for Dll4(hi)DC programming to reduce GVHD toxicities of alloreactive T cells. Absence of T-cell IFN-γ led to improved survival and expansion of Dll4(hi)DC-induced CD4(+) T cells in transplant recipients and caused lethal GVHD. Our findings demonstrate that Dll4(hi)DC programming can overcome GVHD toxicity of donor T cells and produce leukemia-reactive T cells for effective immunotherapy. PMID:27143255

  11. ALLOGENEIC NATURAL KILLER CELLS FOR REFRACTORY LYMPHOMA

    PubMed Central

    Bachanova, Veronika; Burns, Linda J.; McKenna, David H.; Curtsinger, Julie; Panoskaltsis-Mortari, Angela; Lindgren, Bruce R.; Cooley, Sarah; Weisdorf, Daniel; Miller, Jeffrey S.

    2014-01-01

    We reported that IL-2 activated autologous NK cells can induce, but not maintain durable remissions in lymphoma patients. We hypothesized that allogeneic NK cells may overcome class I MHC-mediated inhibition of NK cell killing. In a pilot study we evaluated infusion of haploidentical donor NK cells for anti-tumor efficacy. Six patients with advanced B-cell non-Hodgkin lymphoma (NHL) received rituximab, cyclophosphamide, and fludarabine as immunosupression to permit homeostatic NK cell expansion, followed by CD3-depleted NK cell enriched cell products followed by subcutaneous IL-2 administration (10×106 units every other day × 6 doses). At 2 months, four patients showed an objective clinical response. We observed early donor cell persistence in 2 patients (blood and in tumor-bearing node), but this was not detectable beyond 7 days. All patients demonstrated substantial increases in host regulatory T cells (Treg) after NK cell and IL-2 therapy (180±80 cells/μl vs baseline: 58±24 cells/μl, p=0.04) which may have limited donor cell expansion in vivo. These findings suggest safety and feasibility of allogeneic NK cell therapy in patients with lymphoma; however host Treg and inadequate immunodepletion may contribute to a hostile milieu for NK cell survival and expansion. Cell therapy trials should incorporate novel strategies to limit Treg expansion. PMID:20680271

  12. 21 CFR 1271.265 - Receipt, predistribution shipment, and distribution of an HCT/P.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Current Good Tissue... and tracking records pertaining to the HCT/P, and, on the basis of that record review, you must...

  13. 21 CFR 1271.265 - Receipt, predistribution shipment, and distribution of an HCT/P.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Current Good Tissue... and tracking records pertaining to the HCT/P, and, on the basis of that record review, you must...

  14. Primary Graft Failure after Myeloablative Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies

    PubMed Central

    Olsson, Richard F.; Logan, Brent R.; Chaudhury, Sonali; Zhu, Xiaochun; Akpek, Görgün; Bolwell, Brian J.; Bredeson, Christopher N.; Dvorak, Christopher C.; Gupta, Vikas; Ho, Vincent T.; Lazarus, Hillard M.; Marks, David I.; Ringdén, Olle T.H.; Pasquini, Marcelo C.; Schriber, Jeffrey R.; Cooke, Kenneth R.

    2015-01-01

    Clinical outcomes after primary graft failure (PGF) remain poor. Here we present a large retrospective analysis (n=23,272) which investigates means to prevent PGF and early detection of patients at high risk. In patients with hematologic malignancies, who underwent their first myeloablative allogeneic hematopoietic cell transplantation, PGF was reported in 1,278 (5.5%), and there was a marked difference in PGFs using peripheral blood stem cell compared to bone marrow grafts (2.5 vs. 7.3%; P<0.001). A 4-fold increase of PGF was observed in myeloproliferative disorders compared to acute leukemia (P<0.001). Other risk factors for PGF included recipient age below 30, HLA-mismatch, male recipients of female donor grafts, ABO-incompatibility, busulfan/cyclophosphamide conditioning, and cryopreservation. In bone marrow transplants, total nucleated cell doses ≤2.4 × 108/kg were associated with PGF (OR 1.39; P<0.001). The use of tacrolimus-based immunosuppression and granulocyte colony-stimulating factor were associated with decreased PGF risk. These data, allow clinicians to do more informed choices with respect to graft source, donor selection, conditioning and immunosuppressive regimens to reduce the risk of PGF. Moreover, a novel risk score determined on day 21 post-transplant may provide the rationale for an early request for additional hematopoietic stem cells. PMID:25772027

  15. Antibody-Functionalized Peptidic Membranes for Neutralization of Allogeneic Skin Antigen-Presenting Cells

    PubMed Central

    Wen, Yi; Liu, Wen; Bagia, Christina; Zhang, Shaojuan; Bai, Mingfeng; Janjic, Jelena M.; Giannoukakis, Nick; Gawalt, Ellen S.; Meng, Wilson S.

    2014-01-01

    We report herein application of an in situ material strategy to attenuate allograft T cell responses in a skin transplant mouse model. Functionalized peptidic membranes were used to impede trafficking of donor antigen-presenting cells (dAPCs) from skin allografts in recipient mice. Membranes formed by self-assembling peptides (SAPs) presenting antibodies were found to remain underneath grafted skins for up to 6 days. At the host-graft interface, dAPCs were targeted by using a monoclonal antibody that binds to a class II MHC molecule (IAd) expressed exclusively by donor cells. Using a novel cell labeling near-infrared nanoemulsion, we found more dAPCs remained in allografts treated with membranes loaded with aI-Ad than without. In vitro, dAPCs released from skin explants were found adsorbed preferentially on aI-Ad membranes. Recipient T cells from these mice produced lower concentrations of interferon-gamma cultured ex vivo with donor cells. Taken together, the data indicate that the strategy has the potential to alter the natural course of rejection immune mechanisms in stringent allogeneic models. PMID:25117952

  16. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Jenq, Robert R.; Perales, Miguel-Angel; Littmann, Eric R.; Morjaria, Sejal; Ling, Lilan; No, Daniel; Gobourne, Asia; Viale, Agnes; Dahi, Parastoo B.; Ponce, Doris M.; Barker, Juliet N.; Giralt, Sergio; van den Brink, Marcel; Pamer, Eric G.

    2014-01-01

    Highly diverse bacterial populations inhabit the gastrointestinal tract and modulate host inflammation and promote immune tolerance. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the gastrointestinal mucosa is damaged, and colonizing bacteria are impacted, leading to an impaired intestinal microbiota with reduced diversity. We examined the impact of intestinal diversity on subsequent mortality outcomes following transplantation. Fecal specimens were collected from 80 recipients of allo-HSCT at the time of stem cell engraftment. Bacterial 16S rRNA gene sequences were characterized, and microbial diversity was estimated using the inverse Simpson index. Subjects were classified into high, intermediate, and low diversity groups and assessed for differences in outcomes. Mortality outcomes were significantly worse in patients with lower intestinal diversity; overall survival at 3 years was 36%, 60%, and 67% for low, intermediate, and high diversity groups, respectively (P = .019, log-rank test). Low diversity showed a strong effect on mortality after multivariate adjustment for other clinical predictors (transplant related mortality: adjusted hazard ratio, 5.25; P = .014). In conclusion, the diversity of the intestinal microbiota at engraftment is an independent predictor of mortality in allo-HSCT recipients. These results indicate that the intestinal microbiota may be an important factor in the success or failure in allo-HSCT. PMID:24939656

  17. Serum citrulline as a biomarker of gastrointestinal function during hematopoietic cell transplantation (HCT) in children

    PubMed Central

    Gosselin, Kerri B.; Feldman, Henry A.; Sonis, Andrew L.; Bechard, Lori J.; Kellogg, Mark D.; Gura, Kathleen; Venick, Robert; Gordon, Catherine M.; Guinan, Eva C.; Duggan, Christopher

    2014-01-01

    Objective We sought to determine if serum citrulline (CIT), an amino acid produced by small bowel enterocytes, was associated with clinical and biochemical markers of gastrointestinal function in children undergoing hematopoietic cell transplantation (HCT). Methods We conducted a multi-center, prospective cohort study of 26 children to define time-related changes in serum CIT over the course of HCT. Markers of gastrointestinal function including oral energy intake, emesis, stool volume, presence of graft-versus-host disease (GVHD), oral mucositis severity, and cytokine and neurohormone levels were measured. Weekly serum CIT concentrations were obtained from 10 days prior until 30 days after HCT. Results Mean baseline CIT concentration was 22.7 µmol/L (95% CI 17.7 – 27.6) on day −10, which decreased to a nadir of 7.5 µmol/L (95% CI 3.1 – 18.0, p = 0.017) on day +8 following HCT before returning to baseline by day 30. After adjustment for IL-6 level (1.0% lower CIT per 10% increase in IL-6, p=0.004), presence of acute graft-versus-host disease (GVHD), (27% lower CIT, p=0.025) and oral energy intake (2.1% lower CIT per 10% decrease in energy intake, p=0.018), the nadir shifted to day +10, when mean CIT concentration was lower in patients with severe oral mucositis (6.7 µmol/L, 95% CI 3.4–13.1) than in those without severe mucositis (11.9 µmol/L, 95% CI 5.8–24.4, p=0.003). Change in CIT was not correlated with stool volume, C-reactive protein, TNF-alpha, leptin, or ghrelin. Conclusion In children undergoing HCT, serum CIT correlates with measures of gastrointestinal function (oral mucositis severity, dietary intake, acute GVHD) and may reflect mucosal injury to the gastrointestinal tract. PMID:24614125

  18. Epidemiology and Outcomes of Clostridium difficile Infections in Hematopoietic Stem Cell Transplant Recipients

    PubMed Central

    Alonso, Carolyn D.; Treadway, Suzanne B.; Hanna, David B.; Huff, Carol Ann; Neofytos, Dionissios; Carroll, Karen C.

    2012-01-01

    Background. Clostridium difficile is the leading cause of infectious diarrhea among hospitalized patients and is a major concern for patients undergoing hematopoietic stem cell transplantation (HSCT). Risk factors and the natural history of C. difficile infection (CDI) are poorly understood in this population. Methods. We performed a retrospective nested case-control study to describe the epidemiology, timing, and risk factors for CDI among adult patients who received HSCTs at our center from January 2003 through December 2008. Results. The overall 1-year incidence of CDI was 9.2% among HSCTs performed (n = 999). The median time to diagnosis of CDI was short among both autologous and allogeneic HSCT recipients (6.5 days and 33 days, respectively). Risk factors for CDI in allogeneic HSCT recipients included receipt of chemotherapy prior to conditioning for HSCT, broad-spectrum antimicrobial use, and acute graft-versus-host disease (GVHD; adjusted odds ratio [AOR], 4.45; 95% confidence interval [CI], 1.54–12.84; P = .006). There was a strong relationship between early CDI and subsequent development of gastrointestinal tract GVHD in the year following allogeneic HSCT (P < .001). Gastrointestinal GVHD was also strongly associated with an increased risk for recurrent CDI (AOR, 4.23 [95% CI, 1.20–14.86]; P = .02). Conclusions. These results highlight the high incidence and early timing of CDI after HSCT. Early timing, coupled with the noted risk of pretransplant chemotherapy, suggests that the natural history of disease in some patients may involve colonization prior to HSCT. A potentially important interplay between CDI and GVHD involving the gastrointestinal tract was observed. PMID:22412059

  19. Cancer in the Transplant Recipient

    PubMed Central

    Chapman, Jeremy R.; Webster, Angela C.; Wong, Germaine

    2013-01-01

    Malignancy has become one of the three major causes of death after transplantation in the past decade and is thus increasingly important in all organ transplant programs. Death from cardiovascular disease and infection are both decreasing in frequency from a combination of screening, prophylaxis, aggressive risk factor management, and interventional therapies. Cancer, on the other hand, is poorly and expensively screened for; risk factors are mostly elusive and/or hard to impact on except for the use of immunosuppression itself; and finally therapeutic approaches to the transplant recipient with cancer are often nihilistic. This article provides a review of each of the issues as they come to affect transplantation: cancer before wait-listing, cancer transmission from the donor, cancer after transplantation, outcomes of transplant recipients after a diagnosis of cancer, and the role of screening and therapy in reducing the impact of cancer in transplant recipients. PMID:23818517

  20. Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia.

    PubMed

    Saber, Wael; Opie, Shaun; Rizzo, J Douglas; Zhang, Mei-Jie; Horowitz, Mary M; Schriber, Jeff

    2012-04-26

    Approximately one-third of patients with an indication for hematopoietic cell transplantation (HCT) have an HLA-matched related donor (MRD) available to them. For the remaining patients, a matched unrelated donor (MUD) is an alternative. Prior studies comparing MRD and MUD HCT provide conflicting results, and the relative efficacy of MRD and MUD transplantation is an area of active investigation. To address this issue, we analyzed outcomes of 2223 adult acute myelogenous leukemia patients who underwent allogeneic HCT between 2002 and 2006 (MRD, n = 624; 8/8 HLA locus matched MUD, n = 1193; 7/8 MUD, n = 406). The 100-day cumulative incidence of grades B-D acute GVHD was significantly lower in MRD HCT recipients than in 8/8 MUD and 7/8 MUD HCT recipients (33%, 51%, and 53%, respectively; P < .001). In multivariate analysis, 8/8 MUD HCT recipients had a similar survival rate compared with MRD HCT recipients (relative risk [RR], 1.03; P = .62). 7/8 MUD HCT recipients had higher early mortality than MRD HCT recipients (RR, 1.40; P < .001), but beyond 6 months after HCT, their survival rates were similar (RR, 0.88; P = .30). These results suggest that transplantation from MUD and MRD donors results in similar survival times for patients with acute myelogenous leukemia. PMID:22327226

  1. Normal karyotype acute myeloid leukemia patients with CEBPA double mutation have a favorable prognosis but no survival benefit from allogeneic stem cell transplant.

    PubMed

    Ahn, Jae-Sook; Kim, Jae-Young; Kim, Hyeoung-Joon; Kim, Yeo-Kyeoung; Lee, Seung-Shin; Jung, Sung-Hoon; Yang, Deok-Hwan; Lee, Je-Jung; Kim, Nan Young; Choi, Seung Hyun; Minden, Mark D; Jung, Chul Won; Jang, Jun-Ho; Kim, Hee Je; Moon, Joon Ho; Sohn, Sang Kyun; Won, Jong-Ho; Kim, Sung-Hyun; Kim, Dennis Dong Hwan

    2016-01-01

    Normal karyotype acute myeloid leukemia (NK-AML) with CCAAT/enhancer binding protein α (CEBPA) mutations is known to have a more favorable prognosis. However, direct comparison of the clinical significance according to consolidation therapy has not been widely performed in patients with NK-AML. A total of 404 patients with NK-AML who received intensive induction chemotherapy were included in the present study. Diagnostic samples from the patients were evaluated for CEBPA mutations by direct sequencing. CEBPA single (sm) or double mutation (dm) was observed in 27 (6.7 %) and 51 (12.6 %) patients, respectively. CEBPA (dm) was associated with GATA2 (mut), and it was less frequently associated with FLT3-ITD(pos), NPM1 (mut), and DNMT3A (mut) in comparison with CEBPA (wild) or CEBPA (sm) (all p values <0.05). On multivariate analysis, CEBPA (dm) (p = 0.007, OR 39.593) was an independent risk factor for achievement of complete remission (CR). With a median follow-up of 40.1 months, CEBPA (dm) showed a favorable overall survival (OS), event-free survival (EFS), and lower relapse incidence (RI) in comparison with CEBPA (wild) (all p values <0.005). Comparison of clinical outcome analyses (consolidation chemotherapy vs. allogeneic hematopoietic cell transplantation (HCT)) demonstrated the role of consolidation treatment in patients with CEBPA (dm). Allogeneic HCT was associated with lower EFS and RI and a trend of higher non-relapse mortality. However, there was no statistically significant difference in OS. In conclusion, CEBPA (dm) was associated with other molecular mutations. Consolidation chemotherapy alone may overcome higher relapse rates by reducing the treatment mortality and increasing survival after relapse events in patients with CEBPA (dm) in NK-AML. PMID:26537612

  2. Feasibility of Frequent Patient-Reported Outcome Surveillance in Patients Undergoing Hematopoietic Cell Transplantation

    PubMed Central

    Wood, William A.; Deal, Allison M.; Abernethy, Amy; Basch, Ethan; Battaglini, Claudio; Kim, Yoon Hie; Whitley, Julia; Shatten, Charlotte; Serody, Jon; Shea, Thomas; Reeve, Bryce B.

    2012-01-01

    Patient-reported outcomes (PROs), including symptoms and health-related quality of life (HRQOL), provide a patient-centered description of hematopoietic cell transplantation (HCT)-related toxicity. These data characterize the patient experience after HCT and may have prognostic usefulness for long-term outcomes after HCT. We conducted a study of 32 patients after HCT (10 autologous HCT recipients, 11 full-intensity conditioning allogeneic HCT recipients, and 11 reduced-intensity conditioning allogeneic HCT recipients) to determine the feasibility of weekly electronic PRO collection from HCT until day (D) + 100. We used questions from the PRO version of the Common Terminology Criteria for Adverse Events to capture symptoms, and the Patient-Reported Outcomes Measurement Information System Global Health scale to measure physical and mental HRQOL. The vast majority (94%) of patients used the electronic PRO system, with only 6% opting for paper-and-pencil only. The median weekly percentage of participants who completed the surveys was 100% in all cohorts through hospital discharge, and remained 100% for the autologous HCT and reduced-intensity allogeneic HCT cohorts through D+100. Patients were satisfied with the electronic system, giving high marks for readability, comfort, and questionnaire length. Symptom severity varied by absolute level and type of symptom across the 3 cohorts, with the full-intensity allogeneic HCT cohort exhibiting the greatest median overall symptom severity, peaking at D+7. Median physical health HRQOL scores decreased with time in the 3 cohorts, and HRQOL was generally correlated with overall symptom severity. Our results demonstrate the feasibility of frequent electronic PROs in the early post-HCT period. Future studies in larger populations to explore predictive models using frequent PRO data for outcomes, including long-term HRQOL and survival, are warranted. PMID:23253558

  3. Allogeneic and autologous bone marrow transplantation for acute nonlymphocytic leukemia.

    PubMed

    Hurd, D D

    1987-12-01

    Current results show that 50% of young patients with ANLL who undergo allogeneic BMT experience prolonged DFS and may be cured. Encouraging results with high-dose chemo/radiotherapy and autologous BMT are likewise being reported. In addition, some studies using intensive postremission treatment without BMT have shown results comparable to many transplant series. As better ways of preventing GVHD are found, the morbidity and mortality of allogeneic BMT should be reduced and the benefits of transplantation for curing patients with ANLL should be increased. However, the applicability of allogeneic BMT will remain limited due to the availability of compatible donors whether related or unrelated. Further studies are needed in the use of postremission intensive therapy with and without autologous bone marrow support. However, results to date should engender the same degree of enthusiastic optimism that followed the early reports of improved outcome with allogeneic BMT when applied to first remission patients. PMID:3321445

  4. Allogeneic stem cell transplantation with peripheral blood stem cells mobilized by pegylated G-CSF.

    PubMed

    Hill, Geoffrey R; Morris, Edward S; Fuery, Madonna; Hutchins, Cheryl; Butler, Jason; Grigg, Andrew; Roberts, Andrew; Bradstock, Ken; Szer, Jeffrey; Kennedy, Glen; Morton, James; Durrant, Simon

    2006-06-01

    Mobilization of stem cells with pegylated granulocyte colony-stimulating factor (peg-G-CSF) modulates donor T- and natural killer T-cell (NKT-cell) functions, thus separating graft-versus-host from graft-versus-leukemia disease in animal models. We report a phase I/II study that analyzed the feasibility of mobilizing stem cells from normal donors with peg-G-CSF and the ability of these cells to restore hematopoiesis in allogeneic transplant recipients after myeloablative conditioning. Administration of 6 mg of peg-G-CSF resulted in suboptimal stem cell mobilization, with a peak peripheral blood CD34+ count of 29+/-5/microL. Apheresis 4 days after peg-G-CSF yielded 2.7+/-.4x10(6) CD34+ cells/kg recipient weight, and all donors required a second collection on day 5 to yield a total of 4.2+/-.5x10(6) CD34+ cells/kg recipient weight. After escalation of the dose to 12 mg, the peak CD34+ count was 99+/-11/microL and 12 of 13 donors collected sufficient stem cells for transplantation in a single apheresis (8.9+/-1.4x10(6) CD34+ cells/kg recipient weight). Late transient increases in serum hepatic transaminases were noted, but other side effects (predominantly bone pain) were otherwise similar to those seen in donors mobilized with standard G-CSF. Median neutrophil and platelet engraftments occurred on days 18 and 14, respectively, after transplantation and were identical to those seen with in recipients of grafts mobilized with standard G-CSF. With a median follow-up of 357 days, the incidence of grade II-IV acute graft-versus-host disease was 50% and there have been no relapses to date. Mobilization of stem cells with peg-G-CSF in normal donors is feasible and 12 mg results in mobilization characteristics similar to those of standard G-CSF. PMID:16737933

  5. HLA-Identical Sibling Allogeneic Transplants versus Chemotherapy in Acute Myelogenous Leukemia with t(8;21) in First Complete Remission: Collaborative Study Between the German AML Intergroup and CIBMTR

    PubMed Central

    Schlenk, Richard F.; Pasquini, Marcelo C.; Pérez, Waleska S.; Zhang, Mei-Jie; Krauter, Jürgen; Antin, Joseph H.; Bashey, Asad; Bolwell, Brian J.; Büchner, Thomas; Cahn, Jean-Yves; Cairo, Mitchell S.; Copelan, Edward A.; Cutler, Corey S.; Döhner, Hartmut; Gale, Robert Peter; Ilhan, Osman; Lazarus, Hillard M.; Liesveld, Jane L.; Litzow, Mark R.; Marks, David I.; Maziarz, Richard T.; McCarthy, Philip L.; Nimer, Stephen D.; Sierra, Jorge; Tallman, Martin S.; Weisdorf, Daniel J.; Horowitz, Mary M.; Ganser, Arnold

    2008-01-01

    We studied the role of HLA-matched sibling hematopoietic cell transplantation (HCT) in treating t(8;21) AML in first remission. Outcomes of 118 patients receiving HCT and reported to the Center for International Blood and Marrow Transplant Research were compared with 132 similar patients receiving chemotherapy selected from eight German AML Intergroup multicenter trials. Characteristics of the cohorts were similar except that chemotherapy recipients were significantly older. To adjust for time to treatment bias, outcomes were compared using left-truncated Cox regression models. Transplants were associated with higher treatment-related mortality [relative risk (RR) 6.76, 95% confidence interval (CI) 2.95–15.45, p<0.001], lower relapse (RR 0.47, 95% CI 0.25–0.85, p=0.01) and similar relapse-free survival (p=0.2). Loss of sex chromosomes (LOS) in addition to t(8;21) negatively impacted overall survival in patients receiving chemotherapy. Patients without LOS experienced shorter survival after HCT comparing to chemotherapy (RR 3.05, p=0.02), whereas patients with LOS had similar survival regardless of postremission therapy. In both cohorts, white blood cell count (WBC) at diagnosis > 25 x109/L was associated with a higher relapse risk (RR=2.09, p=0.03), lower relapse-free (RR=1.9, p=0.008) and overall survival (RR=1.91, p=0.01). In this cohort of patients with t(8;21) AML , HCT did not improve overall survival, since reduction of relapse was offset by high transplant-related mortality. In the group without LOS, survival after chemotherapy was far superior to HCT. These results suggest that patients with t(8;21) AML without poor prognostic factors have higher rates of survival after chemotherapy as a post remission therapy compared to HCT. PMID:18215779

  6. Donor, recipient, and transplant characteristics as risk factors after unrelated donor PBSC transplantation: beneficial effects of higher CD34+ cell dose

    PubMed Central

    Chitphakdithai, Pintip; Logan, Brent R.; Leitman, Susan F.; Anderlini, Paolo; Klein, John P.; Horowitz, Mary M.; Miller, John P.; King, Roberta J.; Confer, Dennis L.

    2009-01-01

    We report outcomes of 932 recipients of unrelated donor peripheral blood stem cell hematopoietic cell transplantation (URD-PBSC HCT) for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome enrolled on a prospective National Marrow Donor Program trial from 1999 through 2003. Preparative regimens included myeloablative (MA; N = 611), reduced-intensity (RI; N = 160), and nonmyeloablative (NMA; N = 161). For MA recipients, CD34+ counts greater than 3.8 × 106/kg improved neutrophil and platelet engraftment, whereas improved overall survival (OS) and reduced transplant-related mortality (TRM) were seen for all preparative regimens when CD34+ cell doses exceeded 4.5 × 106/kg. Higher infused doses of CD34+ cell dose did not result in increased rates of either acute or chronic graft-versus-host disease (GVHD). Three-year OS and disease-free survival (DFS) of recipients of MA, RI, and NMA approaches were similar (33%, 35%, and 32% OS; 33%, 30%, and 29% DFS, respectively). In summary, recipients of URD-PBSC HCT receiving preparative regimens differing in intensity experienced similar survival. Higher CD34+ cell doses resulted in more rapid engraftment, less TRM, and better 3-year OS (39% versus 25%, MA, P = .004; 38% versus 21% RI/NMA, P = .004) but did not increase the risk of GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00785525. PMID:19608747

  7. Changes in Subcellular Localization of Visfatin in Human Colorectal HCT-116 Carcinoma cell Line After Cytochalasin-B Treatment

    PubMed Central

    Skonieczna, M.; Bułdak, Ł; Matysiak, N.; Mielańczyk, Ł; Wyrobiec, G.; Kukla, M.; Michalski, M.; Żwirska-Korczala, K.

    2014-01-01

    The aim of the study was to assess the expression and subcellular localization of visfatin in HCT-116 colorectal carcinoma cells after cytokinesis failure using Cytochalasin B (CytB) and the mechanism of apoptosis of cells after CytB. We observed translocation of visfatin’s antigen in cytB treated colorectal carcinoma HCT-116 cells from cytosol to nucleus. Statistical and morphometric analysis revealed significantly higher area-related numerical density visfatin-bound nano-golds in the nuclei of cytB-treated HCT-116 cells compared to cytosol. Reverse relation to visfatin subcellular localization was observed in un-treated HCT-116 cells. The total amount of visfatin protein and visfatin mRNA level in HCT-116 cells was also decreased after CytB treatment. Additionally, CytB significantly decreased cell survival, increased levels of G2/M fractions, induced bi-nuclei formation as well as increased reactive oxygen species (ROS) level in HCT-116 cells. CytB treatment showed cytotoxic effect that stem from oxidative stress and is connected with the changes in the cytoplasmic/nuclear amount of visfatin in HCT-116 cells. PMID:25308845

  8. 21 CFR 1271.37 - Will establishment registrations and HCT/P listings be available for inspection, and how do I...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Will establishment registrations and HCT/P... § 1271.37 Will establishment registrations and HCT/P listings be available for inspection, and how do I... provided. The following information submitted under the HCT/P requirements is illustrative of the type...

  9. 21 CFR 1271.37 - Will establishment registrations and HCT/P listings be available for inspection, and how do I...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Will establishment registrations and HCT/P... § 1271.37 Will establishment registrations and HCT/P listings be available for inspection, and how do I... provided. The following information submitted under the HCT/P requirements is illustrative of the type...

  10. De novo alloreactive memory CD8+ T cells develop following allogeneic challenge when CNI immunosuppression is delayed.

    PubMed

    Hart-Matyas, M; Gareau, A J; Hirsch, G M; Lee, T D G

    2015-01-01

    Allospecific memory T cells are a recognized threat to the maintenance of solid-organ transplants. Limited information exists regarding the development of alloreactive memory T cells when post-transplant immunosuppression is present. The clinical practice of delaying calcineurin inhibitor (CNI) initiation post-transplant may permit the development of a de novo allospecific memory population. We investigated the development of de novo allospecific memory CD8+ T cells following the introduction of CNI immunosuppression in a murine model using allogeneic cell priming. Recipient mice alloprimed with splenocytes from fully mismatched donors received cyclosporine (CyA), initiated at 0, 2, 6, or 10days post-prime. Splenocytes from recipients were analyzed by flow cytometry or enzyme-linked immunosorbent assay for evidence of memory cell formation. Memory and effector CD8+ T cell development was prevented when CyA was initiated at 0day or 2days post-prime (p<0.001), but not 6days post-prime. Following a boost challenge, these memory CD8+ T cells were capable of producing a similarly sized population of secondary effectors as recipients not treated with CyA (p>0.05). Delaying CyA up to 6days or later post-prime permits the development of functional de novo allospecific memory CD8+ T cells. The development of this potentially detrimental T cell population in patients could be prevented by starting CNI immunosuppression early post-transplant. PMID:25315500

  11. Long-term enzyme replacement therapy in beta-glucuronidase--deficient mice by allogeneic bone marrow transplantation

    SciTech Connect

    Yatziv, S.; Weiss, L.; Morecki, S.; Fuks, Z.; Slavin, S.

    1982-06-01

    Enzyme replacement therapy was successfully accomplished in beta-Glu-deficient C3H/HeJ mice after transplantation of BM cells obtained from normal BALB/c donors. Marrow recipients were prepared for transplantation by fractionated TLI. Enzyme activity increased from 20.5 +/- 7.0 nmol/mg of protein per hour to 180 +/- 30.2 in the liver (p less than 0.001) and from 8.2 +/- 2.0 to 17.5 +/- 5.0 nmol/ml/hr in the plasma (p less than 0.05) at 50 days after marrow infusion. Normal enzyme activity was maintained in treated mice for at least 100 days after marrow transplantation, as documented by repeated liver biopsies and examination of plasma samples. The marrow donors and the recipients were fully histoincompatible. Both immunologic rejection of the marrow allograft and GVHD were prevented by the prior conditioning of the recipients with TLI, resulting in bilateral transplantation tolerance of host vs. graft and graft vs. host. The data suggest that allogeneic BM transplantation may provide a possible therapeutic approach for certain enzyme deficiency syndromes.

  12. Natural product-based design, synthesis and biological evaluation of Albiziabioside A derivatives that selectively induce HCT116 cell death.

    PubMed

    Wei, Gaofei; Cui, Shanshan; Luan, Weijing; Wang, Shuai; Hou, Zhuang; Liu, Yongxiang; Liu, Yang; Cheng, Maosheng

    2016-05-01

    A series of Albiziabioside A coupled substituents of cinnamoyl derivatives were designed and synthesized. The synthesized compounds were screened for anticancer activity against a panel of six human cancer cell lines using a MTT assay. Synthetic derivatives showed excellent selectivity, as they were toxic against only HCT116 cell line. Some compounds exhibited better anti-cancer activity against HCT116 compared to positive controls, such as 5-fluorouracil and Albiziabioside A. Compound 8n was the most active derivative. Importantly, it was also found that the anti-proliferative activity of 8n could be attributed to the induction of cell cycle arrest and apoptosis in HCT116 cells. PMID:26922223

  13. Cytotoxic effect of fucoidan extracted from Sargassum cinereum on colon cancer cell line HCT-15.

    PubMed

    Somasundaram, Sivasankara Narayani; Shanmugam, Saravanan; Subramanian, Bharathiraja; Jaganathan, Ravindran

    2016-10-01

    The present study was aimed to investigate the antioxidant and cytotoxicity activity against HCT-15 of fucoidan from Sargassum cinereum. Purification of fucoidan was done by DEAE cellulose and dialysis. Physicochemical characterization of fucoidan was analysed by calorimetric assay, FT-IR, HPLC and NMR. The extracted fucoidan contains 65.753% of fucose and 3.7±1.54% of sulphate respectively. HPLC results showed that the fucoidan contains the monosaccharide composition such as fucose, galactose, mannose and xylose. Antioxidant effect of fucoidan in Sargassum Cinereum was determined by DPPH. The maximum DPPH activity was found at the concentration of 100μg, where as the crude extract showed the scavenging activity was 63.58±0.56%. Cytotoxicity effect was done by MTT assay. Fucoidan extract caused about 50% of cell death after 24h of incubation with 75±0.9037μg/ml against HCT-15. PMID:27370748

  14. Pharmacometabonomic Prediction of Busulfan Clearance in Hematopoetic Cell Transplant Recipients.

    PubMed

    Navarro, Sandi L; Randolph, Timothy W; Shireman, Laura M; Raftery, Daniel; McCune, Jeannine S

    2016-08-01

    Intravenous (IV) busulfan doses are often personalized to a concentration at steady state (Css) using the patient's clearance, which is estimated with therapeutic drug monitoring. We sought to identify biomarkers of IV busulfan clearance using a targeted pharmacometabonomics approach. A total of 200 metabolites were quantitated in 106 plasma samples, each obtained before IV busulfan administration in hematopoietic cell transplant (HCT) recipients. Both univariate linear regression with false discovery rate (FDR) and pathway enrichment analyses using the Global test were performed. In the univariate analysis, glycine, N-acetylglycine, 2-hydroxyisovaleric acid, creatine, serine, and tyrosine were statistically significantly associated with IV busulfan clearance at P < 0.05, with the first three satisfying the FDR of q < 0.1. Using pathway enrichment analysis, the glycine, serine, and threonine metabolism pathway was statistically significantly associated with IV busulfan clearance at P < 0.05 and q < 0.1, and a pathway impact >0.1. Glycine is a component of glutathione, which is conjugated with busulfan via glutathione transferase enzymes. These results demonstrate the potential utility of pharmacometabonomics to inform IV busulfan dosing. Future studies are required to validate these findings. PMID:27350098

  15. Cellular Uptake of Decitabine by Equilibrative Nucleoside Transporters in HCT116 Cells.

    PubMed

    Ueda, Kumiko; Hosokawa, Mika; Iwakawa, Seigo

    2015-01-01

    DNA hypermethylation, an epigenetic change that silences gene expression without altering nucleotide sequences, plays a critical role in the formation and progression of colorectal cancers as well as in the acquisition of drug resistance. Decitabine (DAC), a DNA methyltransferase 1 inhibitor of nucleoside analogues, has been shown to restore gene expression silenced by hypermethylation. In the present study, the mechanisms underlying both uridine and DAC uptake were examined in the human colon cancer cell line HCT116. Real-time polymerase chain reaction analysis revealed that ENT1 mRNA was the most abundant among the nucleoside transporters examined in HCT116 cells. The ENT1 protein was detected in the membrane fraction, as determined by Western blotting. The uptake of uridine or DAC was time- and concentration-dependent, but also Na(+)-independent. The uptake of these agents was inhibited by S-(4-nitrobenzyl)-6-thioinosine (NBMPR), an inhibitor of equilibrative nucleoside transporters (ENTs), and was also decreased in cells treated with ENT1 small interfering RNA. The uptake of both uridine and DAC was inhibited by uridine, cytidine, adenosine, or inosine, while that of DAC was also inhibited by thymidine. The expression of MAGEA1 mRNA, the DNA of which was methylated in HCT116 cells, was increased by DAC treatment, and this increment was attenuated by concomitant treatment with NBMPR. The IC50 value of DAC was also increased in the presence of NBMPR. These results suggest that DAC is mainly taken up by ENT1 and that this uptake is one of the key determinants of the activity of DAC in HCT116 cells. PMID:26235575

  16. Analysis of the efficiency and costs of antifungal prophylaxis and mycological diagnostics in patients undergoing allogeneic haematopoietic cell transplantation: "real life" evaluation.

    PubMed

    Bertz, Hartmut; Drognitz, Kathrin; Finke, Jürgen

    2016-02-01

    Antifungal prophylaxis/therapy (AP/AT) raises the cost of allogeneic haematopoietic cell transplantation (alloHCT). Its efficacy, different approaches for AP/AT, diagnostic measures and cost-effectiveness must still be evaluated. In 2010, we conducted a prospective study with 106 consecutive patients receiving an alloHCT analysing AP/AT, choice and costs of diagnostics applied including CT scans, galactomannan (Gal) and β-D-glucan (β-D) testing. Antifungal prophylaxis in 91 patients consisted of fluconazole (FLU) or L-AMB (AmBisome™ 1 or 3 mg/kg/day b.w.), and antifungal therapy had to be initiated in 38 % of the FLU/L-AMB-1-mg patients but in none with L-AMB 3 mg. Empirical AT consisted of L-AMB 1 mg/kg (n = 12) and preemptive AT of L-AMB 3 mg/kg (n = 17) and proved very efficacious with no further antifungal drug escalation in 89.6 %. Mean costs of diagnostic measures were 402 €/alloHCT; however, only 22 % of the CT scans, 4 % of β-D and 3 % of galactomannan testing were positive. We detected one proven, 17 probable and 14 possible fungal infections. Due to the German diagnosis-related group system with additional compensation, all our AP/AT strategies were adequately reimbursed. While clinical symptoms and CT scans are the most commonly used, inexpensive decision-making tools for starting AT, the expensive laboratory diagnostic procedures are ineffective; we have therefore discontinued regular GAL/β-D testing and changed our AP in patients at risk. PMID:26627891

  17. Evodiamine Induces Apoptosis and Inhibits Migration of HCT-116 Human Colorectal Cancer Cells.

    PubMed

    Zhao, Lv-Cui; Li, Jing; Liao, Ke; Luo, Nian; Shi, Qing-Qiang; Feng, Zi-Qiang; Chen, Di-Long

    2015-01-01

    Evodiamine (EVO) exhibits strong anti-cancer effects. However, the effect of EVO on the human colorectal cancer cell line HCT-116 has not been explored in detail, and its underlying molecular mechanisms remain unknown. In the present study, cell viability was assessed by Cell Counting Kit-8 (CCK-8). Cell cycle and apoptosis were measured by flow cytometry, and morphological changes in the nucleus were examined by fluorescence microscopy and Hoechst staining. Cell motility was detected by Transwell assay. ELISA was used to assess the protein levels of autocrine motility factor (AMF) in the cell supernatant, and protein expression was determined by Western blotting. Our results showed that EVO inhibited the proliferation of HCT-116 cells, caused accumulation of cells in S and G2/M phases, and reduced the levels of the secreted form of AMF. The protein levels of tumor suppressor protein (p53), Bcl-2 Associated X protein (Bax), B cell CLL/lymphoma-2 (Bcl-2), phosphoglucose isomerase (PGI), phosphorylated signal transducers and activators of transcription 3 (p-STAT3) and matrix metalloproteinase 3 (MMP3) were altered in cells treated with EVO. Taken together, our results suggest that EVO modulates the activity of the p53 signaling pathway to induce apoptosis and downregulate MMP3 expression by inactivating the JAK2/STAT3 pathway through the downregulation of PGI to inhibit migration of HCT-116 human colorectal cancer cells. PMID:26580615

  18. Mechanism of transport and intracellular binding of porfiromycin in HCT 116 human colon carcinoma cells.

    PubMed

    Pan, S S; Johnson, R; Gonzalez, H; Thohan, V

    1989-09-15

    The mechanism of uptake and efflux of porfiromycin (PFM) by HCT 116 human colon carcinoma cells or freshly obtained human RBC was investigated. The time course of uptake of radioactivity upon exposure of HCT 116 cells to [14C]PFM showed one fast and one slow phase of linear increase. The initial phase of PFM uptake was not saturable with external drug concentrations from 2 to 100 microM. PFM accumulation was temperature dependent with a temperature coefficient (Q10 24-37 degrees C) of 2.3 +/- 0.3. PFM uptake was not affected either by individual inhibitors such as 1 mM 2,4-dinitrophenol, sodium azide, iodoacetic acid, ouabain, 0.02 mM oligomycin, p-hydroxylmercuribenzoate, 0.2 mM N-ethylmaleimide, or by combinations of inhibitors. PFM uptake did not demonstrate competitive inhibition by unlabeled PFM and mitomycin C. Efflux of cellular radioactivity was not affected by the above mentioned inhibitors or by verapamil, diltiazem, or trifluoperazine. Only aliphatic alcohols accelerated the initial influx rate. The RBC, however, only exhibited the initial fast accumulation of [14C]PFM, and all the 14C accumulated by RBC was exchangeable. These data demonstrate that the uptake and the efflux of PFM in HCT 116 cells and RBC comprise a passive diffusion process. PMID:2766276

  19. Methylsulfonylmethane Induces p53 Independent Apoptosis in HCT-116 Colon Cancer Cells

    PubMed Central

    Karabay, Arzu Zeynep; Koc, Asli; Ozkan, Tulin; Hekmatshoar, Yalda; Sunguroglu, Asuman; Aktan, Fugen; Buyukbingol, Zeliha

    2016-01-01

    Methylsulfonylmethane (MSM) is an organic sulfur-containing compound which has been used as a dietary supplement for osteoarthritis. MSM has been shown to reduce oxidative stress and inflammation, as well as exhibit apoptotic or anti-apoptotic effects depending on the cell type or activating stimuli. However, there are still a lot of unknowns about the mechanisms of actions of MSM. In this study, MSM was tested on colon cancer cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis revealed that MSM inhibited cell viability and increased apoptotic markers in both HCT-116 p53 +/+ and HCT-116 p53 −/− colon cancer cells. Increased poly (ADP-ribose) polymerase (PARP) fragmentation and caspase-3 activity by MSM also supported these findings. MSM also modulated the expression of various apoptosis-related genes and proteins. Moreover, MSM was found to increase c-Jun N-terminal kinases (JNK) phosphorylation in both cell lines, dose-dependently. In conclusion, our results show for the first time that MSM induces apoptosis in HCT-116 colon cancer cells regardless of their p53 status. Since p53 is defective in >50% of tumors, the ability of MSM to induce apoptosis independently of p53 may offer an advantage in anti-tumor therapy. Moreover, the remarkable effect of MSM on Bim, an apoptotic protein, also suggests its potential use as a novel chemotherapeutic agent for Bim-targeted anti-cancer therapies. PMID:27428957

  20. Effect of select medium supplements on in vitro development of Cryptosporidium andersoni in HCT-8 cells.

    PubMed

    Wu, Liang; Chen, Sheng-xia; Jiang, Xu-gan; Shen, Yu-juan; Lu, Zhao-xi; Tu, Guo-hua; Fu, Xing-li; Cao, Jian-ping

    2009-10-01

    We evaluated the effect of fetal calf serum (FCS), glucose, ascorbic acid, calcium pantothenate, folic acid, and insulin on the growth of Cryptosporidium andersoni in human colon tumor (HCT-8) cells. After being incubated for 48 h, the proliferation of parasites was determined by real-time polymerase chain reaction (PCR) assay, and the development of C. andersoni was observed by transmission electron microscopy (TEM). Ten percent FCS was the best concentration for C. andersoni culture. Glucose, ascorbic acid, and insulin had a significant effect on the growth of C. andersoni when added into 10% FCS RPMI 1640. Calcium pantothenate had no significant effect and folic acid had the inhibited effect. We also observed the stages of trophozoite, macrogamont, microgamont, type I meront, type II meront, and sporozoite of C. andersoni in HCT-8 cells by TEM. Our results indicated that the best medium for C. andersoni was 10% FCS RPMI 1640 medium containing 50 mM glucose, 50 microg/ml ascorbic acid, and 0.3 U/ml insulin. Real-time PCR could provide a quick and precise technique to determine the proliferation of parasites. Cultivation of C. andersoni in HCT-8 cells will facilitate the study of interactions between parasites and host cells as well as provide a reliable system for evaluating anticryptosporidial compound efficacy. PMID:19641939

  1. 21 CFR 1271.65 - How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION HUMAN CELLS, TISSUES, AND CELLULAR AND... first-degree or second-degree blood relative; (ii) The HCT/P consists of reproductive cells or...

  2. 21 CFR 1271.65 - How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND DRUG ADMINISTRATION HUMAN CELLS, TISSUES, AND CELLULAR AND... first-degree or second-degree blood relative; (ii) The HCT/P consists of reproductive cells or...

  3. 5 CFR 1315.15 - Grant recipients.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Grant recipients. 1315.15 Section 1315.15 Administrative Personnel OFFICE OF MANAGEMENT AND BUDGET OMB DIRECTIVES PROMPT PAYMENT § 1315.15 Grant recipients. Recipients of Federal assistance may pay interest penalties if so specified in their contracts...

  4. 5 CFR 1315.15 - Grant recipients.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 5 Administrative Personnel 3 2012-01-01 2012-01-01 false Grant recipients. 1315.15 Section 1315.15 Administrative Personnel OFFICE OF MANAGEMENT AND BUDGET OMB DIRECTIVES PROMPT PAYMENT § 1315.15 Grant recipients. Recipients of Federal assistance may pay interest penalties if so specified in their contracts...

  5. 5 CFR 1315.15 - Grant recipients.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 5 Administrative Personnel 3 2014-01-01 2014-01-01 false Grant recipients. 1315.15 Section 1315.15 Administrative Personnel OFFICE OF MANAGEMENT AND BUDGET OMB DIRECTIVES PROMPT PAYMENT § 1315.15 Grant recipients. Recipients of Federal assistance may pay interest penalties if so specified in their contracts...

  6. 5 CFR 1315.15 - Grant recipients.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Grant recipients. 1315.15 Section 1315.15 Administrative Personnel OFFICE OF MANAGEMENT AND BUDGET OMB DIRECTIVES PROMPT PAYMENT § 1315.15 Grant recipients. Recipients of Federal assistance may pay interest penalties if so specified in their contracts...

  7. 10 CFR 607.660 - Recipient.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Recipient. 607.660 Section 607.660 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 607.660 Recipient. Recipient means any individual, corporation,...

  8. 31 CFR 20.660 - Recipient.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance: Treasury 1 2011-07-01 2011-07-01 false Recipient. 20.660 Section 20.660 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 20.660 Recipient. Recipient means any...

  9. 31 CFR 20.660 - Recipient.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance: Treasury 1 2013-07-01 2013-07-01 false Recipient. 20.660 Section 20.660 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 20.660 Recipient. Recipient means any...

  10. 31 CFR 20.660 - Recipient.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance: Treasury 1 2014-07-01 2014-07-01 false Recipient. 20.660 Section 20.660 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 20.660 Recipient. Recipient means any...

  11. 31 CFR 20.660 - Recipient.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Recipient. 20.660 Section 20.660 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 20.660 Recipient. Recipient means any...

  12. 31 CFR 20.660 - Recipient.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance: Treasury 1 2012-07-01 2012-07-01 false Recipient. 20.660 Section 20.660 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 20.660 Recipient. Recipient means any...

  13. 20 CFR 439.660 - Recipient.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Recipient. 439.660 Section 439.660 Employees' Benefits SOCIAL SECURITY ADMINISTRATION GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 439.660 Recipient. Recipient means any individual, corporation,...

  14. 10 CFR 603.510 - Recipient qualifications.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Recipient qualifications. 603.510 Section 603.510 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Pre-Award Business Evaluation Recipient Qualification § 603.510 Recipient qualifications. Prior to award of a TIA,...

  15. The incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post first and second hematopoietic stem cell transplant

    PubMed Central

    Ahmed, Ibrahim; Teruya, Jun; Murray-Krezan, Cristina; Krance, Robert

    2015-01-01

    The reported incidence of post allogeneic hematopoietic stem cell transplant (HSCT) auto-immune hemolytic anemia (AIHA) was between 4.4% and 6% following a single transplant. Cord blood transplantation, T-cell depletion and chronic GvHD are significantly associated with post-transplant AIHA. During an 11 year period, data for 500 pediatric HSCT recipients were eligible for evaluation of the incidence of AIHA post first and second transplants. Demographic, transplant, and post-transplant related variables were analyzed. Twelve/500 (2.4%) recipients at a median of 273 days and 7/72 (9.7%) recipients at a median of 157 days developed AIHA post first and second HSCT respectively. Post first HSCT, none of the matched related donor recipients developed AIHA (0/175 MRD vs. 12/325 other donors, p=0.04). Four/12 required a second HSCT to control the AIHA. Post the second HSCT, matched unrelated donor was significantly associated with the development of AIHA. No other variables were associated with the post-second transplant AIHA. The incidence of AIHA post first and second HSCT was less than reported. The increased incidence of AIHA among recipients of second HSCT is most likely due to the profound immune dysregulation. A much larger, prospective study would be needed to evaluate the incidence, complications and management of post-transplant AIHA. PMID:25809012

  16. p21{sup WAF1/CIP1} deficiency induces mitochondrial dysfunction in HCT116 colon cancer cells

    SciTech Connect

    Kim, Ae Jeong; Jee, Hye Jin; Song, Naree; Kim, Minjee; Jeong, Seon-Young; Yun, Jeanho

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer p21{sup -/-} HCT116 cells exhibited an increase in mitochondrial mass. Black-Right-Pointing-Pointer The expression levels of PGC-1{alpha} and AMPK were upregulated in p21{sup -/-} HCT116 cells. Black-Right-Pointing-Pointer The proliferation of p21{sup -/-} HCT116 cells in galactose medium was significantly impaired. Black-Right-Pointing-Pointer p21 may play a role in maintaining proper mitochondrial mass and respiratory function. -- Abstract: p21{sup WAF1/CIP1} is a critical regulator of cell cycle progression. However, the role of p21 in mitochondrial function remains poorly understood. In this study, we examined the effect of p21 deficiency on mitochondrial function in HCT116 human colon cancer cells. We found that there was a significant increase in the mitochondrial mass of p21{sup -/-} HCT116 cells, as measured by 10-N-nonyl-acridine orange staining, as well as an increase in the mitochondrial DNA content. In contrast, p53{sup -/-} cells had a mitochondrial mass comparable to that of wild-type HCT116 cells. In addition, the expression levels of the mitochondrial biogenesis regulators PGC-1{alpha} and TFAM and AMPK activity were also elevated in p21{sup -/-} cells, indicating that p21 deficiency induces the rate of mitochondrial biogenesis through the AMPK-PGC-1{alpha} axis. However, the increase in mitochondrial biogenesis in p21{sup -/-} cells did not accompany an increase in the cellular steady-state level of ATP. Furthermore, p21{sup -/-} cells exhibited significant proliferation impairment in galactose medium, suggesting that p21 deficiency induces a defect in the mitochondrial respiratory chain in HCT116 cells. Taken together, our results suggest that the loss of p21 results in an aberrant increase in the mitochondrial mass and in mitochondrial dysfunction in HCT116 cells, indicating that p21 is required to maintain proper mitochondrial mass and respiratory function.

  17. Inhibition of autophagy by 3-MA potentiates purvalanol-induced apoptosis in Bax deficient HCT 116 colon cancer cells.

    PubMed

    Coker-Gurkan, Ajda; Arisan, Elif Damla; Obakan, Pinar; Guvenir, Esin; Unsal, Narcin Palavan

    2014-10-15

    The purine-derived analogs, roscovitine and purvalanol are selective synthetic inhibitors of cyclin-dependent kinases (CDKs) induced cell cycle arrest and lead to apoptotic cell death in various cancer cells. Although a number of studies investigated the molecular mechanism of each CDK inhibitor on apoptotic cell death mechanism with their therapeutic potential, their regulatory role on autophagy is not clarified yet. In this paper, our aim was to investigate molecular mechanism of CDK inhibitors on autophagy and apoptosis in wild type (wt) and Bax deficient HCT 116 cells. Exposure of HCT 116 wt and Bax(-/-) cells to roscovitine or purvalanol for 24h decreased cell viability in dose-dependent manner. However, Bax deficient HCT 116 cells were found more resistant against purvalanol treatment compared to wt cells. We also established that both CDK inhibitors induced apoptosis through activating mitochondria-mediated pathway in caspase-dependent manner regardless of Bax expression in HCT 116 colon cancer cells. Concomitantly, we determined that purvalanol was also effective on autophagy in HCT 116 colon cancer cells. Inhibition of autophagy by 3-MA treatment enhanced the purvalanol induced apoptotic cell death in HCT 116 Bax(-/-) cells. Our results revealed that mechanistic action of each CDK inhibitor on cell death mechanism differs. While purvalanol treatment activated apoptosis and autophagy in HCT 116 cells, roscovitine was only effective on caspase-dependent apoptotic pathway. Another important difference between two CDK inhibitors, although roscovitine treatment overcame Bax-mediated drug resistance in HCT 116 cells, purvalanol did not exert same effect. PMID:25088259

  18. 21 CFR 1271.21 - When do I register, submit an HCT/P list, and submit updates?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false When do I register, submit an HCT/P list, and submit updates? 1271.21 Section 1271.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH... Listing § 1271.21 When do I register, submit an HCT/P list, and submit updates? (a) You must register...

  19. Second Cancer Risk and Late Mortality in Adult Australians Receiving Allogeneic Hematopoietic Stem Cell Transplantation: A Population-Based Cohort Study.

    PubMed

    Vajdic, Claire M; Mayson, Eleni; Dodds, Anthony J; O'Brien, Tracey; Wilcox, Leonie; Nivison-Smith, Ian; Le Marsney, Renate; Daniels, Benjamin; Ashton, Lesley J

    2016-05-01

    We quantified the risk of second cancer and late mortality in a population-based Australian cohort of 3273 adult (≥15 years) allogeneic hematopoietic stem cell transplant recipients (1992 to 2007). Most recipients received nonradiation-based conditioning and a peripheral blood graft from a matched related donor. Using record linkage with death and cancer registries, 79 second cancers were identified a median of 3.5 years after transplantation. The competing-risk adjusted cumulative incidence of second cancers was 3.35% (95% CI, 2.59 to 4.24) at 10 years, and the cancer risk relative to the matched general population was 2.10 (95% CI, 1.65 to 2.56). We observed an excess risk of melanoma and lip, tongue, esophagus, and soft tissue cancers. Cancer risk relative to the general population was elevated for those transplanted for lymphoma, some leukemia subtypes, and severe aplastic anemia, recipients who developed chronic graft-versus-host disease (cGVHD) and irrespective of radiation-based conditioning or stem cell source. In those alive 2 years after transplantation (n = 1463), the cumulative incidence of late mortality was 22.2% (95% CI, 19.7 to 24.9) at 10 years, and the risk of death relative to the matched general population was 13.8 (95% CI, 12.2 to 15.6). In multivariable modeling, risk of late death was reduced for females compared with males and those transplanted for chronic myeloid leukemia compared with acute myeloid leukemia; risk was increased for recipients with discordant sex donors, cGVHD, those undergoing second transplants, and disease relapse. Adults undergoing allogeneic transplantation have unique cancer and mortality risk profiles that continue to warrant prevention and surveillance activities targeted at high-risk subgroups. PMID:26860637

  20. Late altered organ function in very long-term survivors after allogeneic hematopoietic stem cell transplantation: a paired comparison with their HLA-identical sibling donor

    PubMed Central

    Rovó, Alicia; Daikeler, Thomas; Halter, Jörg; Heim, Dominik; Tsakiris, Dimitrios A.; Stern, Martin; Waltimo, Tuomas; Studt, Jan Dirk; Tyndall, Alan; Gratwohl, Alois; Tichelli, André

    2011-01-01

    Background Hematopoietic stem cell transplantation has become an established procedure worldwide. Severe early and late complications are well described. Little is known about more subtle changes in general health status of very long-term survivors. The study objective was to assess health status of very long-term survivors in comparison with their respective human leukocyte antigen-identical sibling donors. Design and Methods Case matched comparison in a cross-sectional cohort was performed in a tertiary university hospital and referral center for hematopoietic stem cell transplantation. Forty-four pairs of recipients and their respective donors with a very long-term (17.5 years median; 11–26 years range) follow up after allogeneic hematopoietic stem cell transplantation were included. A comparative clinical evaluation and examination of routine clinical chemistry tests was carried out. Results Recipients more frequently had a lower Karnofsky score (P=0.05), hypertension (P=0.015) and dyslipidemia (P=0.002) but were less likely to be smokers (P=0.016). Recipients showed systematically lower glomerular filtration rates (P<0.0001), higher liver function tests (P=0.0004 for Aspartat-Amino-Transferase) and reduced thyroid function (P=0.002) despite normal or near normal values, and independent of presence or absence of chronic graft-versus-host disease. Indicators of inflammation were more frequent in recipients (9 of 44) with ongoing chronic graft-versus-host disease as measured by higher C-reactive protein (P=0.001) and higher von Willebrand factor (P=0.002). Conclusions Clinically very long-term survivors after an allogeneic hematopoietic stem cell transplantation present more frequently with cardiovascular risk factors and with subtle signs of altered organ function compared to their sibling donors. Even minimal ongoing chronic graft-versus-host disease remains associated with elevated laboratory indicators of inflammation. The clinical significance of these

  1. The use of stimulated granulocyte transfusions to prevent recurrence of past severe infections after allogeneic stem cell transplantation.

    PubMed

    Kerr, J Paul; Liakopolou, Effie; Brown, Jessica; Cornish, Jacqueline M; Fleming, David; Massey, Edwin; Oakhill, Anthony; Pamphilon, Derwood H; Robinson, Stephen P; Totem, April; Valencia, Alexandra M P I; Marks, David I

    2003-10-01

    The predictable neutropenia that follows allogeneic stem cell transplantation (ASCT) may be associated with recurrence of previous life-threatening infection. We describe nine patients with either previous invasive aspergillosis (IA) or considered to be at high risk of developing IA who underwent ASCT with prophylactic granulocyte transfusions. The study group, when compared with a control group, had a significant reduction in the incidence and duration of fevers (P < 0.05) and maximum C-reactive protein (P < 0.05). There were significantly fewer days of neutropenia (P < 0.05). There was also radiological improvement of pulmonary infiltrates in four out of seven assessable patients. No serious toxicity was encountered in donors or recipients. We conclude that prophylactic granulocyte donations can be given safely, and that they significantly reduce the number of days of neutropenia. Further investigation is warranted to determine whether granulocyte donations can prevent the recurrence of IA in patients at risk of fungal infection. PMID:14510952

  2. Recovery from CMV esophagitis after allogeneic bone marrow transplantation using non-myeloablative conditioning: the role of immunosuppression.

    PubMed

    Fiegl, Michael; Gerbitz, Armin; Gaeta, Antonia; Campe, Hartmut; Jaeger, Gundula; Kolb, Hans-Jochem

    2005-11-01

    Cytomegalovirus (CMV) positive recipients of CMV negative bone marrow bear a significantly higher risk of developing CMV disease compared to all other constellations. Here, we report a case of severe CMV induced esophagitis after allogeneic bone marrow transplantation for paroxysmal nocturnal hemoglobinuria. The patient developed the first symptoms between day 10 and 20 after dose reduced conditioning and HLA-matched unrelated stem cell transplantation. Esophageal tissue biopsies as well as peripheral blood proved positive for CMV DNA by PCR. Treatment with acyclovir, ganciclovir, foscarnet, cidofovir, and immunoglobulines resulted in elimination of CMV in peripheral blood but not in clinical improvement. Only tapering of cyclosporine at day +120 eventually led to the development of CMV-specific T-cells and resolution of esophagitis. PMID:16129661

  3. Lipids in liver transplant recipients

    PubMed Central

    Hüsing, Anna; Kabar, Iyad; Schmidt, Hartmut H

    2016-01-01

    Hyperlipidemia is very common after liver transplantation and can be observed in up to 71% of patients. The etiology of lipid disorders in these patients is multifactorial, with different lipid profiles observed depending on the immunosuppressive agents administered and the presence of additional risk factors, such as obesity, diabetes mellitus and nutrition. Due to recent improvements in survival of liver transplant recipients, the prevention of cardiovascular events has become more important, especially as approximately 64% of liver transplant recipients present with an increased risk of cardiovascular events. Management of dyslipidemia and of other modifiable cardiovascular risk factors, such as hypertension, diabetes and smoking, has therefore become essential in these patients. Treatment of hyperlipidemia after liver transplantation consists of life style modification, modifying the dose or type of immunosuppressive agents and use of lipid lowering agents. At the start of administration of lipid lowering medications, it is important to monitor drug-drug interactions, especially between lipid lowering agents and immunosuppressive drugs. Furthermore, as combinations of various lipid lowering drugs can lead to severe side effects, such as myopathies and rhabdomyolysis, these combinations should therefore be avoided. To our knowledge, there are no current guidelines targeting the management of lipid metabolism disorders in liver transplant recipients. This paper therefore recommends an approach of managing lipid abnormalities occurring after liver transplantation. PMID:27022213

  4. Demodicosis in Renal Transplant Recipients.

    PubMed

    Chovatiya, R J; Colegio, O R

    2016-02-01

    Solid organ transplant recipients have an increased incidence of skin infections resulting from immunosuppression. Common pathogens include herpes simplex virus, varicella zoster virus, Gram-positive bacteria and dermatophytes; however, the contribution of multicellular parasitic organisms to dermatologic disease in this population remains less studied. Demodex folliculorum and brevis are commensal mites that reside on human skin. Proliferation of Demodex mites, or demodicosis, is associated with rosacea and rosacea-like disorders, particularly in immunocompromised populations, although their ability to cause disease is still the subject of debate. We present a case series of four renal transplant recipients with the singular chief complaint of acne rosacea who we diagnosed with demodicosis. Although one of the four patients showed complete resolution following initial antiparasitic therapy, the other three required subsequent antibacterial treatment to fully resolve their lesions. We suggest that demodicosis may be more prevalent than once thought in solid organ transplant recipients and showed that Demodex-associated acne rosacea can be effectively treated in this population. PMID:26431451

  5. Lipids in liver transplant recipients.

    PubMed

    Hüsing, Anna; Kabar, Iyad; Schmidt, Hartmut H

    2016-03-28

    Hyperlipidemia is very common after liver transplantation and can be observed in up to 71% of patients. The etiology of lipid disorders in these patients is multifactorial, with different lipid profiles observed depending on the immunosuppressive agents administered and the presence of additional risk factors, such as obesity, diabetes mellitus and nutrition. Due to recent improvements in survival of liver transplant recipients, the prevention of cardiovascular events has become more important, especially as approximately 64% of liver transplant recipients present with an increased risk of cardiovascular events. Management of dyslipidemia and of other modifiable cardiovascular risk factors, such as hypertension, diabetes and smoking, has therefore become essential in these patients. Treatment of hyperlipidemia after liver transplantation consists of life style modification, modifying the dose or type of immunosuppressive agents and use of lipid lowering agents. At the start of administration of lipid lowering medications, it is important to monitor drug-drug interactions, especially between lipid lowering agents and immunosuppressive drugs. Furthermore, as combinations of various lipid lowering drugs can lead to severe side effects, such as myopathies and rhabdomyolysis, these combinations should therefore be avoided. To our knowledge, there are no current guidelines targeting the management of lipid metabolism disorders in liver transplant recipients. This paper therefore recommends an approach of managing lipid abnormalities occurring after liver transplantation. PMID:27022213

  6. Fecal calprotectin as a biomarker of intestinal graft versus host disease after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Lorenz, Fryderyk; Marklund, Stefan; Werner, Mårten; Palmqvist, Richard; Wahlin, Björn Engelbrekt; Wahlin, Anders

    2015-01-01

    The diagnosis of gastrointestinal graft versus host disease (GI-GVHD) is based on clinical symptoms and histological findings. In clinical practice, it is often difficult to decide whether abdominal symptoms in an allogeneic transplant recipient are caused by GVHD or other disorders. Endoscopic biopsies are helpful in establishing the diagnosis, but endoscopy is not always possible to perform due to poor general condition of the patients. No biomarkers are routinely used to predict GVHD. The aim of fecal calprotectin and alpha-1 antitrypsin testing in our study was to find out whether determination of the concentrations of these proteins may be used as a screening method for enteric GVHD. We studied prospectively 51 patients, 8 of whom developed GI-GVHD. Our data demonstrate that elevated fecal calprotectin levels were significantly associated with presence of GI-GVHD. We found a positive association between high F-calprotectin and severe gastrointestinal GVHD. In bivariate analysis, only calprotectin but not alpha-1 antitrypsin was independently associated with GI-GVHD. Testing for fecal calprotectin after allogeneic stem cell transplantation may be a useful screening tool. PMID:25605402

  7. Fecal calprotectin as a biomarker of intestinal graft versus host disease after allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Lorenz, Fryderyk; Marklund, Stefan; Werner, Mårten; Palmqvist, Richard; Wahlin, Björn Engelbrekt; Wahlin, Anders

    2015-01-01

    The diagnosis of gastrointestinal graft versus host disease (GI-GVHD) is based on clinical symptoms and histological findings. In clinical practice, it is often difficult to decide whether abdominal symptoms in an allogeneic transplant recipient are caused by GVHD or other disorders. Endoscopic biopsies are helpful in establishing the diagnosis, but endoscopy is not always possible to perform due to poor general condition of the patients. No biomarkers are routinely used to predict GVHD. The aim of fecal calprotectin and alpha-1 antitrypsin testing in our study was to find out whether determination of the concentrations of these proteins may be used as a screening method for enteric GVHD. We studied prospectively 51 patients, 8 of whom developed GI-GVHD. Our data demonstrate that elevated fecal calprotectin levels were significantly associated with presence of GI-GVHD. We found a positive association between high F-calprotectin and severe gastrointestinal GVHD. In bivariate analysis, only calprotectin but not alpha-1 antitrypsin was independently associated with GI-GVHD. Testing for fecal calprotectin after allogeneic stem cell transplantation may be a useful screening tool. PMID:25605402

  8. Effect of acute and chronic graft-versus-host disease on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma

    PubMed Central

    Ringdén, Olle; Shrestha, Smriti; da Silva, Gisela Tunes; Zhang, Mei-Jie; Dispenzieri, Angela; Remberger, Mats; Kamble, Rammurti; Freytes, Cesar O.; Gale, Robert Peter; Gibson, John; Gupta, Vikas; Holmberg, Leona; Lazarus, Hillard; McCarthy, Philip; Meehan, Kenneth; Schouten, Harry; Milone, Gustavo A.; Lonial, Sagar; Hari, Parameswaran N

    2011-01-01

    We evaluated the effect of acute and chronic graft-versus-host disease (GVHD) on relapse and survival after allogeneic haematopoietic stem cell transplantation (HSCT) for multiple myeloma (MM) using non-myeloablative conditioning (NMA) and reduced-intensity conditioning (RIC). The outcomes of 177 HLA-identical sibling HSCT recipients between 1997 and 2005 following NMA (n=98) or RIC (n=79) were analyzed. In 105 patients, autografting was followed by planned NMA/RIC allogeneic transplantation. The impact of GVHD was assessed as a time-dependent covariate using Cox models. The incidence of acute GVHD (grades I–IV) was 42% (95% confidence interval (CI) 35 – 49%) and of chronic GVHD at five years was 59% (95% CI 49 – 69%), with 70% developing extensive chronic GVHD. In multivariate analysis, acute GVHD (≥ grade I) was associated with an increased risk of TRM (relative risk (RR)=2.42; p=0.016), whereas limited chronic GVHD significantly decreased the risk of myeloma relapse (RR=0.35, p=0.035) and was associated with superior event-free survival (RR=0.40, p=0.027). Acute GVHD had a detrimental effect on survival, especially in those receiving autologous followed by allogeneic HSCT (RR=3.52; p=0.001). The reduction in relapse risk associated with chronic GVHD is consistent with a beneficial graft-versus-myeloma effect, but this did not translate into a survival advantage. PMID:21946381

  9. 21 CFR 1271.420 - HCT/Ps offered for import.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... recipient for reproductive use. (d) This section does not apply to peripheral blood stem/progenitor cells... peripheral blood stem/progenitor cells may present an unreasonable risk of communicable disease...

  10. 21 CFR 1271.420 - HCT/Ps offered for import.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... recipient for reproductive use. (d) This section does not apply to peripheral blood stem/progenitor cells... peripheral blood stem/progenitor cells may present an unreasonable risk of communicable disease...

  11. 21 CFR 1271.420 - HCT/Ps offered for import.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... recipient for reproductive use. (d) This section does not apply to peripheral blood stem/progenitor cells... peripheral blood stem/progenitor cells may present an unreasonable risk of communicable disease...

  12. 21 CFR 1271.420 - HCT/Ps offered for import.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... recipient for reproductive use. (d) This section does not apply to peripheral blood stem/progenitor cells... peripheral blood stem/progenitor cells may present an unreasonable risk of communicable disease...

  13. 21 CFR 1271.420 - HCT/Ps offered for import.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... recipient for reproductive use. (d) This section does not apply to peripheral blood stem/progenitor cells... peripheral blood stem/progenitor cells may present an unreasonable risk of communicable disease...

  14. Infections with the 2009 H1N1 influenza virus among hematopoietic SCT recipients: a single center experience.

    PubMed

    Rihani, R; Hayajneh, W; Sultan, I; Ghatasheh, L; Abdel-Rahman, F; Hussein, N; Hussein, A; Al-Zaben, A; Sarhan, M; Saad, M

    2011-11-01

    We retrospectively reviewed medical records of 39 hematopoietic SCT (HSCT) recipients who presented at our hospital between 1 October 2009 and 31 January 2010 with the 2009 H1N1 influenza infection. The median age at presentation was 13.8 years (range: 3.3-56.9), infections developed at a median of 585 days (range: 0-2316) post transplant, the majority (n=27, 69%) occurred in allogeneic HSCT recipients, 12 (31%) patients were on immunosuppressive therapy and 12 (31%) had GVHD. Lower airway disease was present in 8 patients (21%). In total, 15 patients (39%) were hospitalized with a median duration of 4.5 days (range: 3-27 days) and 3 (8%) required mechanical ventilation; 2 of whom died. PMID:21243021

  15. Outcome of pandemic H1N1 infections in hematopoietic stem cell transplant recipients

    PubMed Central

    Ljungman, Per; de la Camara, Rafael; Perez-Bercoff, Lena; Abecasis, Manuel; Nieto Campuzano, Jose Bartolo; Cannata-Ortiz, M. Jimena; Cordonnier, Catherine; Einsele, Hermann; Gonzalez-Vicent, Marta; Espigado, Ildefonso; Halter, Jörg; Martino, Rodrigo; Mohty, Bilal; Sucak, Gülsan; Ullmann, Andrew J; Vázquez, Lourdes; Ward, Katherine N.; Engelhard, Dan

    2011-01-01

    During 2009, a new strain of A/H1N1 influenza appeared and became pandemic. A prospective study was performed to collect data regarding risk factors and outcome of A/H1N1 in hematopoietic stem cell transplant recipients. Only verified pandemic A/H1N1 influenza strains were included: 286 patients were reported, 222 allogeneic and 64 autologous recipients. The median age was 38.3 years and the median time from transplant was 19.4 months. Oseltamivir was administered to 267 patients and 15 patients received zanamivir. One hundred and twenty-five patients (43.7%) were hospitalized. Ninety-three patients (32.5%) developed lower respiratory tract disease. In multivariate analysis, risk factors were age (OR 1.025; 1.01–1.04; P=0.002) and lymphopenia (OR 2.49; 1.33–4.67; P<0.001). Thirty-three patients (11.5%) required mechanical ventilation. Eighteen patients (6.3%) died from A/H1N1 infection or its complications. Neutropenia (P=0.03) and patient age (P=0.04) were significant risk factors for death. The 2009 A/H1N1 influenza pandemic caused severe complications in stem cell transplant recipients. PMID:21546495

  16. Outcome of pandemic H1N1 infections in hematopoietic stem cell transplant recipients.

    PubMed

    Ljungman, Per; de la Camara, Rafael; Perez-Bercoff, Lena; Abecasis, Manuel; Nieto Campuzano, Jose Bartolo; Cannata-Ortiz, M Jimena; Cordonnier, Catherine; Einsele, Hermann; Gonzalez-Vicent, Marta; Espigado, Ildefonso; Halter, Jörg; Martino, Rodrigo; Mohty, Bilal; Sucak, Gülsan; Ullmann, Andrew J; Vázquez, Lourdes; Ward, Katherine N; Engelhard, Dan

    2011-08-01

    During 2009, a new strain of A/H1N1 influenza appeared and became pandemic. A prospective study was performed to collect data regarding risk factors and outcome of A/H1N1 in hematopoietic stem cell transplant recipients. Only verified pandemic A/H1N1 influenza strains were included: 286 patients were reported, 222 allogeneic and 64 autologous recipients. The median age was 38.3 years and the median time from transplant was 19.4 months. Oseltamivir was administered to 267 patients and 15 patients received zanamivir. One hundred and twenty-five patients (43.7%) were hospitalized. Ninety-three patients (32.5%) developed lower respiratory tract disease. In multivariate analysis, risk factors were age (OR 1.025; 1.01-1.04; P=0.002) and lymphopenia (OR 2.49; 1.33-4.67; P<0.001). Thirty-three patients (11.5%) required mechanical ventilation. Eighteen patients (6.3%) died from A/H1N1 infection or its complications. Neutropenia (P=0.03) and patient age (P=0.04) were significant risk factors for death. The 2009 A/H1N1 influenza pandemic caused severe complications in stem cell transplant recipients. PMID:21546495

  17. Allogeneic hematopoietic stem cell transplantation in mycosis fungoides*

    PubMed Central

    Atalla, Angelo; Hallack Neto, Abrahão Elias; Siqueira, Denise Bittencourt; Toledo, Gabriela Cumani

    2013-01-01

    Mycosis Fungoides is typically an indolent disease in early stages. However, approximately 30% of patients have advanced staged disease at presentation and 20% will develop it at some time. These patients have a poorer prognosis with a median survival of 2-4 years. The only curative option for mycosis fungoides may be hematopoietic allogeneic stem cell transplantation. We report the case of a patient with mycosis fungoides in an advanced stage (IIB), refractory to treatment options. She underwent allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The patient remains in complete remission nineteen months after allo-HSCT. Allogeneic transplantation can alter the natural history of mycosis fungoides and should be considered in patients who have refractory disease or short-lived responses with standard therapies. PMID:24346924

  18. Cellular therapy following allogeneic stem-cell transplantation

    PubMed Central

    Rager, Alison

    2011-01-01

    Allogeneic hematopoietic stem-cell transplantation (HSCT) is the most effective approach for many patients with hematologic malignancies. Unfortunately, relapse remains the most common cause of death after allogeneic HSCT, and the prognosis of relapsed disease is poor for most patients. Induction of a graft-versus-leukemia (GVL), or graft-versus-tumor, effect through the use of donor leukocyte infusion (DLI), or donor lymphocyte infusion, has been remarkably successful for relapsed chronic myelogenous leukemia. Unfortunately, response to DLI in other hematologic malignancies is much less common and depends on many factors including histology, pace and extent of relapse, and time from HSCT to relapse. Furthermore, graft-versus-host disease (GVHD) is common after DLI and often limits successful immunotherapy. Ultimately, manipulations to minimize GVHD while preserving or enhancing GVL are necessary to improve outcomes for relapse after allogeneic HSCT. PMID:23556106

  19. Autologous and allogeneic serum eye drops. The Dutch perspective.

    PubMed

    van der Meer, Pieter F; Seghatchian, Jerard; de Korte, Dirk

    2015-08-01

    If regular artificial tears are ineffective for treatment of ocular surface disorders (including extreme dry eye syndrome), serum eye drops (SEDs) may provide a way to relieve the symptoms. However, not all patients are eligible to donate blood to produce autologous SEDs. Therefore, the use of allogeneic SEDs (obtained from voluntary blood donors) should be explored as an alternative for autologous SEDs. The Dutch blood bank organization is currently looking into the possibilities to provide allogeneic SEDs, as (GMP) regulations become stricter, making it for hospitals more difficult to provide autologous SEDs. To demonstrate effectiveness of both autologous and allogeneic SEDs, a clinical trial is planned. The current status of SEDs in The Netherlands is described. This paper is based on summary of the presentation given at the DGTI meeting in Dresden. PMID:26138910

  20. A new immuno-, dystrophin-deficient model, the NSG-mdx(4Cv) mouse, provides evidence for functional improvement following allogeneic satellite cell transplantation.

    PubMed

    Arpke, Robert W; Darabi, Radbod; Mader, Tara L; Zhang, Yu; Toyama, Akira; Lonetree, Cara-Lin; Nash, Nardina; Lowe, Dawn A; Perlingeiro, Rita C R; Kyba, Michael

    2013-08-01

    Transplantation of a myogenic cell population into an immunodeficient recipient is an excellent way of assessing the in vivo muscle-generating capacity of that cell population. To facilitate both allogeneic and xenogeneic transplantations of muscle-forming cells in mice, we have developed a novel immunodeficient muscular dystrophy model, the NSG-mdx(4Cv) mouse. The IL2Rg mutation, which is linked to the Dmd gene on the X chromosome, simultaneously depletes NK cells and suppresses thymic lymphomas, issues that limit the utility of the SCID/mdx model. The NSG-mdx(4Cv) mouse presents a muscular dystrophy of similar severity to the conventional mdx mouse. We show that this animal supports robust engraftment of both pig and dog muscle mononuclear cells. The question of whether satellite cells prospectively isolated by flow cytometry can confer a functional benefit upon transplantation has been controversial. Using allogeneic Pax7-ZsGreen donors and NSG-mdx(4Cv) recipients, we demonstrate definitively that as few as 900 FACS-isolated satellite cells can provide functional regeneration in vivo, in the form of an increased mean maximal force-generation capacity in cell-transplanted muscles, compared to a sham-injected control group. These studies highlight the potency of satellite cells to improve muscle function and the utility of the NSG-mdx(4Cv) model for studies on muscle regeneration and Duchenne muscular dystrophy therapy. PMID:23606600

  1. Treatment of BK virus-associated hemorrhagic cystitis with low-dose intravenous cidofovir in patients undergoing allogeneic hematopoietic cell transplantation

    PubMed Central

    Lee, Seung-Shin; Jung, Sung-Hoon; Ahn, Seo-Yeon; Kim, Jae-Yong; Jang, Hee-Chang; Kang, Seung-Ji; Jang, Mi-Ok; Yang, Deok-Hwan; Kim, Yeo-Kyeoung; Lee, Je-Jung; Kim, Hyeoung-Joon

    2015-01-01

    Background/Aims BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC) in recipients of hematopoietic stem cell transplantation (HSCT). Cidofovir has been used at higher doses (3 to 5 mg/kg/wk) with probenecid prophylaxis; however, cidofovir may result in nephrotoxicity or cytopenia at high doses. Methods Allogeneic HSCT recipients with BKV-associated HC are treated with 1 mg/kg intravenous cidofovir weekly at our institution. A microbiological response was defined as at least a one log reduction in urinary BKV viral load, and a clinical response was defined as improvement in symptoms and stability or reduction in cystitis grade. Results Eight patients received a median of 4 weekly (range, 2 to 11) doses of cidofovir. HC occurred a median 69 days (range, 16 to 311) after allogeneic HSCT. A clinical response was detected in 7/8 patients (86%), and 4/5 (80%) had a measurable microbiological response. One patient died of uncontrolled graft-versus-host disease; therefore, we could not measure the clinical response to HC treatment. One microbiological non-responder had a stable BKV viral load with clinical improvement. Only three patients showed transient grade 2 serum creatinine toxicities, which resolved after completion of concomitant calcineurin inhibitor treatment. Conclusions Weekly intravenous low-dose cidofovir without probenecid appears to be a safe and effective treatment option for patients with BKV-associated HC. PMID:25750563

  2. Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and High-Dose Rituximab for Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma: A Phase Two Multicenter Trial from the Blood and Marrow Transplant Clinical Trials Network.

    PubMed

    Laport, Ginna G; Wu, Juan; Logan, Brent; Bachanova, Veronika; Hosing, Chitra; Fenske, Timothy; Longo, Walter; Devine, Steven M; Nademanee, Auayporn; Gersten, Iris; Horowitz, Mary; Lazarus, Hillard M; Riches, Marcie L

    2016-08-01

    Allogeneic (allo) hematopoietic cell transplantation (HCT) can induce long-term remissions in chemosensitive relapsed follicular lymphoma (FL). The Blood and Marrow Transplant Clinical Trials Network conducted a multicenter phase 2 trial to examine the efficacy of alloHCT using reduced-intensity conditioning with rituximab (RTX) in multiply relapsed, chemosensitive FL. The primary endpoint was 2-year progression-free survival (PFS). The conditioning regimen consisted of fludarabine, cyclophosphamide, and high-dose RTX (FCR), in which 3 of the 4 doses of RTX were administered at a dose of 1 gm/m(2). Graft-versus-host disease (GVHD) prophylaxis was with tacrolimus and methotrexate. Sixty-five patients were enrolled and 62 were evaluable. Median age was 55 years (range, 29 to 74). This group was heavily pretreated: 77% had received ≥ 3 prior regimens, 32% had received ≥ 5 prior regimens, and 11% had received prior autologous HCT. Donors were HLA-matched siblings (n = 33) or HLA-matched unrelated adults (n = 29). No graft failures occurred. The overall response rate after HCT was 94% with 90% in complete remission (CR), including 24 patients not in CR before alloHCT. With a median follow-up of 47 months (range, 30 to 73), 3-year PFS and overall survival rates were 71% (95% confidence interval, 58% to 81%) and 82% (95% confidence interval, 70% to 90%), respectively. Three-year cumulative incidences of relapse/progression and nonrelapse mortality were 13% and 16%, respectively. Two-year cumulative incidences of grades 2 to 4 and grades 3 or 4 acute GVHD were 27% and 10%, respectively, and extensive chronic GVHD incidence was 55%. Serum RTX concentrations peaked at day +28 and remained detectable as late as 1 year in 59% of patients with available data. In conclusion, alloHCT with FCR conditioning confers high CR rates, a low incidence of relapse/progression, and excellent survival probabilities in heavily pretreated FL patients. PMID:27118571

  3. Chimerism analysis following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning.

    PubMed

    Valcárcel, D; Martino, R; Caballero, D; Mateos, M V; Pérez-Simón, J A; Canals, C; Fernández, F; Bargay, J; Muñiz-Díaz, E; Gonzalez, M; San Miguel, J F; Sierra, J

    2003-03-01

    We have performed a prospective study to evaluate early chimerism and its kinetics after allogeneic peripheral blood stem cell transplantation among 68 patients who received a reduced-intensity conditioning (RIC) regimen with fludarabine plus melphalan (n=40) or busulphan (n=28). Chimerism was analyzed by polymerase chain reaction amplification of short tandem repeats in unfractionated (UF) and/or fractionated nucleated cells from bone marrow and peripheral blood (PB). All of the patients showed initial donor engraftment and no patient presented primary or secondary graft failure. In UF samples, the probability of achieving stable complete donor chimerism (CDC) in PB within the first 6 months was 70% on day +30, 85% on day +100 and 95% on day +180. CDC in granulocytes was observed in nearly all cases from day +30 onwards. CDC in T cells, however, differed among melphalan and busulphan recipients during the first 3 months (100 vs 0% on day +30 and 93 vs 20% on day +90, respectively). In multivariate analysis, the only significant variable associated with the achievement of early CDC was having received more than two lines of chemotherapy pretransplant (P<0.02). No correlation was found between the rate of achieving early CDC and the occurrence of acute graft-versus-host disease (GVHD) or disease progression post-transplant. In multivariate analysis, the only variable that influenced the incidence of disease progression post-transplant was the development of chronic extensive GVHD (P<0.05). In conclusion, a state of CDC is readily obtained within the first 6 months after our RIC protocols. Donor myeloid engraftment occurs rapidly in all cases, while early T-cell CDC is more common in more immunosuppressed hosts and, perhaps, in melphalan recipients. PMID:12634730

  4. Anti-bacterial immunity to Listeria monocytogenes in allogeneic bone marrow chimera in mice

    SciTech Connect

    Onoe, K.; Good, R.A.; Yamamoto, K.

    1986-06-01

    Protection and delayed-type hypersensitivity (DTH) to the facultative intracellular bacterium Listeria monocytogenes (L.m.) were studied in allogeneic and syngeneic bone marrow chimeras. Lethally irradiated AKR (H-2k) mice were successfully reconstituted with marrow cells from C57BL/10 (B10) (H-2b), B10 H-2-recombinant strains or syngeneic mice. Irradiated AKR mice reconstituted with marrow cells from H-2-compatible B10.BR mice, (BR----AKR), as well as syngeneic marrow cells, (AKR----AKR), showed a normal level of responsiveness to the challenge stimulation with the listeria antigens when DTH was evaluated by footpad reactions. These mice also showed vigorous activities in acquired resistance to the L.m. By contrast, chimeric mice that had total or partial histoincompatibility at the H-2 determinants between donor and recipient, (B10----AKR), (B10.AQR----AKR), (B10.A(4R)----AKR), or (B10.A(5R)----AKR), were almost completely unresponsive in DTH and antibacterial immunity. However, when (B10----AKR) H-2-incompatible chimeras had been immunized with killed L.m. before challenge with live L.m., these mice manifested considerable DTH and resistance to L.m. These observations suggest that compatibility at the entire MHC between donor and recipient is required for bone marrow chimeras to be able to manifest DTH and protection against L.m. after a short-term immunization schedule. However, this requirement is overcome by a preceding or more prolonged period of immunization with L.m. antigens. These antigens, together with marrow-derived antigen-presenting cells, can then stimulate and expand cell populations that are restricted to the MHC (H-2) products of the donor type.

  5. Cryptosporidium parvum induces an endoplasmic stress response in the intestinal adenocarcinoma HCT-8 cell line.

    PubMed

    Morada, Mary; Pendyala, Lakhsmi; Wu, Gang; Merali, Salim; Yarlett, Nigel

    2013-10-18

    Invasion of human intestinal epithelial cells (HCT-8) by Cryptosporidium parvum resulted in a rapid induction of host cell spermidine/spermine N(1)-acetyltransferase 1 (hSSAT-1) mRNA, causing a 4-fold increase in SSAT-1 enzyme activity after 24 h of infection. In contrast, host cell SSAT-2, spermine oxidase, and acetylpolyamine oxidase (hAPAO) remained unchanged during this period. Intracellular polyamine levels of C. parvum-infected human epithelial cells were determined, and it was found that spermidine remained unchanged and putrescine increased by 2.5-fold after 15 h and then decreased after 24 h, whereas spermine decreased by 3.9-fold after 15 h. Concomitant with these changes, N(1)-acetylspermine and N(1)-acetylspermidine both increased by 115- and 24-fold, respectively. Increased SSAT-1 has previously been shown to be involved in the endoplasmic reticulum (ER) stress response leading to apoptosis. Several stress response proteins were increased in HCT-8 cells infected with C. parvum, including calreticulin, a major calcium-binding chaperone in the ER; GRP78/BiP, a prosurvival ER chaperone; and Nrf2, a transcription factor that binds to antioxidant response elements, thus activating them. However, poly(ADP-ribose) polymerase, a protein involved in DNA repair and programmed cell death, was decreased. Cumulatively, these results suggest that the invasion of HCT-8 cells by C. parvum results in an ER stress response by the host cell that culminates in overexpression of host cell SSAT-1 and elevated N(1)-acetylpolyamines, which can be used by a parasite that lacks ornithine decarboxylase. PMID:23986438

  6. NOD2 Expression is Regulated by microRNAs in Colonic Epithelial HCT116 Cells

    PubMed Central

    Chuang, Alice Y.; Chuang, Jim C.; Zhai, Zili; Wu, Feng; Kwon, John H.

    2016-01-01

    Background Crohn's disease (CD) is associated with defective sensing of pathogens in genetically susceptible individuals. Nucleotide-binding oligomerization domain containing 2 (NOD2) mutations in coding regions are strongly linked to CD pathogenesis. Our laboratory has reported that microRNAs (miRNAs) are differentially expressed in CD. However, miRNA regulation of NOD2 remains unknown. This study was designed to determine whether miRNAs regulate NOD2 expression as well as downstream nuclear factor kappaB activation and inflammatory responses in colonic epithelial HCT116 cells. Methods NOD2 and miRNA expression in stimulated HCT116 cells were assessed by quantitative reverse transcription–polymerase chain reaction. Regulation of NOD2 expression by miRNAs was determined by luciferase reporter construct assays and transfection of specific miRNA mimics. Regulation of NOD2 signaling and immune response by miRNAs was assessed by transfection of mimics followed by muramyl dipeptide stimulation. Results Muramyl dipeptide-induced increases in NOD2, interleukin-8, and CXCL3 expression were inversely associated with miRNA expression. Overexpression of miR-192, miR-495, miR-512, and miR-671 suppressed NOD2 expression, muramyl dipeptide-mediated NF-κB activation, and messenger RNA expressions of interleukin-8 and CXCL3 in HCT116 cells. A single-nucleotide polymorphism (rs3135500) located in the NOD2 3′-untranslated region significantly reduced miR-192 effects on NOD2 gene expression. Conclusions To our knowledge, this is the first report demonstrating that miRNAs regulate NOD2 and its signaling pathway. Four miRNAs downregulate NOD2 expression, suppress NF-κB activity, and inhibit interleukin-8 and CXCL3 messenger RNA expression. Treatment of CD with miRNAs may represent a potential anti-inflammatory therapeutic strategy in CD patients with and without NOD2 gene mutations. PMID:24297055

  7. A novel microtubule depolymerizing colchicine analogue triggers apoptosis and autophagy in HCT-116 colon cancer cells.

    PubMed

    Kumar, Ashok; Singh, Baljinder; Sharma, Parduman R; Bharate, Sandip B; Saxena, Ajit K; Mondhe, D M

    2016-03-01

    Colchicine is a tubulin-binding natural product isolated from Colchicum autumnale. Here we report the in vitro anticancer activity of C-ring modified semi-synthetic derivative of colchicine; N-[(7S)-1,2,3-trimethoxy-9-oxo-10-(4-phenyl-piperidin-1-yl)-5,6,7,9 tetrahydrobenzo[a]heptalen-7-yl]acetamide (4h) on colon cancer HCT-116 cell line. The compound 4h was screened for anti-proliferative activity against different human cancer cell lines and was found to exhibit higher cytotoxicity against colon cancer cell lines HCT-116 and Colo-205 with IC50 of 1 and 0.8 μM respectively. Cytotoxicity of the compound to the normal fR2 breast epithelial cells and normal HEK293 human embryonic kidney cells was evaluated in concentration and time-dependent manner to estimate its selectivity for cancer cells which showed much better selectivity than that of colchicine. Compound 4h induced cell death in HCT-116 cells by activating apoptosis and autophagy pathways. Autophagy inhibitor 3-MA blocked the production of LC3-II and reduced the cytotoxicity in response to 4h, but did not affect apoptosis, suggesting thereby that these two were independent events. Reactive oxygen species scavenger ascorbic acid pretreatment not only decreased the reactive oxygen species level but also reversed 4h induced cytotoxicity. Treatment with compound 4h depolymerized microtubules and the majority of cells arrested at the G2/M transition. Together, these data suggest that 4h has better selectivity and is a microtubule depolymerizer, which activates dual cell-death machineries, and thus, it could be a potential novel therapeutic agent in cancer therapy. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26919061

  8. Functionally Active HIV-Specific T Cells that Target Gag and Nef Can Be Expanded from Virus-Naïve Donors and Target a Range of Viral Epitopes: Implications for a Cure Strategy after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Patel, Shabnum; Lam, Sharon; Cruz, Conrad Russell; Wright, Kaylor; Cochran, Christina; Ambinder, Richard F; Bollard, Catherine M

    2016-03-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) can potentially cure human immunodeficiency virus (HIV) by eliminating infected recipient cells, particularly in the context of technologies that may confer HIV resistance to these stem cells. But, to date, the Berlin patient remains the only case of HIV cure despite multiple attempts to eradicate infection with HSCT. One approach to improve this is to administer virus-specific T cells, a strategy that has proven success in preventing other infections after transplantation. Although we have reported that broadly HIV-specific T cells can be expanded from HIV+ patients, allogeneic transplantations only contain virus-naïve T cells. Modifying this approach for the allogeneic setting requires a robust, reproducible platform that can expand HIV-specific cells from the naïve pool. Hence, we hypothesized that HIV-specific T cells could be primed ex vivo from seronegative individuals to effectively target HIV. Here, we show that ex vivo-primed and expanded HIV-specific T cells released IFNγ in response to HIV antigens and that these cells have enhanced ability to suppress replication in vitro. This is the first demonstration of ex vivo priming and expansion of functional, multi-HIV antigen-specific T cells from HIV-negative donors, which has implications for use of allogeneic HSCT as a functional HIV cure. PMID:26721209

  9. Polychlorinated biphenyls (PCBs) depress allogeneic natural cytotoxicity by earthworm coelomocytes

    SciTech Connect

    Suzuki, M.M.; Cooper, E.L.; Eyambe, G.S.; Goven, A.J.; Fitzpatrick, L.C.; Venables, B.J. |

    1995-10-01

    Coelomocytes of the earthworm Lumbricus terrestris caused significant spontaneous allogeneic cytotoxicity in a 24-h trypan blue assay, but not in an assay using lactate dehydrogenase (LDH) release. Allogeneic cytotoxicity assays using cells from worms exposed to polychlorinated biphenyls (PCBs) suggest that PCBs can suppress a natural killing (NK-like) reaction. The implications of this work are twofold: understanding the evolution of natural killing (NK-like) activity and providing preliminary information on how spontaneous killing, a component of cellular immunity, may be compromised by pollutants.

  10. RCT photometry and HCT spectroscopy of blazar candidates in the Kepler field of view

    NASA Astrophysics Data System (ADS)

    Carini, Michael T.; Goyal, A.; Jose, J.

    2014-01-01

    The results of photometric and spectroscopic monitoring of 9 blazar candidates in the Kepler field of view are presented. These sources were identified as blazar candidates based on their position in the so-called WISE blazar strip. Finding charts and comparison sequences were created using the NOMAD database. R band photometric monitoring was begun in spring 2013 with the Robotically Controlled Telescope(RCT), and spectroscopic observations of 7 of the sources were obtained with the Himalayan Chandra Telescope (HCT) in September, 2013. Light curves for all 9 sources and preliminary spectroscopic classifications for the 7 sources with spectra will be presented.

  11. Survivorship after allogeneic transplantation-management recommendations for the primary care provider.

    PubMed

    Tichelli, André; Rovó, Alicia

    2015-03-01

    Prognosis after allogeneic hematopoietic stem cell transplantation (HSCT) has greatly improved. Therefore, long-term survivorship becomes an important issue. A number of malignant and nonmalignant late effects can cause substantial morbidity, with considerable impact on health and quality of life. The main factors responsible for late effects after HSCT are total body irradiation-based conditioning and chronic graft-versus-host disease and its treatment. The knowledge on late effects serves as guidance for surveillance and management decision. Aftercare includes screening and counseling for prevention and treatment of late complications. The care of HSCT recipients tends with time to be transferred from the transplant center back to the primary care provider, who might not be however familiar with the unique needs of long-term survivors. A broad expertise is needed for the post-transplant management; therefore, transplant centers together with primary care providers should ensure complementary care delivery. Standardized follow-up guidelines on late effects represent the best tool to guaranty good management of long-term survivors. Distribution, broad promotion, and applications of these guidelines are therefore needed. PMID:25667128

  12. Macrophage function in murine allogeneic bone marrow radiation chimeras in the early phase after transplantation

    SciTech Connect

    Roesler, J.; Baccarini, M.; Vogt, B.; Lohmann-Matthes, M.L. )

    1989-08-01

    We tested several of the functions of macrophages (M phi) in the early phase after allogeneic bone marrow transfer to get information about this important aspect of the nonspecific immune system in the T-cell-deficient recipient. On days 3-5 after transfer, the number of M phi was reduced in the spleen, liver, lungs, and peritoneal cavity (Pe). The phagocytosis of sheep red blood cells (SRBC) by these M phi was normal or even enhanced, as in the case of Pe-M phi. Already on days 8-12 after transfer, the number of M phi in spleen and liver exceeded that of controls, whereas the number was still reduced in lungs and Pe. We examined their ability to kill P815 tumor cells, to produce tumor necrosis factor-alpha (TNF alpha), to phagocytose SRBC, to produce reactive oxygen intermediates (ROI) in vitro and to kill Listeria monocytogenes in vivo. Most functions were normal and often even enhanced, depending on the organ origin, but the ability of Pe-M phi to produce ROI was reduced. Proliferative response to macrophage colony-stimulating factor (M-CSF) and killing of YAC-1 tumor cells revealed a high frequency of macrophage precursor cells in the spleen and liver and a high natural killer (NK) activity in the liver. Altogether, enhanced nonspecific immune function, especially preactivated M phi, may enable chimeras to survive attacks by opportunistic pathogens.

  13. Outcomes of Autologous or Allogeneic Stem Cell Transplantation for Non-Hodgkin Lymphoma

    PubMed Central

    Reddy, Nishitha M.; Oluwole, Olalekan; Greer, John P.; Engelhardt, Brian G.; Jagasia, Madan H.; Savani, Bipin N.

    2016-01-01

    Transplant outcomes of autologous or allogeneic stem cell transplantation (SCT) have not been elucidated as a single cohort in non-Hodgkin lymphoma (NHL). We analyzed the outcomes of 270 adult recipients receiving auto (n=198) or allo-SCT (n=72) for NHL between year 2000 and 2010. Five-year overall survival for B-cell and T-cell NHL were 58% and 50%, respectively (allo-SCT 51% vs. 54% for B and T-cell NHL, and auto-SCT 60% vs. 47% for B and T-cell lymphoma, respectively) (p=NS). In multivariate analysis, number of chemotherapy regimens and disease status pre-SCT were independently associated with long-term outcome after SCT (for both auto and allo-SCT). We conclude that based on patient selection and disease related factors, the type of transplantation offered to patients can achieve long term survival highlighting the importance of further improvement in disease control and reducing procedure related mortality. The role of transplantation needs to be reevaluated in the era of targeted therapy. PMID:24096123

  14. Adverse Late and Long-Term Treatment Effects in Adult Allogeneic Hematopoietic Stem Cell Transplant Survivors.

    PubMed

    Mosesso, Kara

    2015-11-01

    Hematopoietic stem cell transplantation (HSCT) has become the standard of care for many malignant and nonmalignant hematologic diseases that don't respond to traditional therapy. There are two types: autologous transplantation (auto-HSCT), in which an individual's stem cells are collected, stored, and infused back into that person; and allogeneic transplantation (allo-HSCT), in which healthy donor stem cells are infused into a recipient whose bone marrow has been damaged or destroyed. There have been numerous advancements in this field, leading to marked increases in the number of transplants performed annually. This article--the first of several on cancer survivorship--focuses on the care of adult allo-HSCT survivors because of the greater complexity of their posttransplant course. The author summarizes potential adverse late and long-term treatment-related effects, with special focus on the evaluation and management of several cardiovascular disease risk factors that can occur either independently or concurrently as part of the metabolic syndrome. These risk factors are potentially modifiable with appropriate nursing interventions and lifestyle modifications. PMID:26473441

  15. What do we need to know about allogeneic hematopoietic stem cell transplant survivors?

    PubMed

    Clark, C A; Savani, M; Mohty, M; Savani, B N

    2016-08-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for over 70 benign and malignant hematologic and immunological processes. Over the past several decades, significant technological and post-transplant supportive advances have been made, resulting in a decrease in early transplant mortality and continued growth in the population of allo-HSCT survivors. With the expansion in the number of long-term survivors, as well as of those considering a transplant, the focus of transplant medicine has been shifted significantly to include a more prominent role for the care of the 'long-term' survivor. These patients have survived the acute critical phase of transplantation and have potentially achieved remission from their primary disease, yet allo-HSCT patients do not return to pre-transplant health status. For survivors >2 years removed, the time of transplant all-cause mortality is four- to nine-fold higher than age-matched peers within the general population. These patients represent a distinct, high-risk population that must be monitored for long-term transplant complications, including chronic GvHD (cGvHD), multi-organ dysfunctions and secondary malignancies. This article will review in a non-exhaustive manner, the approach to long-term care of an allo-HSCT recipient. PMID:27064688

  16. Neoplasia in adoptively immunosuppressed rats. A possible model for tumorigenesis in transplant recipients

    SciTech Connect

    Dorsch, S.E.; Cook, E.P.

    1983-07-01

    An extremely high incidence of malignant tumors was observed in groups of rats that had previously been exposed to whole body irradiation, grafted with allogeneic tissue, and injected with lymphocytes capable of specifically suppressing the rejection of the grafted tissue. Neoplasia in these adoptively immunosuppressed rats had features in common with that in therapeutically immunosuppressed transplant recipients. Increased tumor incidence could not be accounted for on the basis of the effects of whole body irradiation or failure of immune surveillance, nor could it be a direct effect of lymphoid tissue stimulation. It is suggested that cell mediated suppressor responses play a critical role in tumorigenesis. The mechanism of this is not simply direct stimulation of lymphoid tissue proliferation.

  17. 7 CFR 621.14 - Recipient responsibility.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... § 621.14 Recipient responsibility. Leadership in arrangements for other needed Federal, State, and local... NRCS policy and procedures, the requesting agency has leadership responsibility for developing...

  18. 7 CFR 621.14 - Recipient responsibility.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... § 621.14 Recipient responsibility. Leadership in arrangements for other needed Federal, State, and local... NRCS policy and procedures, the requesting agency has leadership responsibility for developing...

  19. 7 CFR 621.14 - Recipient responsibility.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... § 621.14 Recipient responsibility. Leadership in arrangements for other needed Federal, State, and local... NRCS policy and procedures, the requesting agency has leadership responsibility for developing...

  20. 7 CFR 621.14 - Recipient responsibility.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... § 621.14 Recipient responsibility. Leadership in arrangements for other needed Federal, State, and local... NRCS policy and procedures, the requesting agency has leadership responsibility for developing...

  1. [Alpha-1 Antitrypsin Affects U0126-Induced Cytotoxicity in Colon Cancer Cell Line (HCT116)].

    PubMed

    Ljujic, M; Mijatovic, S; Bulatovic, M Z; Mojic, M; Maksimovic-Ivanic, D; Radojkovic, D; Topic, A

    2016-01-01

    Alpha-1-antitrypsin (AAT), an acute phase protein, is the principal circulatory anti-protease. This multifunctional protein is encoded by the SERPINA1 gene. Although AAT was recognised as a potential tumour marker, its role in cancer biology remains unknown. Given that it has been demonstrated that AAT has an anti-apoptotic property against non-malignant cells, we aimed to investigate whether AAT affects apoptosis in a colon cancer cell line (HCT116). The presence of AAT in the HCT116 cell culture antagonized cytotoxicity of blockers of MEK1/2, PI3K/Akt pathways as well as NF-κB. The dominantly recovered cell viability was observed in the co-treatment with MEK1/2 inhibitor U0126. In addition, it was revealed that AAT almost completely abolished U0126-induced apoptosis through maintenance of the autophagy process. Our study revealed for the first time that the observed cyto-protection triggered by AAT was accompanied by sustained autophagy which opposed apoptosis. These results may contribute to understanding of the role of AAT in cancer development and evaluation of efficacy of cancer therapy. PMID:27028823

  2. Tolerance of Organ Transplant Recipients to Physical Activity during a High-Altitude Expedition: Climbing Mount Kilimanjaro

    PubMed Central

    van Adrichem, Edwin J.; Siebelink, Marion J.; Rottier, Bart L.; Dilling, Janneke M.; Kuiken, Greetje; van der Schans, Cees P.; Verschuuren, Erik A. M.

    2015-01-01

    Background It is generally unknown to what extent organ transplant recipients can be physically challenged. During an expedition to Mount Kilimanjaro, the tolerance for strenuous physical activity and high-altitude of organ transplant recipients after various types of transplantation was compared to non-transplanted controls. Methods Twelve organ transplant recipients were selected to participate (2 heart-, 2 lung-, 2 kidney-, 4 liver-, 1 allogeneic stem cell- and 1 small bowel-transplantation). Controls comprised the members of the medical team and accompanying family members (n = 14). During the climb, cardiopulmonary parameters and symptoms of acute mountain sickness were recorded twice daily. Capillary blood analyses were performed three times during the climb and once following return. Results Eleven of the transplant participants and all controls began the final ascent from 4700 meters and reached over 5000 meters. Eight transplant participants (73%) and thirteen controls (93%) reached the summit (5895m). Cardiopulmonary parameters and altitude sickness scores demonstrated no differences between transplant participants and controls. Signs of hyperventilation were more pronounced in transplant participants and adaptation to high-altitude was less effective, which was related to a decreased renal function. This resulted in reduced metabolic compensation. Conclusion Overall, tolerance to strenuous physical activity and feasibility of a high-altitude expedition in carefully selected organ transplant recipients is comparable to non-transplanted controls. PMID:26606048

  3. Allogenic benefit in stem cell therapy: cardiac repair and regeneration.

    PubMed

    Al-Daccak, R; Charron, D

    2015-09-01

    Stem cell (SC)-based therapies are a developing mean to repair, restore, maintain, or enhance organ functioning through life span. They are in particular a fast track to restore function in failing heart. Various types of SCs have been used in experimental and clinical studies showing the potential of these cells to revolutionize the treatment of heart diseases. Autologous cells have been privileged to overpass immunological barriers. The field has progressed tremendously and the hurdles, which have been largely overlooked in the excitement over the expected benefit the immunogenicity, have been revealed. Also, manufacturing of patient-specific clinical grade SC product, whether adult stem or reprogrammed induced pluripotent SCs, and the availability of these cells in sufficient amounts and status when needed is questionable. In contrast, adult SCs derived from healthy donors, thus allogeneic, have the advantage to be immediately available as an 'off-the-shelf' therapeutic product. The challenge is to overcome the immunological barriers to their transplantation. Recent research provided new insights into the mode of action and immune behavior of SCs in autologous as well as allogeneic settings. Lessons are learned and immune paradigms are changing: allogenicity, if balanced could be part of the dynamic and durable mechanisms that are critical to sustain cardiac regeneration and repair. We discuss the hurdles, lessons, and advances accomplished in the field through the progressive journey of cardiac-derived stem/progenitor cells toward allogeneic cardiac regenerative/reparative therapy. PMID:26206374

  4. Cell salvage for minimising perioperative allogeneic blood transfusion

    PubMed Central

    Carless, Paul A; Henry, David A; Moxey, Annette J; O’Connell, Dianne; Brown, Tamara; Fergusson, Dean A

    2014-01-01

    Background Concerns regarding the safety of transfused blood have prompted reconsideration of the use of allogeneic (from an unrelated donor) red blood cell (RBC) transfusion, and a range of techniques to minimise transfusion requirements. Objectives To examine the evidence for the efficacy of cell salvage in reducing allogeneic blood transfusion and the evidence for any effect on clinical outcomes. Search methods We identified studies by searching CENTRAL (The Cochrane Library 2009, Issue 2), MEDLINE (1950 to June 2009), EMBASE (1980 to June 2009), the internet (to August 2009) and bibliographies of published articles. Selection criteria Randomised controlled trials with a concurrent control group in which adult patients, scheduled for non-urgent surgery, were randomised to cell salvage (autotransfusion) or to a control group who did not receive the intervention. Data collection and analysis Data were independently extracted and the risk of bias assessed. Relative risks (RR) and weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Data were pooled using a random-effects model. The primary outcomes were the number of patients exposed to allogeneic red cell transfusion and the amount of blood transfused. Other clinical outcomes are detailed in the review. Main results A total of 75 trials were included. Overall, the use of cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 38% (RR 0.62; 95% CI 0.55 to 0.70). The absolute reduction in risk (ARR) of receiving an allogeneic RBC transfusion was 21% (95% CI 15% to 26%). In orthopaedic procedures the RR of exposure to RBC transfusion was 0.46 (95% CI 0.37 to 0.57) compared to 0.77 (95% CI 0.69 to 0.86) for cardiac procedures. The use of cell salvage resulted in an average saving of 0.68 units of allogeneic RBC per patient (WMD −0.68; 95% CI −0.88 to −0.49). Cell salvage did not appear to impact adversely on clinical outcomes. Authors’ conclusions

  5. β-d-Glucan Screening for Detection of Invasive Fungal Disease in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Koltze, Antonia; Rath, Peter; Schöning, Stefan; Steinmann, Jörg; Wichelhaus, Thomas A.; Bader, Peter; Bochennek, Konrad

    2015-01-01

    While the assessment of β-d-glucan (BDG) levels in adults improves the early diagnosis of invasive fungal disease (IFD), data on BDG levels in children are limited. We therefore assessed in a prospective cohort study the value of serial BDG screening for early detection of IFD in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT). IFD was defined according to the revised European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria, with the necessary modification that BDG was not included as a microbiological criterion. For the analysis, a total of 702 serum samples were obtained in 34 pediatric HSCT recipients. Proven IFD occurred in two patients (fusariosis and Candida sepsis, respectively), and probable invasive aspergillosis was diagnosed in four patients. Analyses including different cutoff values for BDG levels and different definitions of the onset of IFD demonstrated that the BDG assay has a relatively high sensitivity and good negative predictive value, whereas the positive predictive value has major limitations (<30%). Receiver operating characteristic analyses suggested an optimal cutoff between 60 and 70 pg/ml for different definitions of the onset of IFD. Our data show that BDG screening in pediatric HSCT recipients has a low positive predictive value and is therefore of limited usefulness. PMID:26041896

  6. Establishment of banking system for allogeneic cultured dermal substitute.

    PubMed

    Kuroyanagi, Yoshimitsu; Kubo, Kentaro; Matsui, Hiromich; Kim, Hyun Jung; Numari, Shinichiro; Mabuchi, Yho; Kagawa, Shizuko

    2004-01-01

    Allogeneic cultured dermal substitute (CDS) was prepared by culturing fibroblasts on a two-layered spongy matrix of hyaluronic acid (HA) and atelo-collagen (Col). Allogeneic CDS can be cryopreserved and transported to other hospitals in a frozen state. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), platelet derived growth factor (PDGF)-AA, transforming growth factor (TGF)-beta1, keratinocytes growth factor (KGF), interleukin (IL)-6 and IL-8 were contained in the culture medium which was used in preparing CDS over a cultivation period of one week (fresh CDS culture medium sample). After thawing a cryopreserved CDS, the CDS was recultured in a culture medium for one week. VEGF, bFGF, HGF, TGF-beta1 and IL-8 were contained in the culture medium which was used in reculturing CDS for one week (cryopreserved CDS culture medium sample), although some cytokines were detected at a lower level than those before freezing. This finding suggests that the cryopreserved CDS retains its ability to release these cytokines. Clinical research on allogeneic CDS, which was newly developed at the R & D Center for Artificial Skin of Kitasato University, has been carried out in medical centers across Japan with the support of the Millennium Project of the Ministry of Health, Labor and Welfare. It was demonstrated that the allogeneic CDS functions as an excellent cell therapy for intractable skin ulcers as well as burn injuries. The spongy matrix itself, as well as the cytokines released from the allogeneic CDS, seemed to be beneficial for the treatment of intractable skin defect. PMID:14720283

  7. 15 CFR 20.17 - Remedial action by recipients.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ..., Conciliation, and Enforcement Procedures § 20.17 Remedial action by recipients. (a) Where DOC finds that a recipient has discriminated on the basis of age, the recipient shall take any remedial action that DOC may... recipient that has discriminated, DOC may require both recipients to take remedial action. (b) Even in...

  8. 15 CFR 20.17 - Remedial action by recipients.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ..., Conciliation, and Enforcement Procedures § 20.17 Remedial action by recipients. (a) Where DOC finds that a recipient has discriminated on the basis of age, the recipient shall take any remedial action that DOC may... recipient that has discriminated, DOC may require both recipients to take remedial action. (b) Even in...

  9. 15 CFR 20.17 - Remedial action by recipients.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ..., Conciliation, and Enforcement Procedures § 20.17 Remedial action by recipients. (a) Where DOC finds that a recipient has discriminated on the basis of age, the recipient shall take any remedial action that DOC may... recipient that has discriminated, DOC may require both recipients to take remedial action. (b) Even in...

  10. 15 CFR 20.17 - Remedial action by recipients.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., Conciliation, and Enforcement Procedures § 20.17 Remedial action by recipients. (a) Where DOC finds that a recipient has discriminated on the basis of age, the recipient shall take any remedial action that DOC may... recipient that has discriminated, DOC may require both recipients to take remedial action. (b) Even in...

  11. 15 CFR 20.17 - Remedial action by recipients.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., Conciliation, and Enforcement Procedures § 20.17 Remedial action by recipients. (a) Where DOC finds that a recipient has discriminated on the basis of age, the recipient shall take any remedial action that DOC may... recipient that has discriminated, DOC may require both recipients to take remedial action. (b) Even in...

  12. Mechanism of protection from graft-vs-host disease in murine mixed allogeneic chimeras. I. Development of a null cell population suppressive of cell-mediated lympholysis responses and derived from the syngeneic bone marrow component

    SciTech Connect

    Sykes, M.; Eisenthal, A.; Sachs, D.H.

    1988-05-01

    Splenocyte populations from whole body-irradiated recipients of mixed T cell-depleted (TCD) syngeneic and allogeneic (complete H-2 disparity) bone marrow, or of TCD syngeneic marrow alone, contain cells with the ability to suppress the generation of cell-mediated lympholysis responses in vitro. This activity, which is present by 8 days after bone marrow transplantation and persists for several weeks, has been analyzed for possible veto-like or other specificity. Although reproducible patterns of suppression were observed, depending both on host strain and on the genetic combination of the response examined, the overall suppression in vitro most closely resembles that which has been ascribed to natural suppressor cells in other systems. The suppression appears to be mediated by a non-T cell, non-B cell, nonadherent, asialo GM1-negative population. Cold target inhibition and CTL activity of chimeric cells have been ruled out as factors contributing to the observed suppression. Significantly, in mixed chimeras, suppression was found to be mediated exclusively by cells which were syngeneic to the recipient in both recipient strains tested. The rapid development of this suppressive activity may explain the resistance to graft-vs-host disease conferred on whole body-irradiated mice by the addition of TCD syngeneic marrow to an allogeneic graft-vs-host disease-producing inoculum.

  13. Crocin, the main active saffron constituent, mitigates dichlorvos-induced oxidative stress and apoptosis in HCT-116 cells.

    PubMed

    Ben Salem, Intidhar; Boussabbeh, Manel; Kantaoui, Hiba; Bacha, Hassen; Abid-Essefi, Salwa

    2016-08-01

    The protective effects of Crocin (CRO), a carotenoid with wide spectrum of pharmacological effects, against the cytotoxicity and the apoptosis produced by exposure to Dichlorvos (DDVP) in HCT116 cells were investigated in this work. The cytotoxicity was monitored by cell viability, ROS generation, antioxidant enzymes activities, malondialdehyde (MDA) production and DNA fragmentation. The apoptosis was assessed through the measurement of the mitochondrial transmembrane potential (ΔΨm) and caspases activation. The results indicated that pretreatment of HCT116 cells with CRO, 2h prior to DDVP exposure, significantly increased the survival of cells, inhibited the ROS generation, modulated the activities of catalase (CAT) and superoxide dismutase (SOD) and reduced the MDA level. The reduction in mitochondrial membrane potential, DNA fragmentation and caspases activation were also inhibited by CRO. These findings suggest that CRO can protect HCT116 cells from DDVP-induced oxidative stress and apoptosis. PMID:27470340

  14. Aspergillus Infections in Transplant Recipients

    PubMed Central

    Singh, Nina; Paterson, David L.

    2005-01-01

    Aspergillus infections are occurring with an increasing frequency in transplant recipients. Notable changes in the epidemiologic characteristics of this infection have occurred; these include a change in risk factors and later onset of infection. Management of invasive aspergillosis continues to be challenging, and the mortality rate, despite the use of newer antifungal agents, remains unacceptably high. Performing molecular studies to discern new targets for antifungal activity, identifying signaling pathways that may be amenable to immunologic interventions, assessing combination regimens of antifungal agents or combining antifungal agents with modulation of the host defense mechanisms, and devising diagnostic assays that can rapidly and reliably diagnose infections represent areas for future investigations that may lead to further improvement in outcomes. PMID:15653818

  15. Carnosic acid inhibits STAT3 signaling and induces apoptosis through generation of ROS in human colon cancer HCT116 cells.

    PubMed

    Kim, Do-Hee; Park, Ki-Woong; Chae, In Gyeong; Kundu, Juthika; Kim, Eun-Hee; Kundu, Joydeb Kumar; Chun, Kyung-Soo

    2016-06-01

    Carnosic acid (CA), the main antioxidant compound of Rosmarinus officinalis L., has been reported to possess anticancer activity. However, the molecular mechanisms underlying the anticancer effects of CA remain poorly understood. Our study revealed that CA treatment significantly reduced the viability of human colon cancer HCT116, SW480, and HT-29 cells. Treatment with CA induced apoptosis, which was associated with the induction of p53 and Bax, inhibition of Mdm2, Bcl-2, and Bcl-xl expression, activation of caspase-9, and -3, and the cleavage of PARP in HCT116 cells. CA inhibited the constitutive phosphorylation, the DNA binding and the reporter gene activity of STAT3 in HCT116 cells by blocking the phosphorylation of upstream JAK2 and Src kinases. Moreover, CA attenuated the expression of STAT3 target gene products, such as survivin, cyclin D1, D2, and D3. In STAT3-overexpressed HCT116 cells, CA inhibited cell viability and the expression of cyclin D1 and survivin. Furthermore, CA treatment induced the generation of ROS in these colon cancer cells. Pretreatment of cells with ROS scavenger N-acetyl cysteine abrogated the inhibitory effect of CA on the JAK2-STAT3/Src-STAT3 signaling and rescued cells from CA-induced apoptosis by blocking the induction of p53 and the cleavage of caspase-3 and PARP in HCT116 cells. However, L-buthionine-sulfoximine, a pharmacological inhibitor of GSH synthesis, increased CA-induced ROS production, thereby potentiating apoptotic effect of CA. In conclusion, our study provides the first report that CA induced apoptosis in HCT116 cells via generation of ROS, induction of p53, activation of caspases, and inhibition of STAT3 signaling pathway. © 2015 Wiley Periodicals, Inc. PMID:26152521

  16. Job Performance and Retention among Welfare Recipients.

    ERIC Educational Resources Information Center

    Holzer, Harry J.; Stoll, Michael A.; Wissoker, Douglas

    Data from interviews with 750 employers in Chicago, Cleveland, Milwaukee, and Los Angeles were used to analyze the job performance and retention rates of recently hired welfare recipients. The 20-minute interviews focused on employers' subjective ratings of recently hired welfare recipients' job performance and whether employers experienced the…

  17. 7 CFR 248.6 - Recipient eligibility.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 4 2013-01-01 2013-01-01 false Recipient eligibility. 248.6 Section 248.6 Agriculture Regulations of the Department of Agriculture (Continued) FOOD AND NUTRITION SERVICE, DEPARTMENT OF AGRICULTURE CHILD NUTRITION PROGRAMS WIC FARMERS' MARKET NUTRITION PROGRAM (FMNP) Recipient Eligibility §...

  18. 7 CFR 248.6 - Recipient eligibility.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 4 2010-01-01 2010-01-01 false Recipient eligibility. 248.6 Section 248.6 Agriculture Regulations of the Department of Agriculture (Continued) FOOD AND NUTRITION SERVICE, DEPARTMENT OF AGRICULTURE CHILD NUTRITION PROGRAMS WIC FARMERS' MARKET NUTRITION PROGRAM (FMNP) Recipient Eligibility §...

  19. 7 CFR 248.6 - Recipient eligibility.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 4 2014-01-01 2014-01-01 false Recipient eligibility. 248.6 Section 248.6 Agriculture Regulations of the Department of Agriculture (Continued) FOOD AND NUTRITION SERVICE, DEPARTMENT OF AGRICULTURE CHILD NUTRITION PROGRAMS WIC FARMERS' MARKET NUTRITION PROGRAM (FMNP) Recipient Eligibility §...

  20. 7 CFR 248.6 - Recipient eligibility.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 4 2012-01-01 2012-01-01 false Recipient eligibility. 248.6 Section 248.6 Agriculture Regulations of the Department of Agriculture (Continued) FOOD AND NUTRITION SERVICE, DEPARTMENT OF AGRICULTURE CHILD NUTRITION PROGRAMS WIC FARMERS' MARKET NUTRITION PROGRAM (FMNP) Recipient Eligibility §...

  1. 7 CFR 248.6 - Recipient eligibility.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 4 2011-01-01 2011-01-01 false Recipient eligibility. 248.6 Section 248.6 Agriculture Regulations of the Department of Agriculture (Continued) FOOD AND NUTRITION SERVICE, DEPARTMENT OF AGRICULTURE CHILD NUTRITION PROGRAMS WIC FARMERS' MARKET NUTRITION PROGRAM (FMNP) Recipient Eligibility §...

  2. 40 CFR 35.583 - Eligible recipients.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Eligible recipients. 35.583 Section 35.583 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE STATE AND LOCAL ASSISTANCE Environmental Program Grants for Tribes Water Pollution Control (sections 106 and 518) § 35.583 Eligible recipients. A...

  3. 40 CFR 725.420 - Recipient microorganisms.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Recipient microorganisms. 725.420 Section 725.420 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT REPORTING REQUIREMENTS AND REVIEW PROCESSES FOR MICROORGANISMS General Exemptions for New Microorganisms § 725.420 Recipient...

  4. 40 CFR 35.583 - Eligible recipients.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Eligible recipients. 35.583 Section 35.583 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE STATE AND LOCAL ASSISTANCE Environmental Program Grants for Tribes Water Pollution Control (sections 106 and 518) § 35.583 Eligible recipients. A...

  5. 40 CFR 7.85 - Recipients.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... request of the OCR, provide the following information to show compliance with this part: (1) A brief...) Additional compliance information. If necessary, the OCR may require recipients to submit data and... recipient shall: (1) Give the OCR access during normal business hours to its books, records, accounts...

  6. 40 CFR 7.85 - Recipients.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... request of the OCR, provide the following information to show compliance with this part: (1) A brief... compliance information. If necessary, the OCR may require recipients to submit data and information specific... resolved. (f) Accessibility to compliance information. A recipient shall: (1) Give the OCR access...

  7. 40 CFR 7.85 - Recipients.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... request of the OCR, provide the following information to show compliance with this part: (1) A brief...) Additional compliance information. If necessary, the OCR may require recipients to submit data and... recipient shall: (1) Give the OCR access during normal business hours to its books, records, accounts...

  8. 40 CFR 7.85 - Recipients.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... request of the OCR, provide the following information to show compliance with this part: (1) A brief...) Additional compliance information. If necessary, the OCR may require recipients to submit data and... recipient shall: (1) Give the OCR access during normal business hours to its books, records, accounts...

  9. 40 CFR 7.85 - Recipients.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... request of the OCR, provide the following information to show compliance with this part: (1) A brief...) Additional compliance information. If necessary, the OCR may require recipients to submit data and... recipient shall: (1) Give the OCR access during normal business hours to its books, records, accounts...

  10. The Importance of Tracking Doctoral Recipients.

    ERIC Educational Resources Information Center

    Unruh, David; And Others

    1996-01-01

    This article focuses on issues related to outcomes for doctoral degree recipients and the efforts of the University of California at Los Angeles (UCLA) to develop a coherent and consistent approach to employment tracking. Recent (1994-95) UCLA doctoral recipients (n=893) were surveyed concerning their initial employment placements. The article…

  11. 40 CFR 725.420 - Recipient microorganisms.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Recipient microorganisms. 725.420 Section 725.420 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT REPORTING REQUIREMENTS AND REVIEW PROCESSES FOR MICROORGANISMS General Exemptions for New Microorganisms § 725.420 Recipient...

  12. 40 CFR 725.420 - Recipient microorganisms.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Recipient microorganisms. 725.420 Section 725.420 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT REPORTING REQUIREMENTS AND REVIEW PROCESSES FOR MICROORGANISMS General Exemptions for New Microorganisms § 725.420 Recipient...

  13. 40 CFR 725.420 - Recipient microorganisms.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Recipient microorganisms. 725.420 Section 725.420 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT REPORTING REQUIREMENTS AND REVIEW PROCESSES FOR MICROORGANISMS General Exemptions for New Microorganisms § 725.420 Recipient...

  14. 40 CFR 35.686 - Eligible recipients.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Eligible recipients. 35.686 Section 35.686 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE STATE AND LOCAL ASSISTANCE Environmental Program Grants for Tribes Underground Water Source Protection (section 1443(b)) § 35.686 Eligible recipients....

  15. 40 CFR 35.583 - Eligible recipients.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Eligible recipients. 35.583 Section 35.583 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE STATE AND LOCAL ASSISTANCE Environmental Program Grants for Tribes Water Pollution Control (sections 106 and 518) § 35.583 Eligible recipients. A...

  16. 40 CFR 35.583 - Eligible recipients.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Eligible recipients. 35.583 Section 35.583 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE STATE AND LOCAL ASSISTANCE Environmental Program Grants for Tribes Water Pollution Control (sections 106 and 518) § 35.583 Eligible recipients. A...

  17. 40 CFR 35.583 - Eligible recipients.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Eligible recipients. 35.583 Section 35.583 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE STATE AND LOCAL ASSISTANCE Environmental Program Grants for Tribes Water Pollution Control (sections 106 and 518) § 35.583 Eligible recipients. A...

  18. Effects of ursolic acid and oleanolic acid on human colon carcinoma cell line HCT15

    PubMed Central

    Li, Jie; Guo, Wei-Jian; Yang, Qing-Yao

    2002-01-01

    AIM: Ursolic acid (UA) and oleanolic acid (OA) are triperpene acids having a similar chemical structure and are distributed wildly in plants all over the world. In recent years, it was found that they had marked anti-tumor effects. There is little literature currently available regarding their effects on colon carcinoma cells. The present study was designed to investigate their inhibitory effects on human colon carcinoma cell line HCT15. METHODS: HCT15 cells were cultured with different drugs. The treated cells were stained with hematoxylin-eosin and their morphologic changes observed under a light microscope. The cytotoxicity of these drugs was evaluated by tetrazolium dye assay. Cell cycle analysis was performed by flow cytometry (FCM). Data were expressed as means ± SEM and Analysis of variance and Student’ t-test for individual comparisons. RESULTS: Twenty-four to 72 h after UA or OA 60 μmol/L treatment, the numbers of dead cells and cell fragments were increased and most cells were dead at the 72nd hour. The cytotoxicity of UA was stronger than that of OA. Seventy-eight hours after 30 μmol/L of UA or OA treatment, a number of cells were degenerated, but cell fragments were rarely seen. The IC50 values for UA and OA were 30 and 60 μmol/L, respectively. Proliferation assay showed that proliferation of UA and OA-treated cells was slightly increased at 24 h and significantly decreased at 48 h and 60 h, whereas untreated control cells maintained an exponential growth curve. Cell cycle analysis by FCM showed HCT15 cells treated with UA 30 and OA 60 for 36 h and 72 h gradually accumulated in G0/G1 phase (both drugs P < 0.05 for 72 h), with a concomitant decrease of cell populations in S phase (both drugs P < 0.01 for 72 h) and no detectable apoptotic fraction. CONCLUSION: UA and OA have significant anti-tumor activity. The effect of UA is stronger than that of OA. The possible mechanism of action is that both drugs have an inhibitory effect on tumor cell

  19. Transplant outcomes of the triple-negative NPM1/FLT3-ITD/CEBPA mutation subgroup are equivalent to those of the favourable ELN risk group, but significantly better than the intermediate-I risk group after allogeneic transplant in normal-karyotype AML.

    PubMed

    Ahn, Jae-Sook; Kim, Hyeoung-Joon; Kim, Yeo-Kyeoung; Jung, Sung-Hoon; Yang, Deok-Hwan; Lee, Je-Jung; Kim, Nan Young; Choi, Seung Hyun; Jung, Chul Won; Jang, Jun-Ho; Kim, Hee Je; Moon, Joon Ho; Sohn, Sang Kyun; Won, Jong-Ho; Kim, Sung-Hyun; Kim, Dennis Dong Hwan

    2016-03-01

    The prognostic significance of molecular mutations (FLT3-ITD, NPM1, and CEBPA mutations) was examined in patients with normal-karyotype acute myeloid leukaemia (NK-AML) after allogeneic haematopoietic cell transplantation (HCT). In total, 115 patients received allogeneic HCT for NK-AML and were evaluated for FLT3-ITD, NPM1, and CEBPA mutations in diagnostic samples and for long-term outcomes following HCT, retrospectively. The prevalences of FLT3-ITD(pos), NPM1 (mut), and CEBPA (dm) (double mutations) were 32.2, 43.5, and 24.6 %, respectively. The triple-negative group (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)) showed a similar transplant outcome to those in the favourable European LeukemiaNet (ELN) risk group for overall survival (OS) (60.9 vs. 63.7 %; p = 0.810), but a more favourable OS than others in the intermediate-I risk group (40.0 %; p = 0.034). Also, the triple-negative group showed a similar relapse rate at 5 years compared with those in the favourable risk group (9.7 vs. 15.5 %; p = 0.499), but a lower rate of relapse than the others in the intermediate-I risk group (15.5 vs. 48.6 %; p = 0.004). The 5-year relapse incidences were 4.0 % (NPM1 (mut)/FLT3-ITD(neg)), 14.7 % (CEBPA (dm)), 15.5 % (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)), 39.1 % (NPM1 (mut)/FLT3-ITD(pos)/non-CEBPA (dm)), and 66.7 % (NPM1 (wild)/FLT3-ITD(pos)/non-CEBPA (dm)). Thus, the triple-negative (NPM1 (wild)/FLT3-ITD(neg)/non-CEBPA (dm)) group showed favourable long-term outcomes after allogeneic HCT in NK-AML, similar to those of the favourable risk group by the ELN risk classification. PMID:26692090

  20. Bacterial Infections in Hematopoietic Stem Cell Transplant Recipients

    PubMed Central

    Balletto, Elisa; Mikulska, Małgorzata

    2015-01-01

    Bacterial infections are major complications after Hematopoietic Stem Cell Transplant (HSCT). They consist mainly of bloodstream infections (BSI), followed by pneumonia and gastrointestinal infections, including typhlitis and Clostridium difficile infection. Microbiological data come mostly from BSI. Coagulase negative staphylococci and Enterobacteriaceae are the most frequent pathogens causing approximately 25% of BSI each, followed by enterococci, P. aeruginosa and viridans streptococci. Bacterial pneumonia is frequent after HSCT, and Gram-negatives are predominant. Clostridium difficile infection affects approximately 15% of HSCT recipients, being more frequent in case of allogeneic than autologous HSCT. The epidemiology and the prevalence of resistant strains vary significantly between transplant centres. In some regions, multi-drug resistant (MDR) Gram-negative rods are increasingly frequent. In others, vancomycin-resistant enterococci are predominant. In the era of increasing resistance to antibiotics, the efficacy of fluoroquinolone prophylaxis and standard treatment of febrile neutropenia have been questioned. Therefore, a thorough evaluation of local epidemiology is mandatory to decide the need for prophylaxis and the choice of the best regimen for empirical treatment of febrile neutropenia. For the latter, individualised approach has been proposed, consisting of either escalation or de-escalation strategy. De-escalation strategy is recommended since resistant bacteria should be covered upfront, mainly in patients with severe clinical presentation and previous infection or colonisation with a resistant pathogen. Non-pharmacological interventions, such as screening for resistant bacteria, applying isolation and contact precautions should be put in place to limit the spread of MDR bacteria. Antimicrobial stewardship program should be implemented in transplant centres. PMID:26185610

  1. Efficient natural defense mechanisms against Listeria monocytogenes in T and B cell-deficient allogeneic bone marrow radiation chimeras. Preactivated macrophages are the main effector cells in an early phase after bone marrow transfer

    SciTech Connect

    Roesler, J.; Groettrup, E.B.; Baccarini, M.; Lohmann-Mattes, M.L. )

    1989-09-01

    Radiation chimeras in the early phase after bone marrow transplantation are a good model to study the efficiency of the body's nonspecific defense system represented by macrophages (M phi), polymorphonuclear cells (PMN), and NK cells. These cell types are present in large numbers in spleen and liver at that time, whereas the specific immune system represented by T and B cells is functionally deficient. We previously reported enhanced activities in vitro of M phi (and PMN) from recipient animals in an early phase after allogeneic bone marrow transfer. We here demonstrate that these activities result in enhanced spontaneous resistance against Listeria monocytogenes in vivo: CFU of L. monocytogenes in spleen and liver 48 h after infection were about 1 or 2 to 4 log steps less than in untreated control mice of donor or host haplotype. This enhanced resistance decreased over the 4-mo period after marrow transfer. Preactivated M phi were identified as the most important effector cells. Isolated from spleen and peritoneal cavity, they performed enhanced killing of phagocytosed Listeria. Such preactivated M phi occurred in recipient animals after transfer of allogeneic but not of syngeneic bone marrow. The precise mechanism of M phi activation in the allogeneic radiation chimera in the complete absence of any detectable T cell function is not clear at present. However, these preactivated M phi display an important protective effect against L. monocytogenes: chimeras could eliminate Listeria without acquisition of positive delayed-type sensitivity when infected with 10(3) bacteria. An inoculum of 5 . 10(3) L. monocytogenes resulted either in prolonged survival compared with normal mice of the recipient haplotype or in definitive survival accompanied by a positive delayed-type sensitivity.

  2. Burden of morbidity in 10+ year survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study

    PubMed Central

    Sun, Can-Lan; Kersey, John H.; Francisco, Liton; Armenian, Saro H.; Baker, K. Scott; Weisdorf, Daniel J.; Forman, Stephen J.; Bhatia, Smita

    2013-01-01

    Long-term morbidity after hematopoietic cell transplantation (HCT) is unknown. The risk of physical and psychological health in 324 patients who had survived 10 or more years after HCT, and a sibling comparison group (n=309) was evaluated. Using the CTCAE v3.0, the 15-year cumulative incidence of severe/life-threatening/fatal conditions was 41% (95%CI, 34–48%). HCT survivors were 5.7 times as likely to develop a severe/life-threatening condition (p<0.001), and 2.7 times as likely to report somatic distress (p<0.001) compared with siblings. Compared with allogeneic HCT recipients with no chronic GvHD, those with active chronic GvHD were at a 1.8-fold higher risk of severe/life-threatening health conditions (p=0.006), and 4.5-fold higher risk of somatic distress (p=0.04); allogeneic HCT recipients with resolved chronic GvHD were not at increased risk of morbidity compared with those with no chronic GvHD. Only 27% of the HCT survivors returned to the transplant center for their cancer-related care. The burden of long-term physical and emotional morbidity borne by survivors remains substantial, even beyond 10 years after HCT; however, specialized healthcare is underutilized. Patients, families and healthcare providers need to be made aware of the high burden, such that they can plan for post-HCT care, even many years after HCT. PMID:23583827

  3. Mature microRNAs identified in highly purified nuclei from HCT116 colon cancer cells

    PubMed Central

    Park, Chang Won; Zeng, Yan; Zhang, Xiaoxiao; Subramanian, Subbaya

    2010-01-01

    MicroRNAs (miRNAs) have emerged as one of the major regulatory mechanisms of gene expression. A major function of miRNAs involves the post-transcriptional regulation of target mRNAs, which is reported to occur primarily in the cytoplasm. However, there is a significant amount of evidence demonstrating the existence of small non-coding RNAs, including small-interfering RNA (siRNA), miRNA and Piwi-interacting RNA (piRNA) in the nucleus. In order to elucidate the potential subcellular localizations and functions of miRNAs, we have identified numerous miRNAs that are present in isolated nuclei from human colon cancer HCT116 cells. MicroRNA profiles were compared between cytoplasmic and nuclear fractions of the HCT116 cell line on the basis of multiple microarray analyses. MicroRNA species showing significant existence in isolated and highly purified populations of nuclei were selected and further tested with RT-PCR. The nuclear localization of the mature form of miRNAs was verified again by control RT-PCR excluding the detection of premature forms of miRNA, such as pri-miRNA or pre-miRNA. The elevated levels of representative miRNAs identified in purified nuclei were confirmed by northern blot analysis, supporting the notion that significant numbers of mature miRNAs exist not only in the cytoplasm but also in the nucleus. These results will likely provide a basis for further studies concerning the intracellular trafficking and nuclear location of miRNAs. PMID:20864815

  4. The incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post-first and post-second hematopoietic stem cell transplant.

    PubMed

    Ahmed, Ibrahim; Teruya, Jun; Murray-Krezan, Cristina; Krance, Robert

    2015-06-01

    The reported incidence of post-allogeneic HSCT AIHA was between 4.4% and 6% following a single transplant. Cord blood transplantation, T-cell depletion, and chronic GvHD are significantly associated with post-transplant AIHA. During an 11-yr period, data for 500 pediatric HSCT recipients were eligible for evaluation of the incidence of AIHA post-first and post-second transplants. Demographic, transplant, and post-transplant-related variables were analyzed. Twelve of 500 (2.4%) recipients at a median of 273 days and seven of 72 (9.7%) recipients at a median of 157 days developed AIHA post-first and post-second HSCT, respectively. Post-first HSCT, none of the MRD recipients developed AIHA (0/175 MRD vs. 12/325 other donors, p = 0.04). Four of 12 required a second HSCT to control the AIHA. After the second HSCT, MUD was significantly associated with the development of AIHA. No other variables were associated with the post-second transplant AIHA. The incidence of AIHA post-first and post-second HSCT was less than the reported. The increased incidence of AIHA among recipients of second HSCT is most likely due to the profound immune dysregulation. A much larger, prospective study would be needed to evaluate the incidence, complications, and management of post-transplant AIHA. PMID:25809012

  5. Phase II Study of Haploidentical Natural Killer Cell Infusion for Treatment of Relapsed or Persistent Myeloid Malignancies Following Allogeneic Hematopoietic Cell Transplantation.

    PubMed

    Shaffer, Brian C; Le Luduec, Jean-Benoit; Forlenza, Christopher; Jakubowski, Ann A; Perales, Miguel-Angel; Young, James W; Hsu, Katharine C

    2016-04-01

    We conducted a phase 2 study to determine the efficacy of HLA-haploidentical related donor natural killer (NK) cells after cyclophosphamide-based lymphodepletion in patients with relapsed or progressive acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) following allogeneic hematopoietic cell transplantation (HCT). Eight patients (2 with MDS and 6 with AML) were treated with cyclophosphamide 50 mg/kg on day -3 and day -2 before infusion of NK cells isolated from a haploidentical related donor. One patient also received fludarabine 25 mg/m(2)/day for 4 days. Six doses of 1 million units of interleukin-2 (IL-2) were administered on alternating days beginning on day -1. The median number of NK cells infused was 10.6 × 10(6)/kg (range, 4.3 to 22.4 × 10(6)/kg), and the median number of CD3 cells infused was 2.1 × 10(3)/kg (range, 1.9 to 40 × 10(3)/kg). NK infusions were well tolerated, with a median time to neutrophil recovery of 19 days (range, 7 days to not achieved) and no incidence of graft-versus-host disease after NK infusion. One patient with AML and 1 patient with MDS achieved a complete response, but relapsed at 1.7 and 1.8 months, respectively. One patient with MDS experienced resolution of dysplastic features but persistence of clonal karyotype abnormalities; this patient was stable at 65 months after NK cell therapy. The median duration of survival was 12.9 months (range, 0.8 to 65.3 months). Chimerism analysis of CD3(-)/CD56(+) peripheral blood cells did not detect any circulating haploidentical NK cells after infusion. NK phenotyping was performed in 7 patients during and after IL-2 infusion. We found a slight trend toward greater expression of KIR2DL2/2DL3/2DS2 (5% versus 28%; P = .03) at 14 days in patients who survived longer than 6 months from NK cell infusion (n = 4) compared with those who died within 6 months of NK cell therapy (n = 3). In summary, our data support the safety of haploidentical NK cell

  6. Regulatory T Cells in Allogeneic Stem Cell Transplantation

    PubMed Central

    Nagler, Arnon

    2013-01-01

    Growing evidence suggests that cellular adoptive immunotherapy is becoming an attractive though challenging approach in regulating tumor immunity and alloresponses in clinical transplantation. Naturally arising CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a key component in this regard. Over the last decade, a large body of evidence from preclinical models has demonstrated their crucial role in auto- and tumor immunity and has opened the door to their “first-in-man” clinical application. Initial studies in clinical allogeneic stem cell transplantation are very encouraging and may pave the way for other applications. Further improvements in Treg ex vivo or in vivo expansion technologies will simplify their global clinical application. In this review, we discuss the current knowledge of Treg biology and their potential for cell-based immunotherapy in allogeneic stem cell transplantation. PMID:23737813

  7. 21 CFR 1271.10 - Are my HCT/P's regulated solely under section 361 of the PHS Act and the regulations in this part...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Are my HCT/P's regulated solely under section 361..., AND CELLULAR AND TISSUE-BASED PRODUCTS General Provisions § 1271.10 Are my HCT/P's regulated solely.../P is regulated solely under section 361 of the PHS Act and the regulations in this part if it...

  8. JNK signaling pathway is involved in piperlongumine-mediated apoptosis in human colorectal cancer HCT116 cells

    PubMed Central

    LI, WEN; WEN, CHUANGYU; BAI, HAIYAN; WANG, XIAOYAN; ZHANG, XIAOLI; HUANG, LANLAN; YANG, XIANGLING; IWAMOTO, AIKICHI; LIU, HUANLIANG

    2015-01-01

    Piperlongumine (PPLGM), an alkaloid isolated from the long pepper (Piper longum L.), can selectively trigger cancer cell death in colorectal cancer cells. The present study investigated whether the c-Jun NH2-terminal kinase (JNK) signaling pathway is involved in PPLGM-induced apoptosis in the human colorectal cancer HCT116 cell line. The results demonstrated that PPLGM reduced the cell viability and induced cell apoptosis in a time- and concentration-dependent manner, without a significant effect on cell cycle distribution. Meanwhile, treatment with 10 µM PPLGM resulted in JNK activation within 1 h, and a marked and sustained increase in c-Jun phosphorylation in the HCT116 cells. In addition, SP600125, a general inhibitor of JNK, inhibited PPLGM-induced apoptosis in the HCT116 cells by inhibiting PPLGM-induced c-Jun phosphorylation. Altogether, it can be concluded that the JNK signaling pathway, at least in part, is involved in PPLGM-mediated apoptosis in HCT116 cells. PMID:26622558

  9. 21 CFR 1271.22 - How and where do I register and submit an HCT/P list?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false How and where do I register and submit an HCT/P list? 1271.22 Section 1271.22 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND...

  10. 21 CFR 1271.22 - How and where do I register and submit an HCT/P list?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false How and where do I register and submit an HCT/P list? 1271.22 Section 1271.22 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS UNDER CERTAIN OTHER ACTS ADMINISTERED BY THE FOOD AND...

  11. Denbinobin induces apoptosis by apoptosis-inducing factor releasing and DNA damage in human colorectal cancer HCT-116 cells.

    PubMed

    Chen, Tzu-Hsuan; Pan, Shiow-Lin; Guh, Jih-Hwa; Chen, Chien-Chih; Huang, Yao-Ting; Pai, Hui-Chen; Teng, Che-Ming

    2008-11-01

    Denbinobin is a phenanthraquinone derivative present in the stems of Ephemerantha lonchophylla. We showed that denbinobin induces apoptosis in human colorectal cancer cells (HCT-116) in a concentration-dependent manner. The addition of a pan-caspase inhibitor (zVAD-fmk) did not suppress the denbinobin-induced apoptotic effect, and denbinobin-induced apoptosis was not accompanied by processing of procaspase-3, -6, -7, -9, and -8. However, denbinobin triggered the translocation of the apoptosis-inducing factor (AIF) from the mitochondria into the nucleus. Small interfering RNA targeting of AIF effectively protected HCT-116 cells against denbinobin-induced apoptosis. Denbinobin treatment also caused DNA damage, activation of the p53 tumor suppressor gene, and upregulation of numerous downstream effectors (p21WAF1/CIP1, Bax, PUMA, and NOXA). A HCT-116 xenograft model demonstrated the in vivo efficacy and low toxicity of denbinobin. Taken together, our findings suggest that denbinobin induces apoptosis of human colorectal cancer HCT-116 cells via DNA damage and an AIF-mediated pathway. These results indicate that denbinobin has potential as a novel anticancer agent. PMID:18607570

  12. Anticancer potential of an ethanol extract of Asiasari radix against HCT-116 human colon cancer cells in vitro.

    PubMed

    Oh, Se-Mi; Kim, Jinhee; Lee, Jun; Yi, Jin-Mu; Oh, Dal-Seok; Bang, Ok-Sun; Kim, No Soo

    2013-01-01

    Radix of Asiasarum heterotropoides var. mandshuricum F. Maekawa (A. radix) has been prescribed for treating pain, allergies and inflammatory disorders in traditional oriental medicine. However, only limited information on the anticancer effects of A. radix is currently available. The aim of this study was to determine the anticancer effect of the ethanol extract of A. radix (EEAR) on HCT-116 human colon cancer cells and to investigate its underlying mechanisms of action. EEAR significantly induced G2/M cell cycle arrest and apoptosis in HCT-116 cells. EEAR-induced apoptosis was observed in parallel with activation of caspases and an increased ratio of Bax (pro-apoptotic)/Bcl2 (anti-apoptotic). Western blot analyses revealed that EEAR elevated the expression of p53 and p21(Waf/Cip1) and decreased the expression of the regulator proteins of G2/M phase progression, such as cdc2 and cyclin B. The upregulation of p53 by EEAR was due to the increased levels of p53 mRNA without a similar increase in proteasome-mediated p53 degradation. EEAR-induced apoptosis in HCT-116 cells was dependent on p53 expression, as determined by siRNA-mediated p53 knockdown. Taken together, these results suggest that EEAR inhibits the growth of the HCT-116 cells through induction of G2/M cell cycle arrest and apoptosis, which are mediated by p53 expression. PMID:23255939

  13. LIGNIFICATION IN TRANSGENICS DEFICIENT IN P-COUMARATE 3-HYDROXYLASE (C3H) AND THE ASSOCIATED HYDROXYCINNAMOYL TRANSFERASE (HCT)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effects on lignification of downregulating most of the genes for enzymes on the monolignol biosynthetic pathway have been reasonably well studied in angiosperms. The exception to this is the crucial hydroxylase, cinnamate 3-hydroxylase (C3H), and its associated hydroxycinnamyl transferase (HCT),...

  14. Adipocytokines in renal transplant recipients

    PubMed Central

    Nagy, Kristof; Nagaraju, Shankar Prasad; Rhee, Connie M.; Mathe, Zoltan; Molnar, Miklos Z.

    2016-01-01

    In the last two decades, perceptions about the role of body fat have changed. Adipocytes modulate endocrine and immune homeostasis by synthesizing hundreds of hormones, known as adipocytokines. Many studies have been investigating the influences and effects of these adipocytokines and suggest that they are modulated by the nutritional and immunologic milieu. Kidney transplant recipients (KTRs) are a unique and relevant population in which the function of adipocytokines can be examined, given their altered nutritional and immune status and subsequent dysregulation of adipocytokine metabolism. In this review, we summarize the recent findings about four specific adipocytokines and their respective roles in KTRs. We decided to evaluate the most widely described adipocytokines, including leptin, adiponectin, visfatin and resistin. Increasing evidence suggests that these adipocytokines may lead to cardiovascular events and metabolic changes in the general population and may also increase mortality and graft loss rate in KTRs. In addition, we present findings on the interrelationship between serum adipocytokine levels and nutritional and immunologic status, and mechanisms by which adipocytokines modulate morbidity and outcomes in KTRs. PMID:27274819

  15. Adipocytokines in renal transplant recipients.

    PubMed

    Nagy, Kristof; Nagaraju, Shankar Prasad; Rhee, Connie M; Mathe, Zoltan; Molnar, Miklos Z

    2016-06-01

    In the last two decades, perceptions about the role of body fat have changed. Adipocytes modulate endocrine and immune homeostasis by synthesizing hundreds of hormones, known as adipocytokines. Many studies have been investigating the influences and effects of these adipocytokines and suggest that they are modulated by the nutritional and immunologic milieu. Kidney transplant recipients (KTRs) are a unique and relevant population in which the function of adipocytokines can be examined, given their altered nutritional and immune status and subsequent dysregulation of adipocytokine metabolism. In this review, we summarize the recent findings about four specific adipocytokines and their respective roles in KTRs. We decided to evaluate the most widely described adipocytokines, including leptin, adiponectin, visfatin and resistin. Increasing evidence suggests that these adipocytokines may lead to cardiovascular events and metabolic changes in the general population and may also increase mortality and graft loss rate in KTRs. In addition, we present findings on the interrelationship between serum adipocytokine levels and nutritional and immunologic status, and mechanisms by which adipocytokines modulate morbidity and outcomes in KTRs. PMID:27274819

  16. [Recipients adverse reactions: guidance supports].

    PubMed

    Bazin, A

    2010-12-01

    Since 1994, adverse effects of transfusion transmitted to the French haemovigilance network are registered on "e-fit", the database of the French agency for the safety of health products (Afssaps). In order to improve their analysis, guidance supports have been made by Afssaps working groups. Each support deals with a blood transfusion side effect and is composed of five parts including pathophysiological mechanisms, diagnostic criteria, management recommendations, etiologic investigations and rules of filing the notification form on e-fit. The major characteristics of sheets published or soon-to-be published are presented: transfusion-related acute lung injury, transfusion-transmitted bacterial infection, non-haemolytic febrile reaction, allergic reaction, transfusion-associated circulatory overload, hypotensive transfusion reaction, alloimmunization, erythrocyte incompatibility reaction and hemosiderosis. These new supports give relevant guidelines allowing a better analysis and evaluation of recipients' adverse reactions, particularly their diagnosis, gravity and accountability. They could also initiate studies in European and international haemovigilance and transfusion networks. PMID:21051267

  17. Pancytopenia after allogeneic bone marrow transplant due to copper deficiency.

    PubMed

    Hudspeth, Michelle; Turner, Amy; Miller, Nicole; Lazarchick, John

    2014-05-01

    Pancytopenia occurring 1 year or later after allogeneic bone marrow transplantation typically prompts a primary consideration for relapse. We present the case of a 15-year old-girl who underwent transplantation for therapy-related myelodysplasia secondary to Ewing sarcoma treatment who developed pancytopenia with myelodysplasia 1 year after transplant due to copper deficiency. Copper deficiency is an important consideration in the evaluation of pancytopenia and myelodysplasia in pediatric patients. PMID:23652881

  18. Strength comparison of allogenic bone screws, bioabsorbable screws, and stainless steel screw fixation.

    PubMed

    Rano, James A; Savoy-Moore, Ruth T; Fallat, Lawrence M

    2002-01-01

    Allogenic bone screws are new to the fixation market and have yet to be tested against current fixation materials. An in vitro comparison of the same sizes of stainless steel, bioabsorbable, and allogenic bone screws was undertaken to assess screw resistance to the forces of bending, pullout, and shear. Using aluminum plates to support the screws, forces up to 1000 Newtons were applied to six to eight samples of each type of screw. During each test, stainless steel screws withstood the maximum force that could be exerted by the testing apparatus without failing (bending, 113.9 +/- 11.8 N mean +/- SE; pullout 999.1 +/- 33.7 N; and shear, 997.5 +/- 108.8 N). In each test, compared to bioabsorbable screws, allogenic bone screws failed faster (pullout, allogenic: 12.4 +/- 1.1 seconds vs. bioabsorbable, 120.6 +/- 13.8 seconds; p = .001; bending, allogenic: 53.4 +/- 4.8 seconds vs. bioabsorbable, 201.9 +/- 11.1 seconds; p = .001; shear, allogenic 13.5 +/- 1.4 seconds vs. bioabsorbable, 43.8 +/- 0.9 seconds; p = .001) under equivalent (pullout: bioabsorbable, 385.0 +/- 18.4 N vs. allogenic, 401.0 +/- 35.9 N; p = .001) or lower (bending, allogenic: 4.7 +/- 0.2 N vs. bioabsorbable, 11.0 +/- 0.9 N; p = .675; shear, allogenic: 312.1 +/- 15.5 N vs. bioabsorbable 680.9 +/- 8.5 N; p = .001) loads, and in a highly variable fashion. Overall, the bioabsorbable screws withstood the forces of bending, pullout, and shear better than the allogenic screws, and stainless steel screws outperformed both bioabsorbable and allogenic screws. Despite these results, allogenic screws could still be useful in compliant patients who would benefit from their osteoconductive properties. PMID:11858609

  19. SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Fernandes, Sandra; Brooks, Robert; Gumbleton, Matthew; Park, Mi-Young; Russo, Christopher M.; Howard, Kyle T.; Chisholm, John D.; Kerr, William G.

    2015-01-01

    Hematopoietic stem cell transplantation (HSCT) is a highly effective procedure enabling long-term survival for patients with hematologic malignancy or heritable defects. Although there has been a dramatic increase in the success rate of HSCT over the last two decades, HSCT can result in serious, sometimes untreatable disease due to toxic conditioning regimens and Graft-versus-Host-Disease. Studies utilizing germline knockout mice have discovered several candidate genes that could be targeted pharmacologically to create a more favorable environment for transplant success. SHIP1 deficiency permits improved engraftment of hematopoietic stem-progenitor cells (HS-PCs) and produces an immunosuppressive microenvironment ideal for incoming allogeneic grafts. The recent development of small molecule SHIP1 inhibitors has opened a different therapeutic approach by creating transient SHIP1-deficiency. Here we show that SHIP1 inhibition (SHIPi) mobilizes functional HS-PC, accelerates hematologic recovery, and enhances donor HS-PC engraftment in both allogeneic and autologous transplant settings. We also observed the expansion of key cell populations known to suppress host-reactive cells formed during engraftment. Therefore, SHIPi represents a non-toxic, new therapeutic that has significant potential to improve the success and safety of therapies that utilize autologous and allogeneic HSCT. PMID:26052545

  20. Chimeric autologous/allogeneic constructs for skin regeneration.

    PubMed

    Rasmussen, Cathy Ann; Tam, Joshua; Steiglitz, Barry M; Bauer, Rebecca L; Peters, Noel R; Wang, Ying; Anderson, R Rox; Allen-Hoffmann, B Lynn

    2014-08-01

    The ideal treatment for severe cutaneous injuries would eliminate the need for autografts and promote fully functional, aesthetically pleasing autologous skin regeneration. NIKS progenitor cell-based skin tissues have been developed to promote healing by providing barrier function and delivering wound healing factors. Independently, a device has recently been created to "copy" skin by harvesting full-thickness microscopic tissue columns (MTCs) in lieu of autografts traditionally harvested as sheets. We evaluated the feasibility of combining these two technologies by embedding MTCs in NIKS-based skin tissues to generate chimeric autologous/allogeneic constructs. Chimeric constructs have the potential to provide immediate wound coverage, eliminate painful donor site wounds, and promote restoration of a pigmented skin tissue possessing hair follicles, sweat glands, and sebaceous glands. After MTC insertion, chimeric constructs and controls were reintroduced into air-interface culture and maintained in vitro for several weeks. Tissue viability, proliferative capacity, and morphology were evaluated after long-term culture. Our results confirmed successful MTC insertion and integration, and demonstrated the feasibility of generating chimeric autologous/allogeneic constructs that preserved the viability, proliferative capacity, and structure of autologous pigmented skin. These feasibility studies established the proof-of-principle necessary to further develop chimeric autologous/allogeneic constructs for the treatment of complex skin defects. PMID:25102552

  1. A Novel Therapy to Attenuate Acute Kidney Injury and Ischemic Allograft Damage after Allogenic Kidney Transplantation in Mice

    PubMed Central

    Gueler, Faikah; Shushakova, Nelli; Mengel, Michael; Hueper, Katja; Chen, Rongjun; Liu, Xiaokun; Park, Joon-Keun; Haller, Hermann

    2015-01-01

    Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx). In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV), might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI) and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20–50mg/kg twice daily i.p. for four consecutive days) was initiated 24 hours after IRI when acute kidney injury (AKI) was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg) twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells. PMID:25617900

  2. ALLOGENEIC TRANSPLANTS IN FOLLICULAR LYMPHOMA: HIGHER RISK OF DISEASE PROGRESSION AFTER REDUCED INTENSITY COMPARED TO MYELOABLATIVE CONDITIONING

    PubMed Central

    Hari, Parameswaran; Carreras, Jeanette; Zhang, Mei-Jie; Gale, Robert Peter; Bolwell, Brian J.; Bredeson, Christopher N.; Burns, Linda J.; Cairo, Mitchell S.; Freytes, César O.; Goldstein, Steven C.; Hale, Gregory A.; Inwards, David J.; LeMaistre, Charles F.; Maharaj, Dipnarine; Marks, David I.; Schouten, Harry C.; Slavin, Shimon; Vose, Julie M.; Lazarus, Hillard M.; van Besien, Koen

    2008-01-01

    Reduced intensity conditioning (RIC) regimens have been increasingly used for allogeneic hematopoietic stem cell transplantation (HSCT) in Follicular lymphoma (FL). We compared traditional myeloablative conditioning regimens to RIC in FL. Outcomes of HLA-identical sibling HSCT for follicular lymphoma in 208 recipients reported to the Center for International Blood and Marrow Transplant Research between 1997 and 2002 were studied. Conditioning regimens were categorized as myeloablative (N=120) or reduced-intensity (RIC; N=88). Use of RIC regimens increased from <10% of transplants in 1997 to >80% in 2002 signaling a major shift in practice. Patients receiving RIC were older and had a longer interval from diagnosis to transplant. These differences did not correlate with outcomes. Median follow-up of survivors was 50 mo (4–96 mo) after myeloablative conditioning versus 35 mo (4–82 mo) after RIC (p<0.001). At 3 years, overall survival (OS) for the myeloablative and RIC cohorts were 71 (63–79%) and 62 (51–72%; p=0.15) and progression free survival (PFS), 67 (58–75%) and 55 (44–65%; p=0.07) respectively. Lower Karnofsky performance score (KPS) and resistance to chemotherapy were associated with higher treatment related mortality (TRM), lower OS and PFS. On multivariate analysis, an increased risk of lymphoma progression after RIC was observed (RR=2.97, p=0.04) RIC has become the de facto standard in allogeneic HSCT for FL and appears to result in similar long term outcomes. Although disease free survival is similar compared to myeloablative conditioning, an increased risk of late disease progression after RIC is concerning. PMID:18215784

  3. 6,7,4'-trihydroxyisoflavone inhibits HCT-116 human colon cancer cell proliferation by targeting CDK1 and CDK2.

    PubMed

    Lee, Dong Eun; Lee, Ki Won; Jung, Sung Keun; Lee, Eun Jung; Hwang, Jung A; Lim, Tae-Gyu; Kim, Bo Yeon; Bode, Ann M; Lee, Hyong Joo; Dong, Zigang

    2011-04-01

    Colon cancer is a common epithelial malignancies worldwide. Epidemiologic evidence has shown that nutrition and dietary components are important environmental factors involved in the development of this disease. We investigated the biological activity of 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF, a metabolite of daidzein) in in vitro and in vivo models of human colon cancer. 6,7,4'-THIF suppressed anchorage-dependent and -independent growth of HCT-116 and DLD1 human colon cancer cells more effectively than daidzein. In addition, 6,7,4'-THIF induced cell cycle arrest at the S and G2/M phases in HCT-116 human colon cancer cells. Western blot analysis revealed that 6,7,4'-THIF effectively suppressed the expression of cyclin-dependent kinase (CDK) 2, but had no effect on other S- or G2/M-phase regulatory proteins such as cyclin A, cyclin B1 or CDK1. Daidzein did not affect the expression of any of these proteins. In kinase and pull-down assays, 6,7,4'-THIF, but not daidzein, inhibited CDK1 and CDK2 activities in HCT-116 cells by directly interacting with CDK1 and CDK2. In a xenograft mouse model, 6,7,4'-THIF significantly decreased tumor growth, volume and weight of HCT-116 xenografts. 6,7,4'-THIF bound directly to CDK1 and CDK2 in vivo, resulting in the suppression of CDK1 and CDK2 activity in tumors corresponding with our in vitro results. Collectively, these results suggest that CDK1 and CDK2 are potential molecular targets of 6,7,4'-THIF to suppress HCT-116 cell proliferation in vitro and in vivo. These findings provide insight into the biological actions of 6,7,4'-THIF and might establish a molecular basis for the development of new cancer therapeutic agents. PMID:21258042

  4. Gelam honey and ginger potentiate the anti cancer effect of 5-FU against HCT 116 colorectal cancer cells.

    PubMed

    Hakim, Luqman; Alias, Ekram; Makpol, Suzana; Ngah, Wan Zurinah Wan; Morad, Nor Azian; Yusof, Yasmin Anum Mohd

    2014-01-01

    The development of chemopreventive approaches using a concoction of phytochemicals is potentially viable for combating many types of cancer including colon carcinogenesis. This study evaluated the anti-proliferative effects of ginger and Gelam honey and its efficacy in enhancing the anti-cancer effects of 5-FU (5-fluorouracil) against a colorectal cancer cell line, HCT 116. Cell viability was measured via MTS (3-(4,5-dimethylthiazol-2- yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphenyl)-2H-tetrazolium) assay showing ginger inhibiting the growth of HCT 116 cells more potently (IC50 of 3mg/mL) in comparison to Gelam honey (IC50 of 75 mg/mL). Combined treatment of the two compounds (3mg/mL ginger+75 mg/mL Gelam honey) synergistically lowered the IC50 of Gelam honey to 22 mg/mL. Combination with 35 mg/mL Gelam honey markedly enhanced 5-FU inhibiting effects on the growth of HCT 116 cells. Subsequent analysis on the induction of cellular apoptosis suggested that individual treatment of ginger and Gelam honey produced higher apoptosis than 5-FU alone. In addition, treatment with the combination of two natural compounds increased the apoptotic rate of HCT 116 cells dose- dependently while treatment of either ginger or Gelam honey combined with 5-FU only showed modest changes. Combination index analysis showed the combination effect of both natural compounds to be synergistic in their inhibitory action against HCT 116 colon cancer cells (CI 0.96 < 1). In conclusion, combined treatment of Gelam honey and ginger extract could potentially enhance the chemotherapeutic effect of 5-FU against colorectal cancer. PMID:24969899

  5. Isolation and characterization of alborixin from Streptomyces scabrisporus: A potent cytotoxic agent against human colon (HCT-116) cancer cells.

    PubMed

    Shah, Aabid Manzoor; Wani, Abubakar; Qazi, Parvaiz H; Rehman, Shakeel-U; Mushtaq, Saleem; Ali, Shiekh Abid; Hussain, Aehtesham; Shah, Aiyatullah; Qazi, Asif Khurshid; Makhdoomi, Ubaid Sharif; Hamid, Abid; Kumar, Ajay

    2016-08-25

    The ethyl acetate extract from the fermentation broth of an actinomycete strain, identified as Streptomyces scabrisporus isolated from soil of Kashmir Himalayas - India, exhibited significant cytotoxic activity against a panel of human cancer cell lines. The active fraction subjected to column chromatography led to the isolation of pharmacologically potent anticancer compound whose structure was established to be alborixin on the basis of spectral data analysis. The compound exhibited antiproliferative activity against panel of cell lines N2a, MCF-7, MiaPaca-2, PC-3, HCT-116, MDA-MB-231, HL-60 and A-549 cells with IC50 of 9.7, 15.4, 7.2, 8.1, 3.2, 9.7, 7.5 and 11.5 μM respectively. Alborixin displayed the maximum cytotoxic activity against HCT-116 human colon carcinoma cells and therefore further studies were carried on this cell line. Alborixin decreased the clonogenic potential of HCT-116 cells in a dose dependent manner. It induced apoptotic cell death in HCT116 cells that were confirmed by Flow cytometric analysis of Annexin V/PI staining and microscopic examination of cellular morphology through DAPI-stained cells. Biochemical evidence of apoptosis came from elevating the intracellular ROS level that was accompanied by mitochondrial membrane potential loss, decreasing the expression profile of anti-apoptotic protein Bcl-2, whereas it augments cleavage of caspase-3 and PARP-1, activates caspase-8 and 9 with concomitant increase in expression of proapoptotic protein Bax in a dose dependent manner. These results indicate that alborixin obtained from Streptomyces scabrisporus IIIM55 induces apoptotic cell death in colon cancer cells HCT-116 and can be further evaluated for its potential as an anticancer agent. PMID:27378626

  6. Dibenzocyclooctadiene lignans, gomisins J and N inhibit the Wnt/{beta}-catenin signaling pathway in HCT116 cells

    SciTech Connect

    Kang, Kyungsu; Lee, Kyung-Mi; Yoo, Ji-Hye; Lee, Hee Ju; Kim, Chul Young; Nho, Chu Won

    2012-11-16

    Graphical abstract: Schematic diagram of the possible molecular mechanism underlying the inhibition of the Wnt/{beta}-catenin signaling pathway and the induction of G0/G1-phase arrest by gomisins J and N, derived from the fruits of S. chinensis, in HCT116 human colon cancer cells. Highlights: Black-Right-Pointing-Pointer Gomisins J and N inhibited Wnt/{beta}-catenin signaling pathway in HCT116 cells. Black-Right-Pointing-Pointer Gomisins J and N disrupted the binding of {beta}-catenin to specific DNA sequences, TBE. Black-Right-Pointing-Pointer Gomisins J and N inhibited the HCT116 cell proliferation through G0/G1 phase arrest. Black-Right-Pointing-Pointer Gomisins J and N inhibited the expression of Cyc D1, a Wnt/{beta}-catenin target gene. -- Abstract: Here, we report that gomisin J and gomisin N, dibenzocyclooctadiene type lignans isolated from Schisandra chinensis, inhibit Wnt/{beta}-catenin signaling in HCT116 cells. Gomisins J and N appear to inhibit Wnt/{beta}-catenin signaling by disrupting the interaction between {beta}-catenin and its specific target DNA sequences (TCF binding elements, TBE) rather than by altering the expression of the {beta}-catenin protein. Gomisins J and N inhibit HCT116 cell proliferation by arresting the cell cycle at the G0/G1 phase. The G0/G1 phase arrest induced by gomisins J and N appears to be caused by a decrease in the expression of Cyclin D1, a representative target gene of the Wnt/{beta}-catenin signaling pathway, as well as Cdk2, Cdk4, and E2F-1. Therefore, gomisins J and N, the novel Wnt/{beta}-catenin inhibitors discovered in this study, may serve as potential agents for the prevention and treatment of human colorectal cancers.

  7. Types of Cancer Associated with Transplant Recipients

    MedlinePlus

    ... normal population. Cancer due to suppression of the immune system Transplant recipients have an increased risk of developing ... growth of white blood cells in the body's immune system. There are several treatment options that will require ...

  8. 40 CFR 35.134 - Eligible recipients.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ....134 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE STATE AND LOCAL ASSISTANCE Environmental Program Grants Performance Partnership Grants § 35.134 Eligible recipients. (a) Eligible agencies. All State agencies (including environmental, health, agriculture,...

  9. 40 CFR 35.134 - Eligible recipients.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ....134 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE STATE AND LOCAL ASSISTANCE Environmental Program Grants Performance Partnership Grants § 35.134 Eligible recipients. (a) Eligible agencies. All State agencies (including environmental, health, agriculture,...

  10. The influence of interleukin 7 receptor α chain haplotypes on outcome after allogeneic hematopoietic cell transplantation

    PubMed Central

    Broux, Bieke; Shamim, Zaiba; Wang, Tao; Spellman, Stephen; Haagenson, Michael; Stinissen, Piet; Ryder, Lars Peter; Müller, Klaus; Hellings, Niels

    2014-01-01

    Summary We investigated the influence of IL-7 receptor α chain (IL-7Rα) gene haplotypes in donors on the outcome of haematopoietic cell transplantation (HCT). Unlike the association between single donor SNPs and HCT outcome found previously, only trends towards association were found here, due to “dilution” of SNPs into haplotypes. PMID:25352021

  11. PARACOCCIDIOIDOMYCOSIS IN A RENAL TRANSPLANT RECIPIENT

    PubMed Central

    GÓES, Heliana Freitas de Oliveira; DURÃES, Sandra Maria Barbosa; LIMA, Caren dos Santos; de SOUZA, Mariana Boechat; VILAR, Enoi Aparecida Guedes; DALSTON, Marcos Olivier

    2016-01-01

    Paracoccidioidomycosis (PCM) is the most common endemic mycosis in Latin America. The etiological agents, which comprise two species, Paracoccidioides brasiliensis and P. lutzii, are thermodimorphic fungi that usually affect previously healthy adults. They primarily involve the lungs and then disseminate to other organs. Such mycosis is rare in organ transplant recipients; there have been only three cases reported in literature, until now. We report a case of PCM in a renal transplant recipient with an unusual dermatological presentation. PMID:26910451

  12. Zygomycosis in a renal allograft recipient

    PubMed Central

    Lakshminarayana, G.; Rajesh, R.; Kurian, G.; Unni, V. N.

    2009-01-01

    Invasive fungal infections can cause considerable morbidity and mortality in immunocompromised patients. Zygomycosis is a type of invasive fungal infection with a rapid course and grave prognosis. Renal transplant recipients with concomitant diabetes mellitus are most susceptible to this infection. We report here a case of disseminated zygomycosis (Rhizopus sp.) in a renal allograft recipient with posttransplant diabetes mellitus (PTDM). This is the first reported case of zygomycosis caused by Rhizopus species. PMID:20352010

  13. Cytomegalovirus infection in transplant recipients.

    PubMed

    Azevedo, Luiz Sergio; Pierrotti, Lígia Camera; Abdala, Edson; Costa, Silvia Figueiredo; Strabelli, Tânia Mara Varejão; Campos, Silvia Vidal; Ramos, Jéssica Fernandes; Latif, Acram Zahredine Abdul; Litvinov, Nadia; Maluf, Natalya Zaidan; Caiaffa Filho, Helio Hehl; Pannuti, Claudio Sergio; Lopes, Marta Heloisa; Santos, Vera Aparecida dos; Linardi, Camila da Cruz Gouveia; Yasuda, Maria Aparecida Shikanai; Marques, Heloisa Helena de Sousa

    2015-07-01

    Cytomegalovirus infection is a frequent complication after transplantation. This infection occurs due to transmission from the transplanted organ, due to reactivation of latent infection, or after a primary infection in seronegative patients and can be defined as follows: latent infection, active infection, viral syndrome or invasive disease. This condition occurs mainly between 30 and 90 days after transplantation. In hematopoietic stem cell transplantation in particular, infection usually occurs within the first 30 days after transplantation and in the presence of graft-versus-host disease. The major risk factors are when the recipient is cytomegalovirus seronegative and the donor is seropositive as well as when lymphocyte-depleting antibodies are used. There are two methods for the diagnosis of cytomegalovirus infection: the pp65 antigenemia assay and polymerase chain reaction. Serology has no value for the diagnosis of active disease, whereas histology of the affected tissue and bronchoalveolar lavage analysis are useful in the diagnosis of invasive disease. Cytomegalovirus disease can be prevented by prophylaxis (the administration of antiviral drugs to all or to a subgroup of patients who are at higher risk of viral replication) or by preemptive therapy (the early diagnosis of viral replication before development of the disease and prescription of antiviral treatment to prevent the appearance of clinical disease). The drug used is intravenous or oral ganciclovir; oral valganciclovir; or, less frequently, valacyclovir. Prophylaxis should continue for 90 to 180 days. Treatment is always indicated in cytomegalovirus disease, and the gold-standard drug is intravenous ganciclovir. Treatment should be given for 2 to 3 weeks and should be continued for an additional 7 days after the first negative result for viremia. PMID:26222822

  14. Cytomegalovirus infection in transplant recipients

    PubMed Central

    Azevedo*, Luiz Sergio; Pierrotti, Lígia Camera; Abdala, Edson; Costa, Silvia Figueiredo; Strabelli, Tânia Mara Varejão; Campos, Silvia Vidal; Ramos, Jéssica Fernandes; Latif, Acram Zahredine Abdul; Litvinov, Nadia; Maluf, Natalya Zaidan; Filho, Helio Hehl Caiaffa; Pannuti, Claudio Sergio; Lopes, Marta Heloisa; dos Santos, Vera Aparecida; da Cruz Gouveia Linardi, Camila; Yasuda, Maria Aparecida Shikanai; de Sousa Marques, Heloisa Helena

    2015-01-01

    Cytomegalovirus infection is a frequent complication after transplantation. This infection occurs due to transmission from the transplanted organ, due to reactivation of latent infection, or after a primary infection in seronegative patients and can be defined as follows: latent infection, active infection, viral syndrome or invasive disease. This condition occurs mainly between 30 and 90 days after transplantation. In hematopoietic stem cell transplantation in particular, infection usually occurs within the first 30 days after transplantation and in the presence of graft-versus-host disease. The major risk factors are when the recipient is cytomegalovirus seronegative and the donor is seropositive as well as when lymphocyte-depleting antibodies are used. There are two methods for the diagnosis of cytomegalovirus infection: the pp65 antigenemia assay and polymerase chain reaction. Serology has no value for the diagnosis of active disease, whereas histology of the affected tissue and bronchoalveolar lavage analysis are useful in the diagnosis of invasive disease. Cytomegalovirus disease can be prevented by prophylaxis (the administration of antiviral drugs to all or to a subgroup of patients who are at higher risk of viral replication) or by preemptive therapy (the early diagnosis of viral replication before development of the disease and prescription of antiviral treatment to prevent the appearance of clinical disease). The drug used is intravenous or oral ganciclovir; oral valganciclovir; or, less frequently, valacyclovir. Prophylaxis should continue for 90 to 180 days. Treatment is always indicated in cytomegalovirus disease, and the gold-standard drug is intravenous ganciclovir. Treatment should be given for 2 to 3 weeks and should be continued for an additional 7 days after the first negative result for viremia. PMID:26222822

  15. Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study.

    PubMed

    Yeshurun, Moshe; Shpilberg, Ofer; Herscovici, Corina; Shargian, Liat; Dreyer, Juliet; Peck, Anat; Israeli, Moshe; Levy-Assaraf, Maly; Gruenewald, Tsipora; Mechoulam, Raphael; Raanani, Pia; Ram, Ron

    2015-10-01

    Graft-versus-host-disease (GVHD) is a major obstacle to successful allogeneic hematopoietic cell transplantation (alloHCT). Cannabidiol (CBD), a nonpsychotropic ingredient of Cannabis sativa, possesses potent anti-inflammatory and immunosuppressive properties. We hypothesized that CBD may decrease GVHD incidence and severity after alloHCT. We conducted a phase II study. GVHD prophylaxis consisted of cyclosporine and a short course of methotrexate. Patients transplanted from an unrelated donor were given low-dose anti-T cell globulin. CBD 300 mg/day was given orally starting 7 days before transplantation until day 30. Forty-eight consecutive adult patients undergoing alloHCT were enrolled. Thirty-eight patients (79%) had acute leukemia or myelodysplastic syndrome and 35 patients (73%) were given myeloablative conditioning. The donor was either an HLA-identical sibling (n = 28), a 10/10 matched unrelated donor (n = 16), or a 1-antigen-mismatched unrelated donor (n = 4). The median follow-up was 16 months (range, 7 to 23). No grades 3 to 4 toxicities were attributed to CBD. None of the patients developed acute GVHD while consuming CBD. In an intention-to-treat analysis, we found that the cumulative incidence rates of grades II to IV and grades III to IV acute GVHD by day 100 were 12.1% and 5%, respectively. Compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II to IV acute GVHD among subjects treated with CBD plus standard GVHD prophylaxis was .3 (P = .0002). Rates of nonrelapse mortality at 100 days and at 1 year after transplantation were 8.6% and 13.4%, respectively. Among patients surviving more than 100 days, the cumulative incidences of moderate-to-severe chronic GVHD at 12 and 18 months were 20% and 33%, respectively. The combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of acute GVHD. A randomized double-blind controlled study is warranted

  16. Long-Term Persistence of Donor Alveolar Macrophages in Human Lung Transplant Recipients That Influences Donor-Specific Immune Responses.

    PubMed

    Nayak, D K; Zhou, F; Xu, M; Huang, J; Tsuji, M; Hachem, R; Mohanakumar, T

    2016-08-01

    Steady-state alveolar macrophages (AMs) are long-lived lung-resident macrophages with sentinel function. Evidence suggests that AM precursors originate during embryogenesis and populate lungs without replenishment by circulating leukocytes. However, their presence and persistence are unclear following human lung transplantation (LTx). Our goal was to examine donor AM longevity and evaluate whether AMs of recipient origin seed the transplanted lungs. Origin of AMs was accessed using donor-recipient HLA mismatches. We demonstrate that 94-100% of AMs present in bronchoalveolar lavage (BAL) were donor derived and, importantly, AMs of recipient origin were not detected. Further, analysis of BAL cells up to 3.5 years post-LTx revealed that the majority of AMs (>87%) was donor derived. Elicitation of de novo donor-specific antibody (DSA) is a major post-LTx complication and a risk factor for development of chronic rejection. The donor AMs responded to anti-HLA framework antibody (Ab) with secretion of inflammatory cytokines. Further, in an experimental murine model, we demonstrate that adoptive transfer of allogeneic AMs stimulated humoral and cellular immune responses to alloantigen and lung-associated self-antigens and led to bronchiolar obstruction. Therefore, donor-derived AMs play an essential role in the DSA-induced inflammatory cascade leading to obliterative airway disease of the transplanted lungs. PMID:27062199

  17. Fetal Liver-Derived Mesenchymal Stem Cell Engraftment After Allogeneic In Utero Transplantation into Rabbits

    PubMed Central

    Moreno, Rafael; Martínez-González, Itziar; Rosal, Marta; Nadal, Marga; Petriz, Jordi; Gratacós, Eduard

    2012-01-01

    Prenatal transplantation of genetically engineered mesenchymal stem cells (MSCs) might benefit prevention or treatment of early-onset genetic disorders due to the cells' intrinsic regenerative potential plus the acquired advantage from therapeutic transgene expression. However, a thorough assessment of the safety, accessibility, and behavior of these MSCs in the fetal environment using appropriate animal models is required before we can advance toward a clinical application. We have recently shown that fetal rabbit liver MSCs (fl-MSCs) have superior growth rate, clonogenic capability, and in vitro adherence and differentiation abilities compared with adult rabbit bone marrow MSCs. In this follow-up study, we report safe and widespread distribution of recombinant pSF-EGFP retrovirus-transduced fl-MSCs (EGFP+-fl-MSCs) in neonatal rabbit tissues at 10 days after fetal allogeneic transplantation through both intrahepatic and intra-amniotic administration. Conversely, a more restricted biodistribution pattern according to the route of administration was apparent in the young rabbits intervened at 16 weeks after fetal EGFP+-fl-MSC transplantation. Furthermore, the presence of these cells in the recipients' tissues, tracked with the reporter provirus, was inversely related to the developmental stage of the fetuses at the time of intervention. Long-term engraftment was confirmed both by fluorescence in situ hybridization analysis on touch tissue imprints using a chromosome Y-specific BAC probe, and by immunohistochemical localization of EGFP expression. Finally, there was no evidence of immune responses against the transplanted EGFP+-fl-MSCs or the EGFP transgenic product in the treated young rabbits. Thus, cell transplantation approaches using genetically engineered fetal MSCs may prove particularly valuable to frontier medical treatments for congenital birth defects in perinatology. PMID:21495909

  18. Transient increase of serum IgD levels after allogeneic bone-marrow transplantation.

    PubMed Central

    Korver, K; Radl, J; Schellekens, P T; Vossen, J M

    1988-01-01

    Serum IgD levels were followed longitudinally twice a week for up to 100 days in 60 children undergoing allogeneic bone-marrow transplantation (n = 52) or immunosuppression (n = 8) for the treatment of leukaemia, severe aplastic anaemia or severe combined immunodeficiency. In 40 out of the 49 post-transplantation periods analysed (82%), a transient sharp increase of serum IgD was detected, irrespective of initial disease. A similar peak was found in one out of five children after immunosuppressive treatment. A second IgD peak was only recorded in grafted patients (14/49 post-transfusion periods). Peak levels of IgD ranged from 1.3 to 185.7 IU/ml (median 12.2 IU/ml), which represents a 2.6 to 22.4-fold increase over 'baseline' levels. In the transplanted leukaemia and aplastic anaemia patients, the rise of serum IgD occurred at the same time (geometric mean 16 days after transplantation) and was shown to represent heterogeneous polyclonal IgD in six of them. The onset of the serum IgD peak was significantly delayed in children suffering from severe combined immunodeficiency (P less than 0.05) and was demonstrated in one patient to consist of homogeneous IgD. No relation was found between either the occurrence of clinical acute graft-versus-host disease or infections after treatment, and the time of onset of IgD elevations. To detect transient serum IgD peaks as described here, frequent sampling of sera is necessary. The origin of the early IgD peaks seems to reside within the recipient's cells by an unknown mechanism. The late IgD peaks are most probably an expression of gradual reconstitution of the immune system following bone-marrow transplantation. PMID:3044651

  19. [18F]FHBG PET/CT Imaging of CD34-TK75 Transduced Donor T Cells in Relapsed Allogeneic Stem Cell Transplant Patients: Safety and Feasibility

    PubMed Central

    Eissenberg, Linda G; Rettig, Michael P; Ritchey, Julie K; Prior, Julie L; Schwarz, Sally W; Frye, Jennifer; White, Brian S; Fulton, Robert S; Ghobadi, Armin; Cooper, Matthew L; Couriel, Daniel R; Seegulam, Muhammad Esa; Piwnica-Worms, David; Dehdashti, Farrokh; Cornetta, Kenneth; DiPersio, John F

    2015-01-01

    Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent γ-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity-purified CD34-TK75+-selected donor T cells (1.0–13 × 105)/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-(18F)fluoro-3-hydroxymethyl-butyl]guanine ([18F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [18F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [18F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation. PMID:25807290

  20. [(18)F]FHBG PET/CT Imaging of CD34-TK75 Transduced Donor T Cells in Relapsed Allogeneic Stem Cell Transplant Patients: Safety and Feasibility.

    PubMed

    Eissenberg, Linda G; Rettig, Michael P; Ritchey, Julie K; Prior, Julie L; Schwarz, Sally W; Frye, Jennifer; White, Br