Science.gov

Sample records for acute gvhd grades

  1. Treatment of severe steroid resistant acute GVHD with mesenchymal stromal cells (MSC)

    PubMed Central

    Resnick, Igor B; Barkats, Claudine; Shapira, Michael Y; Stepensky, Polina; Bloom, Allan I; Shimoni, Avichai; Mankuta, David; Varda-Bloom, Nira; Rheingold, Lyudmila; Yeshurun, Moshe; Bielorai, Bella; Toren, Amos; Zuckerman, Tsila; Nagler, Arnon; Or, Reuven

    2013-01-01

    Background: Several studies revealed that MSC from human bone marrow can downregulate graft-versus-host disease (GVHD) after allogeneic HSCT. Methods: Herein we present 50 patients with acute GVHD who got 74 (1-4) MSC infusions for 54 separate episodes of aGVHD. Results: aGVHD was defined as steroid resistant grade IV aGVHD in 42 cases. The major presentation was gastrointestinal GVHD; two (n=18) or more (n=21) systems were involved in the majority of cases. The 1st infusion with MSC was given on day +27 (range, 1 to 136); d+45 (range, +11 to +150) post diagnosis of aGVHD and HSCT, respectively. In 2/3 of the cases treatment was performed with frozen stocked MSCs; in 62 cases early passages (1-3) were used. The median number of infused cells was 1.14±0.47 million per kg in the first injection and up to 4.27 (1.70±1.10) millions in total. The two patients with aggressive liver GVHD received MSCs injections intra hepatic arteries without changes of blood flow or evidence cytolysis, but also without a visible effect. Disease free survival at 3.6 years was 56%. We observed better overall survival in patients with GVHD grade < 4, in responders to the 1st treatment with MSC, and in pediatric group. The multivariate analysis demonstrated independent influence on survival of initial response and younger age. There were no immediate or late toxicity or side effects. Conclusion: Injection of MSCs seems to be a promising and safe treatment of GVHD. The encouraging results obviously should be confirmed in a randomized prospective study. PMID:23997985

  2. Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD.

    PubMed

    Leveque-El Mouttie, Lucie; Koyama, Motoko; Le Texier, Laetitia; Markey, Kate A; Cheong, Melody; Kuns, Rachel D; Lineburg, Katie E; Teal, Bianca E; Alexander, Kylie A; Clouston, Andrew D; Blazar, Bruce R; Hill, Geoffrey R; MacDonald, Kelli P A

    2016-08-11

    Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunologic pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within major histocompatibility complex (MHC) class II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Tregs after BMT also induced cGVHD, whereas adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class II that is induced by aGVHD.

  3. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Société Française de Greffe de Moëlle et Thérapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study.

    PubMed

    Cahn, Jean-Yves; Klein, John P; Lee, Stephanie J; Milpied, Noël; Blaise, Didier; Antin, Joseph H; Leblond, Véronique; Ifrah, Norbert; Jouet, Jean-Pierre; Loberiza, Fausto; Ringden, Olle; Barrett, A John; Horowitz, Mary M; Socié, Gérard

    2005-08-15

    The most commonly used grading system for acute graft-versus-host disease (aGVHD) was introduced 30 years ago by Glucksberg; a revised system was developed by the International Bone Marrow Transplant Registry (IBMTR) in 1997. To prospectively compare the 2 classifications and to evaluate the effect of duration and severity of aGVHD on survival, we conducted a multicenter study of 607 patients receiving T-cell-replete allografts, scored weekly for aGVHD in 18 transplantation centers. Sixty-nine percent of donors were HLA-identical siblings and 28% were unrelated donors. The conditioning regimen included total body irradiation in 442 (73%) patients. The 2 classifications performed similarly in explaining variability in survival by aGVHD grade, although the Glucksberg classification predicted early survival better. There was less physician bias or error in assigning grades with the IBMTR scoring system. With either system, only the maximum observed grade had prognostic significance for survival; neither time of onset nor progression from an initially lower grade of aGVHD was associated with survival once maximum grade was considered. Regardless of scoring system, aGVHD severity accounted for only a small percentage of observed variation in survival. Validity of these results in populations receiving peripheral blood transplants or nonmyeloablative conditioning regimens remains to be tested.

  4. Alemtuzumab as graft-versus-host disease (GVHD) prophylaxis strategy in a developing country: lower rate of acute GVHD, increased risk of cytomegalovirus reactivation

    PubMed Central

    Resende, C.B.; Rezende, B.M.; Bernardes, P.T.T.; Teixeira, G.M.; Teixeira, M.M.; Pinho, V.; Bittencourt, H.

    2017-01-01

    Acute graft-versus-host disease (aGVHD) and cytomegalovirus reactivation are important complications after allogeneic stem cell transplantation (alloHSCT). Here, we evaluated the impact of treatment with alemtuzumab on the occurrence of aGVHD, cytomegalovirus reactivation and survival after alloHSCT. This was a prospective cohort study conducted at the allo-HSCT unit of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, from January 2009 to December 2011. Fifty-seven patients who underwent alloHSCT were included. Forty-five (79%) patients had a malignant disease. Alemtuzumab was administered before the conditioning regimen at a dose of 1 mg/kg in children and 30 mg/day for 2 days in adults or children weighing more than 40 kg (a total dose of 60 mg) with a non-malignant disease or patients with a malignant disease and high-risk for GVHD mortality. Alemtuzumab was used in 23 (40%) patients, of whom 17 received a reduced-intensity conditioning. Eleven patients presented aGVHD (grade 2–4) and only 1 of them received alemtuzumab. Cumulative incidence of aGVHD (grade 2–4) at day 100 after transplantation (D+100) was 4 for patients receiving alemtuzumab and 29% for patients not receiving alemtuzumab. Cumulative incidence of cytomegalovirus reactivation for patients receiving or not alemtuzumab was 62 and 38%, respectively. Sixteen patients died in the first 100 days after alloHSCT, most of them due to bacterial sepsis. Only 2 patients died of aGVHD until D+100. Overall survival was 50% without any impact of alemtuzumab. Alemtuzumab effectively controlled aGVHD but increased the risk of cytomegalovirus reactivation without improving survival. PMID:28198910

  5. Alemtuzumab as graft-versus-host disease (GVHD) prophylaxis strategy in a developing country: lower rate of acute GVHD, increased risk of cytomegalovirus reactivation.

    PubMed

    Resende, C B; Rezende, B M; Bernardes, P T T; Teixeira, G M; Teixeira, M M; Pinho, V; Bittencourt, H

    2017-02-09

    Acute graft-versus-host disease (aGVHD) and cytomegalovirus reactivation are important complications after allogeneic stem cell transplantation (alloHSCT). Here, we evaluated the impact of treatment with alemtuzumab on the occurrence of aGVHD, cytomegalovirus reactivation and survival after alloHSCT. This was a prospective cohort study conducted at the allo-HSCT unit of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, from January 2009 to December 2011. Fifty-seven patients who underwent alloHSCT were included. Forty-five (79%) patients had a malignant disease. Alemtuzumab was administered before the conditioning regimen at a dose of 1 mg/kg in children and 30 mg/day for 2 days in adults or children weighing more than 40 kg (a total dose of 60 mg) with a non-malignant disease or patients with a malignant disease and high-risk for GVHD mortality. Alemtuzumab was used in 23 (40%) patients, of whom 17 received a reduced-intensity conditioning. Eleven patients presented aGVHD (grade 2-4) and only 1 of them received alemtuzumab. Cumulative incidence of aGVHD (grade 2-4) at day 100 after transplantation (D+100) was 4 for patients receiving alemtuzumab and 29% for patients not receiving alemtuzumab. Cumulative incidence of cytomegalovirus reactivation for patients receiving or not alemtuzumab was 62 and 38%, respectively. Sixteen patients died in the first 100 days after alloHSCT, most of them due to bacterial sepsis. Only 2 patients died of aGVHD until D+100. Overall survival was 50% without any impact of alemtuzumab. Alemtuzumab effectively controlled aGVHD but increased the risk of cytomegalovirus reactivation without improving survival.

  6. The predictive value of selected serum microRNAs for acute GVHD by TaqMan MicroRNA arrays.

    PubMed

    Zhang, Chunyan; Bai, Nan; Huang, Wenrong; Zhang, Pengjun; Luo, Yuan; Men, Shasha; Wen, Ting; Tong, Hongli; Wang, Shuhong; Tian, Ya-Ping

    2016-10-01

    Currently, the diagnosis of acute graft-versus-host disease (aGVHD) is mainly based on clinical symptoms and biopsy results. This study was designed to further explore new no noninvasive biomarkers for aGVHD prediction/diagnosis. We profiled miRNAs in serum pools from patients with aGVHD (grades II-IV) (n = 9) and non-aGVHD controls (n = 9) by real-time qPCR-based TaqMan MicroRNA arrays. Then, predictive models were established using related miRNAs (n = 38) and verified by a double-blind trial (n = 54). We found that miR-411 was significantly down regulated when aGVHD developed and recovered when aGVHD was controlled, which demonstrated that miR-411 has potential as an indicator for aGVHD monitoring. We developed and validated a predictive model and a diagnostic model for aGVHD. The predictive model included two miRNAs (miR-26b and miR-374a), which could predict an increased risk for aGVHD 1 or 2 weeks in advance, with an AUC, Positive Predictive Value (PPV), and Negative Predictive Value (NPV) of 0.722, 76.19 %, and 69.70 %, respectively. The diagnostic model included three miRNAs (miR-28-5p, miR-489, and miR-671-3p) with an AUC, PPV, and NPV of 0.841, 85.71 % and 83.33 %, respectively. Our results show that circulating miRNAs (miR-26b and miR-374a, miR-28-5p, miR-489 and miR-671-3p) may serve as biomarkers for the prediction and diagnosis of grades II-IV aGVHD.

  7. Response of Steroid-Refractory Acute GVHD to α1-Antitrypsin.

    PubMed

    Marcondes, A Mario; Hockenbery, David; Lesnikova, Marina; Dinarello, Charles A; Woolfrey, Ann; Gernsheimer, Terry; Loghman-Adham, Mahmoud; Gelmont, David; Storer, Barry; Hansen, John A; Deeg, H Joachim

    2016-09-01

    α1-Antitrypsin (AAT) is a serine protease inhibitor with anti-inflammatory, antiapoptotic, and immunomodulatory properties. It has therapeutic efficacy in animal models of autoimmune diseases, inflammatory disorders, and transplantation. In a phase I/II open-label single-center study, we administered AAT (Glassia; Baxalta/Kamada, New Ziona, Israel) as salvage therapy to 12 patients with steroid-refractory acute graft-versus-host disease (GVHD). AAT was given i.v. at 2 dose levels over a 15-day course. All patients had grades III or IV GVHD with stage 4 gut involvement. After treatment, plasma AAT levels increased in both cohorts and remained within 2 to 4 mg/mL for the duration of treatment. No clinically relevant toxicities attributable to AAT were observed. GVHD manifestations improved in 8 of 12 patients, and 4 responses were complete. Six patients (50%) were alive at last follow-up (>104 to >820 days). These findings show that AAT is well tolerated and has efficacy in the treatment of steroid-refractory severe acute GVHD. Further studies are warranted.

  8. Anti-interleukin-2 receptor monoclonal antibody (BT 563) in the treatment of severe acute GVHD refractory to systemic corticosteroid therapy.

    PubMed

    Cuthbert, R J; Phillips, G L; Barnett, M J; Nantel, S H; Reece, D E; Shepherd, J D; Klingemann, H G

    1992-11-01

    Fourteen patients with corticosteroid-resistant acute GVHD were treated with a murine monoclonal antibody to the pp55 interleukin-2 (IL-2) receptor (MoAb BT 563). Nine of the 14 patients had also failed Xoma-Zyme-H65 as GVHD prophylaxis and/or treatment. Seven patients had received HLA-matched sibling donor bone marrow transplants, five had received HLA-matched transplants from unrelated volunteer donors, and two had received one-antigen mismatched transplants from unrelated volunteer donors. At the time of MoAb BT 563 therapy, the overall clinical grading of acute GVHD (Seattle grading system) was as follows: grade II--one patient, grade III--four patients, and grade IV--nine patients. MoAb BT 563 was administered as a short iv infusion of 5 mg daily for 10 doses, followed by 5 mg on alternate days for a further five doses. A complete response (CR) was observed in four patients (28%), and a partial response (PR) in four patients (28%). All four complete responders were treated within 28 days of first onset of grade > or = II acute GVHD. Four patients (three CR, one PR) remain alive. One complete responder subsequently died from chronic GVHD. MoAb BT 563 administration was well tolerated in all 14 patients; no significant toxicity was observed. We conclude that MoAb BT 563 directed against the IL-2 receptor on activated T lymphocytes may be useful in treating corticosteroid-resistant acute GVHD if given early, but that it is of limited value in attempting to rescue patients with far-advanced refractory acute GVHD.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Acute GVHD after allogeneic hematopoietic transplantation affects early marrow reconstitution and speed of engraftment.

    PubMed

    Milone, Giuseppe; Camuglia, Maria Grazia; Avola, Giuseppe; Di Marco, Annalia; Leotta, Salvatore; Cupri, Alessandra; Spina, Paolo; Romano, Alessandra; Spina, Eleonora; Azzaro, Maria Pia; Berritta, Deja; Parisi, Marina; Tripepi, Giovanni

    2015-06-01

    Our aim was to study the influence of acute graft-versus-host disease (a-GVHD) on primary engraftment times after allogeneic transplantation. Primary engraftment and frequency of marrow granulocyte-macrophage colony-forming units and erythroid burst-forming units, at day +18, were studied in 126 allogeneic transplants. Patients were grouped according to the time when a-GVHD treatment with corticosteroids was started. The no-a-GVHD group are those who, during the first 3 months, had no need for a-GVHD treatment; the early-a-GVHD group are those who needed a-GVHD treatment within 19 days; and the postengraftment-a-GVHD group are those who were not on corticosteroid treatment at the time of engraftment but needed it after day +19. The no-a-GVHD group reached a neutrophil count (N) > 0.5 × 10(9)/L in a median of 17.8 days. The postengraftment-a-GVHD group reached N > 0.5 × 10(9)/L in a median of 21.4 days (p = 0.0003). The early-a-GVHD group had N > 0.5 × 10(9)/L in a median of +17.0 days (p = 0.23). When factors important for engraftment were studied in a multivariate analysis, postengraftment a-GVHD was a significant factor in delayed neutrophil and platelet engraftment. Both the early-a-GVHD and postengraftment-a-GVHD groups showed a significant reduction in frequency of granulocyte-macrophage colony-forming units and erythroid burst-forming units found in marrow at day +18. In conclusion, a-GVHD may influence early marrow reconstitution and is a relevant factor for primary myeloid and platelet engraftment.

  10. Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation.

    PubMed

    Nakasone, H; Fukuda, T; Kanda, J; Mori, T; Yano, S; Kobayashi, T; Miyamura, K; Eto, T; Kanamori, H; Iwato, K; Uchida, N; Mori, S; Nagamura-Inoue, T; Ichinohe, T; Atsuta, Y; Teshima, T; Murata, M

    2015-04-01

    The impact of the conditioning intensity and TBI on acute GVHD (aGVHD) is still a matter of debate. We analyzed 6848 adult recipients who received allogeneic hematopoietic cell transplants (HCT) between 2006 and 2011 in Japan. The subjects were divided into groups who had received myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), either with or without TBI. There was a significant difference in the incidence of aGVHD 2-4 among the different conditioning types: 39% in TBI-MAC, 35% in TBI-RIC and 32% in both no-TBI MAC and no-TBI-RIC (P<0.001). In a multivariate analysis, TBI-MAC, but not no-TBI MAC, was significantly associated with an increased risk of aGVHD 2-4 (hazard ratio (HR) 1.33, P<0.01), whereas TBI-RIC was associated with an increased risk of GVHD 3-4 (HR 1.36, P=0.048). TBI-MAC and TBI-RIC were significantly associated with skin and gastrointestinal aGVHD. Subgroup analyses demonstrated that not only TBI-MAC, but also TBI-RIC, was significantly associated with aGVHD 2-4 in older patients. Furthermore, high-dose TBI only had an adverse impact on aGVHD 2-4 in HLA-matched HCT. Impacts of intensity and TBI on aGVHD differ by patient backgrounds, and this difference should be considered to establish a risk-adapted strategy for the prevention of aGVHD.

  11. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

    PubMed Central

    Carapito, Raphael; Jung, Nicolas; Kwemou, Marius; Untrau, Meiggie; Michel, Sandra; Pichot, Angélique; Giacometti, Gaëlle; Macquin, Cécile; Ilias, Wassila; Morlon, Aurore; Kotova, Irina; Apostolova, Petya; Schmitt-Graeff, Annette; Cesbron, Anne; Gagne, Katia; Oudshoorn, Machteld; van der Holt, Bronno; Labalette, Myriam; Spierings, Eric; Picard, Christophe; Loiseau, Pascale; Tamouza, Ryad; Toubert, Antoine; Parissiadis, Anne; Dubois, Valérie; Lafarge, Xavier; Maumy-Bertrand, Myriam; Bertrand, Frédéric; Vago, Luca; Ciceri, Fabio; Paillard, Catherine; Querol, Sergi; Sierra, Jorge; Fleischhauer, Katharina; Nagler, Arnon; Labopin, Myriam; Inoko, Hidetoshi; von dem Borne, Peter A.; Kuball, Jürgen; Ota, Masao; Katsuyama, Yoshihiko; Michallet, Mauricette; Lioure, Bruno; Peffault de Latour, Régis; Blaise, Didier; Cornelissen, Jan J.; Yakoub-Agha, Ibrahim; Claas, Frans; Moreau, Philippe; Milpied, Noël; Charron, Dominique; Mohty, Mohamad; Zeiser, Robert; Socié, Gérard

    2016-01-01

    Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain–related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B. Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA. MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice. PMID:27549307

  12. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD.

    PubMed

    Carapito, Raphael; Jung, Nicolas; Kwemou, Marius; Untrau, Meiggie; Michel, Sandra; Pichot, Angélique; Giacometti, Gaëlle; Macquin, Cécile; Ilias, Wassila; Morlon, Aurore; Kotova, Irina; Apostolova, Petya; Schmitt-Graeff, Annette; Cesbron, Anne; Gagne, Katia; Oudshoorn, Machteld; van der Holt, Bronno; Labalette, Myriam; Spierings, Eric; Picard, Christophe; Loiseau, Pascale; Tamouza, Ryad; Toubert, Antoine; Parissiadis, Anne; Dubois, Valérie; Lafarge, Xavier; Maumy-Bertrand, Myriam; Bertrand, Frédéric; Vago, Luca; Ciceri, Fabio; Paillard, Catherine; Querol, Sergi; Sierra, Jorge; Fleischhauer, Katharina; Nagler, Arnon; Labopin, Myriam; Inoko, Hidetoshi; von dem Borne, Peter A; Kuball, Jürgen; Ota, Masao; Katsuyama, Yoshihiko; Michallet, Mauricette; Lioure, Bruno; Peffault de Latour, Régis; Blaise, Didier; Cornelissen, Jan J; Yakoub-Agha, Ibrahim; Claas, Frans; Moreau, Philippe; Milpied, Noël; Charron, Dominique; Mohty, Mohamad; Zeiser, Robert; Socié, Gérard; Bahram, Seiamak

    2016-10-13

    Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.

  13. Relation between Acute GVHD and NK Cell Subset Reconstitution Following Allogeneic Stem Cell Transplantation

    PubMed Central

    Ullrich, Evelyn; Salzmann-Manrique, Emilia; Bakhtiar, Shahrzad; Bremm, Melanie; Gerstner, Stephanie; Herrmann, Eva; Bader, Peter; Hoffmann, Petra; Holler, Ernst; Edinger, Matthias; Wolff, Daniel

    2016-01-01

    One of the major challenges of allogeneic stem cell transplantation (allo-SCT) is to reduce the risk of graft-versus-host disease (GVHD) while boosting the graft-versus-leukemia (GVL) effect. The reconstitution of natural killer (NK) cells following allo-SCT is of notable interest due to their known capability to induce GVL without GVHD. Here, in this study, we investigate the association between the incidence and severity of acute graft-versus-host disease (aGVHD) and the early reconstitution of NK cell subsets following allo-SCT. We analyzed 342 samples from 107 patients using flow cytometry, with a focus on immature CD56high and mature cytotoxic CD56dim NK cells. Longitudinal analysis of immune reconstitution after allo-SCT showed that the incidence of aGVHD was associated with a delayed expansion of the entire NK cell population, in particular the CD56high subset. Notably, the disturbed reconstitution of the CD56high NK cells also correlated with the severity of aGVHD. PMID:28066411

  14. Relation between Acute GVHD and NK Cell Subset Reconstitution Following Allogeneic Stem Cell Transplantation.

    PubMed

    Ullrich, Evelyn; Salzmann-Manrique, Emilia; Bakhtiar, Shahrzad; Bremm, Melanie; Gerstner, Stephanie; Herrmann, Eva; Bader, Peter; Hoffmann, Petra; Holler, Ernst; Edinger, Matthias; Wolff, Daniel

    2016-01-01

    One of the major challenges of allogeneic stem cell transplantation (allo-SCT) is to reduce the risk of graft-versus-host disease (GVHD) while boosting the graft-versus-leukemia (GVL) effect. The reconstitution of natural killer (NK) cells following allo-SCT is of notable interest due to their known capability to induce GVL without GVHD. Here, in this study, we investigate the association between the incidence and severity of acute graft-versus-host disease (aGVHD) and the early reconstitution of NK cell subsets following allo-SCT. We analyzed 342 samples from 107 patients using flow cytometry, with a focus on immature CD56(high) and mature cytotoxic CD56(dim) NK cells. Longitudinal analysis of immune reconstitution after allo-SCT showed that the incidence of aGVHD was associated with a delayed expansion of the entire NK cell population, in particular the CD56(high) subset. Notably, the disturbed reconstitution of the CD56(high) NK cells also correlated with the severity of aGVHD.

  15. Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion

    PubMed Central

    Chopra, Martin; Brandl, Andreas; Amich, Jorge; Mottok, Anja; Jordán-Garrote, Ana-Laura; Bäuerlein, Carina A.; Brede, Christian; Ribechini, Eliana; Fick, Andrea; Polz, Johannes; Nishikii, Hidekazu; Mattenheimer, Katharina; Schwinn, Stefanie; Winter, Thorsten; Krappmann, Sven; Einsele, Hermann; Reddehase, Matthias J.; Lutz, Manfred B.

    2016-01-01

    Donor CD4+Foxp3+ regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT [allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2- and T reg cell–dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo. PMID:27526711

  16. A phase 3 randomized trial comparing inolimomab vs usual care in steroid-resistant acute GVHD.

    PubMed

    Socié, Gérard; Vigouroux, Stéphane; Yakoub-Agha, Ibrahim; Bay, Jacques-Olivier; Fürst, Sabine; Bilger, Karin; Suarez, Felipe; Michallet, Mauricette; Bron, Dominique; Gard, Philippe; Medeghri, Zakaria; Lehert, Philippe; Lai, Chinglin; Corn, Tim; Vernant, Jean-Paul

    2017-02-02

    Treatment of steroid-resistant acute graft-versus-host disease (GVHD) remains an unmet clinical need. Inolimomab, a monoclonal antibody to CD25, has shown encouraging results in phase 2 trials. This phase 3 randomized, open-label, multicenter trial compared inolimomab vs usual care in adult patients with steroid-refractory acute GVHD. Patients were randomly selected to receive treatment with inolimomab or usual care (the control group was treated with antithymocyte globulin [ATG]). The primary objective was to evaluate overall survival at 1 year without changing baseline allocated therapy. A total of 100 patients were randomly placed: 49 patients in the inolimomab arm and 51 patients in the ATG arm. The primary criteria were reached by 14 patients (28.5%) in the inolimomab and 11 patients (21.5%) in the ATG arms, with a hazard ratio of 0.874 (P = .28). With a minimum follow-up of 1 year, 26 (53%) and 31 (60%) patients died in the inolimomab and ATG arms, respectively. Adverse events were similar in the 2 arms, with fewer viral infections in the inolimomab arm compared with the ATG arm. The primary end point of this randomized phase 3 trial was not achieved. The lack of a statistically significant effect confirms the need for development of more effective treatments for acute GVHD. This trial is registered to https://www.clinicaltrialsregister.eu/ctr-search/search as EUDRACT 2007-005009-24.

  17. Therapeutic benefit of bortezomib on acute GVHD is tissue specific and is associated with IL-6 levels

    PubMed Central

    Pai, Chien-Chun Steven; Hsiao, Hui-Hua; Sun, Kai; Chen, Mingyi; Hagino, Takeshi; Tellez, Joseph; Mall, Christine; Blazar, Bruce R.; Monjazeb, Arta; Abedi, Mehrdad; Murphy, William J.

    2014-01-01

    Bortezomib, a proteasome inhibitor capable of direct anti-tumor effects, has been shown to prevent acute graft-versus-host disease (aGVHD) when administered in a short course immediately after bone marrow transplantation (BMT) in mice. However, when given continuously, CD4+ T cell mediated gastrointestinal tract damages increase GVHD mortality. To investigate the protective effects of bortezomib on other organs, we have used a CD8 dependent aGVHD model of C3H.SW donor T cells engrafted into irradiated C57BL/6 recipients (minor MHC mismatch), which lack significant gut GVHD. Our data in this model show that bortezomib can be given continuously to prevent and treat aGVHD mediated by CD8+ T cells, but this effect is organ-specific such that only skin, but not liver, protection was observed. Despite the lack of hepatic protection, bortezomib still significantly improved survival primarily due to its skin protection. Reduced skin GVHD by bortezomib was correlated with reduced serum and skin IL-6 levels. Administration of a blocking IL-6 antibody in this model also resulted in similar cutaneous GVHD protection. These results indicate that bortezomib or blockade of IL-6 may prevent CD8+ T cell mediated cutaneous aGVHD. PMID:25064746

  18. The risk of polyomavirus BK-associated hemorrhagic cystitis after allogeneic hematopoietic SCT is associated with myeloablative conditioning, CMV viremia and severe acute GVHD.

    PubMed

    Uhm, J; Hamad, N; Michelis, F V; Shanavas, M; Kuruvilla, J; Gupta, V; Lipton, J H; Messner, H A; Seftel, M; Kim, D D

    2014-12-01

    Hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic SCT (allo-HSCT). Several risk factors have been suggested including BU-containing myeloablative conditioning, unrelated donors and GVHD, but these have not been consistently reported. We conducted a retrospective study including 339 allo-HSCT recipients between 2009 and 2012. Of 339 patients, 79 (23.3%) developed HC with 2-year cumulative incidence of 24.0% (95% confidence interval, 19.4-28.9). The median onset time was 45 days (range, 16-430) after allo-HSCT. Sixty-two patients (84%) out of 74 evaluated for urine BK virus PCR testing showed a positive result (mean 2.0 × 10(10) copies of DNA per mL). In univariate analysis, myeloablative conditioning, HLA-mismatched donor, CMV viremia and acute GVHD (aGVHD) grade 3-4 were significantly associated with the risk of HC. Multivariate analysis confirmed all associating factors identified in univariate analysis except for HLA-mismatched donor: myeloablative conditioning (hazard ratio (HR) 2.63, P=0.003), CMV viremia (HR 1.88, P=0.014) and aGVHD grade 3-4 (HR 1.71, P=0.029). HC did not affect OS or non-relapse mortality. Symptomatic HC is a frequent complication following allo-HSCT, with a 2-year cumulative incidence of 24.0%. Three clinical factors associated with HC were identified including myeloablative conditioning, CMV viremia and severe aGVHD.

  19. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation.

    PubMed

    Shah, Nirali N; Baird, Kristin; Delbrook, Cynthia P; Fleisher, Thomas A; Kohler, Mark E; Rampertaap, Shakuntala; Lemberg, Kimberly; Hurley, Carolyn K; Kleiner, David E; Merchant, Melinda S; Pittaluga, Stefania; Sabatino, Marianna; Stroncek, David F; Wayne, Alan S; Zhang, Hua; Fry, Terry J; Mackall, Crystal L

    2015-01-29

    Natural killer (NK) cells can enhance engraftment and mediate graft-versus-leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), but the potency of graft-versus-leukemia mediated by naturally reconstituting NK cells following HSCT is limited. Preclinical studies demonstrate that activation of NK cells using interleukin-15 (IL-15) plus 4-1BBL upregulates activating receptor expression and augments killing capacity. In an effort to amplify the beneficial effects of NK cells post-HSCT, we conducted a first-in-human trial of adoptive transfer of donor-derived IL-15/4-1BBL-activated NK cells (aNK-DLI) following HLA-matched, T-cell-depleted (1-2 × 10(4) T cells/kg) nonmyeloablative peripheral blood stem cell transplantation in children and young adults with ultra-high-risk solid tumors. aNK-DLI were CD3(+)-depleted, CD56(+)-selected lymphocytes, cultured for 9 to 11 days with recombinant human IL-15 plus 4-1BBL(+)IL-15Rα(+) artificial antigen-presenting cells. aNK-DLI demonstrated potent killing capacity and displayed high levels of activating receptor expression. Five of 9 transplant recipients experienced acute graft-versus-host disease (GVHD) following aNK-DLI, with grade 4 GVHD observed in 3 subjects. GVHD was more common in matched unrelated donor vs matched sibling donor recipients and was associated with higher donor CD3 chimerism. Given that the T-cell dose was below the threshold required for GVHD in this setting, we conclude that aNK-DLI contributed to the acute GVHD observed, likely by augmenting underlying T-cell alloreactivity. This trial was registered at www.clinicaltrials.gov as #NCT01287104.

  20. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell–depleted stem cell transplantation

    PubMed Central

    Shah, Nirali N.; Baird, Kristin; Delbrook, Cynthia P.; Fleisher, Thomas A.; Kohler, Mark E.; Rampertaap, Shakuntala; Lemberg, Kimberly; Hurley, Carolyn K.; Kleiner, David E.; Merchant, Melinda S.; Pittaluga, Stefania; Sabatino, Marianna; Stroncek, David F.; Wayne, Alan S.; Zhang, Hua; Fry, Terry J.

    2015-01-01

    Natural killer (NK) cells can enhance engraftment and mediate graft-versus-leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), but the potency of graft-versus-leukemia mediated by naturally reconstituting NK cells following HSCT is limited. Preclinical studies demonstrate that activation of NK cells using interleukin-15 (IL-15) plus 4-1BBL upregulates activating receptor expression and augments killing capacity. In an effort to amplify the beneficial effects of NK cells post-HSCT, we conducted a first-in-human trial of adoptive transfer of donor-derived IL-15/4-1BBL–activated NK cells (aNK-DLI) following HLA-matched, T-cell–depleted (1-2 × 104 T cells/kg) nonmyeloablative peripheral blood stem cell transplantation in children and young adults with ultra-high-risk solid tumors. aNK-DLI were CD3+-depleted, CD56+-selected lymphocytes, cultured for 9 to 11 days with recombinant human IL-15 plus 4-1BBL+IL-15Rα+ artificial antigen-presenting cells. aNK-DLI demonstrated potent killing capacity and displayed high levels of activating receptor expression. Five of 9 transplant recipients experienced acute graft-versus-host disease (GVHD) following aNK-DLI, with grade 4 GVHD observed in 3 subjects. GVHD was more common in matched unrelated donor vs matched sibling donor recipients and was associated with higher donor CD3 chimerism. Given that the T-cell dose was below the threshold required for GVHD in this setting, we conclude that aNK-DLI contributed to the acute GVHD observed, likely by augmenting underlying T-cell alloreactivity. This trial was registered at www.clinicaltrials.gov as #NCT01287104. PMID:25452614

  1. Low-dose thymoglobulin as second-line treatment for steroid-resistant acute GvHD: an analysis of the JSHCT.

    PubMed

    Murata, M; Ikegame, K; Morishita, Y; Ogawa, H; Kaida, K; Nakamae, H; Ikeda, T; Nishida, T; Inoue, M; Eto, T; Kubo, K; Sakura, T; Mori, T; Uchida, N; Ashida, T; Matsuhashi, Y; Miyazaki, Y; Ichinohe, T; Atsuta, Y; Teshima, T

    2017-02-01

    A nationwide retrospective study for the clinical outcomes of 99 patients who had received thymoglobulin at a median total dose of 2.5 mg/kg (range, 0.5-18.5 mg/kg) as a second-line treatment for steroid-resistant acute GvHD was conducted. Of the 92 evaluable patients, improvement (complete or partial response) was observed in 55 patients (60%). Multivariate analysis demonstrated that male sex and grade III and IV acute GvHD were associated with a lower improvement rate, whereas thymoglobulin dose (<2.0, 2.0-3.9 and ⩾4.0 mg/kg) was NS. Factors associated with significantly higher nonrelapse mortality included higher patient age (⩾50 years), grade IV acute GvHD, no improvement of GvHD and higher dose of thymoglobulin (hazard ratio, 2.55; 95% confidence interval, 1.34-4.85; P=0.004 for 2.0-3.9 mg/kg group and 1.79; 0.91-3.55; P=0.093 for ⩾4.0 mg/kg group). Higher dose of thymoglobulin was associated with a higher incidence of bacterial infections, CMV antigenemia and any additional infection. Taken together, low-dose thymoglobulin at a median total dose of 2.5 mg/kg provides a comparable response rate to standard-dose thymoglobulin reported previously, and <2.0 mg/kg thymoglobulin is recommended in terms of the balance between efficacy and adverse effects.

  2. Administration of short-term immunosuppressive agents after DLI reduces the incidence of DLI-associated acute GVHD without influencing the GVL effect.

    PubMed

    Huang, X-J; Wang, Y; Liu, D-H; Xu, L-P; Liu, K-Y; Chen, H; Chen, Y-H; Han, W; Shi, H-X

    2009-09-01

    Donor lymphocyte infusion (DLI) exerts a GVL effect, but its use is limited by a high incidence of GVHD. We retrospectively evaluated the efficacy of administering short-term immunosuppressive agents for prophylaxis against DLI-associated acute GVHD, and its influence on the GVL effect. Seventy patients with leukaemia received G-CSF primed DLI after HLA-identical sibling haematopoietic stem cell transplantation (HSCT) for treatment or prophylaxis against leukaemia relapse. Short-term immunosuppressive agents were given to 54 patients for prophylaxis against DLI-associated acute GVHD. Seventeen patients experienced acute GVHD; 30 patients developed chronic GVHD; and no GVHD-related death was observed. A significant difference was observed between the group that did not receive prophylaxis against GVHD or received prophylaxis for less than 2 weeks and the group that received prophylaxis for over 2 weeks (CsA or MTX at 10 mg/week) with regard to the incidence of DLI-associated acute GVHD (14/28 vs 3/42, P=0.000); no difference was observed in the relapse rate for prophylactic DLI patients between the two groups (4/10 vs 12/29). Using immunosuppressive agents for 2-4 weeks may reduce DLI-associated acute GVHD without influencing relapse and survival after G-CSF-primed DLI.

  3. Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

    PubMed Central

    Watkins, Benjamin; Tkachev, Victor; Panoskaltsis-Mortari, Angela; Betz, Kayla; Brown, Melanie; Hunt, Daniel J.; Schell, John B.; Zeleski, Katie; Yu, Alison; Giver, Cynthia R.; Waller, Edmund K.; Miller, Jeffrey S.; Blazar, Bruce R.

    2016-01-01

    One of the central challenges of transplantation is the development of alloreactivity despite the use of multiagent immunoprophylaxis. Effective control of this immune suppression–resistant T-cell activation represents one of the key unmet needs in the fields of both solid-organ and hematopoietic stem cell transplant (HCT). To address this unmet need, we have used a highly translational nonhuman primate (NHP) model to interrogate the transcriptional signature of T cells during breakthrough acute graft-versus-host disease (GVHD) that occurs in the setting of clinically relevant immune suppression and compared this to the hyperacute GVHD, which develops in unprophylaxed or suboptimally prophylaxed transplant recipients. Our results demonstrate the complex character of the alloreactivity that develops during ongoing immunoprophylaxis and identify 3 key transcriptional hallmarks of breakthrough acute GVHD that are not observed in hyperacute GVHD: (1) T-cell persistence rather than proliferation, (2) evidence for highly inflammatory transcriptional programming, and (3) skewing toward a T helper (Th)/T cytotoxic (Tc)17 transcriptional program. Importantly, the gene coexpression profiles from human HCT recipients who developed GVHD while on immunosuppressive prophylactic agents recapitulated the patterns observed in NHP, and demonstrated an evolution toward a more inflammatory signature as time posttransplant progressed. These results strongly implicate the evolution of both inflammatory and interleukin 17–based immune pathogenesis in GVHD, and provide the first map of this evolving process in primates in the setting of clinically relevant immunomodulation. This map represents a novel transcriptomic resource for further systems-based efforts to study the breakthrough alloresponse that occurs posttransplant despite immunoprophylaxis and to develop evidence-based strategies for effective treatment of this disease. PMID:27758873

  4. Verification of the new grading scale for ocular chronic graft-versus-host disease developed by the German-Austrian-Swiss consensus conference on chronic GVHD.

    PubMed

    Blecha, Christiane; Wolff, Daniel; Holler, Barbara; Holler, Ernst; Weber, Daniela; Vogt, Regine; Helbig, Horst; Dietrich-Ntoukas, Tina

    2016-02-01

    The purpose of the study was to validate a recently proposed new grading system for ocular manifestations of chronic graft-versus-host disease (cGVHD). Diagnosis of cGVHD was based on the NIH consensus criteria. In addition, a grading scale was applied, which has been developed by the German-Austrian-Swiss Consensus Conference on Clinical Practice in cGVHD. Sixty-six patients (male n = 46, female n = 20, mean age 48 years) with ocular cGVHD were included. Application of the proposed Consensus Conference grading revealed inflammatory activity in all patients with mild (33 %), moderate (44 %), or severe inflammation (23 %). Clinical scoring by the NIH scoring system showed that 6 % of patients had mild symptoms; 59 % of patients had moderate dry eye symptoms partially affecting activities of daily living, without vision impairment; and 35 % of patients had severe dry eye symptoms significantly affecting daily activities. Clinical characterization and grading by the Consensus Conference grading scale revealed that ocular cGVHD (1) frequently leads to severe ocular surface disease based on impaired function of the lacrimal glands and involvement of cornea, conjunctiva, and lids; (2) is mostly associated with ongoing inflammatory activity; (3) often leads to functional impairment and reduced quality of life; and (4) is associated with an increased risk for severe, sight-threatening complications.

  5. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial.

    PubMed

    Pulsipher, Michael A; Langholz, Bryan; Wall, Donna A; Schultz, Kirk R; Bunin, Nancy; Carroll, William L; Raetz, Elizabeth; Gardner, Sharon; Gastier-Foster, Julie M; Howrie, Denise; Goyal, Rakesh K; Douglas, James G; Borowitz, Michael; Barnes, Yvonne; Teachey, David T; Taylor, Candace; Grupp, Stephan A

    2014-03-27

    Sirolimus has activity against acute lymphoblastic leukemia (ALL) in xenograft models and efficacy in preventing acute graft-versus-host disease (aGVHD). We tested whether addition of sirolimus to GVHD prophylaxis of children with ALL would decrease aGVHD and relapse. Patients were randomized to tacrolimus/methotrexate (standard) or tacrolimus/methotrexate/sirolimus (experimental). The study met futility rules for survival after enrolling 146 of 259 patients. Rate of Grade 2-4 aGVHD was 31% vs 18% (standard vs experimental, P = .04), however, grade 3-4 aGVHD was not different (13% vs 10%, P = .28). Rates of veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA) were lower in the nonsirolimus arm (9% vs 21% VOD, P = .05; 1% vs 10% TMA, P = .06). At 2 years, event free survival (EFS) and overall survival (OS) were 56% vs 46%, and 65% vs 55% (standard vs experimental), respectively (P = .28 and .23). Multivariate analysis showed increased relapse risk in children with ≥0.1% minimal residual disease (MRD) pretransplant, and decreased risk in patients with grades 1-3 aGVHD (P = .04). Grades 1-3 aGVHD were associated with improved EFS (P = .02), whereas grade 4 aGVHD and extramedullary disease at diagnosis led to inferior OS. Although addition of sirolimus decreased aGVHD, survival was not improved. This study is registered with ClinicalTrials.gov as #NCT00382109.

  6. Reduced intensity allogeneic hematopoietic stem cell transplantion for MDS using tacrolimus/sirolimus-based GVHD prophylaxis

    PubMed Central

    Nakamura, Ryotaro; Palmer, Joycelynne M.; O'Donnell, Margaret R.; Stiller, Tracey; Thomas, Sandra H.; Chao, Joseph; Alvarnas, Joseph; Parker, Pablo M.; Pullarkat, Vinod; Maegawa, Rodrigo; Stein, Anthony S.; Snyder, David S.; Bhatia, Ravi; Chang, Karen; Wang, Shirong; Cai, Ji-Lian; Senitzer, David; Forman, Stephen J.

    2012-01-01

    We report a consecutive series of 59 patients with MDS who underwent reduced-intensity hematopoietic stem cell transplantation (RI-HSCT) with fludarabine/melphalan conditioning and tacrolimus/sirolimus-based GVHD prophylaxis. Two-year OS, EFS, and relapse incidences were 75.1%, 65.2%, and 20.9%, respectively. The cumulative incidence of non-relapse mortality at 100 days, 1 year, and 2 years was 3.4%, 8.5%, and 10.5%, respectively. The incidence of grade II-IV acute GVHD was 35.4%; grade III-IV was 18.6%. Forty of 55 evaluable patients developed chronic GVHD, 35 extensive grade. This RI-HSCT protocol produces encouraging outcomes in MDS patients, and tacrolimus/sirolimus-based GVHD prophylaxis may contribute to that promising result. PMID:22677229

  7. Low blood lymphocyte count at 30 days post transplant predicts worse acute GVHD and survival but not relapse in a large retrospective cohort.

    PubMed

    Gul, Z; Van Meter, E; Abidi, M; Ditah, I; Abdul-Hussein, M; Deol, A; Ayash, L; Lum, L G; Waller, E K; Ratanatharathorn, V; Uberti, J; Al-Kadhimi, Z

    2015-03-01

    Multiple reports have shown that low absolute lymphocyte count at day 30 (ALC30) after allogeneic hematopoietic SCT (AHSCT) is associated with higher risk of disease relapse and worse OS. However, these reports included heterogeneous populations with different grafts and GVHD prophylaxis. Therefore, we retrospectively evaluated the association of ALC30 with transplant outcomes in a cohort of 381 consecutive patients who underwent AHSCT between 2005 and 2010 and received T-replete PBSC grafts and Tacrolimus/Mycophenolate combination as GVHD prophylaxis. Median follow-up was 57 months. Lower ALC30 (⩽400 × 10(6)/L) was associated with lower OS and increased nonrelapse mortality (NRM) for the whole cohort as well as for recipients of SD and UD grafts separately. Lower ALC30 was associated with more severe acute GVHD (aGVHD; III-IV) for the entire cohort as well as for the SD and UD groups. No association was found between lower ALC30 and relapse. Pretransplant factors associated with lower ALC30 were: unrelated donors; HLA mismatch; older donors; lower recipient age; and lower CD34+ cell dose. In this large retrospective study, ALC30⩽400 × 10(6)/L was associated with worse OS, increased NRM and severe aGVHD.

  8. Lithium Carbonate in Treating Patients With Acute Intestinal Graft-Versus-Host-Disease (GVHD) After Donor Stem Cell Transplant

    ClinicalTrials.gov

    2017-01-24

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, Breakpoint Cluster Region-abl Translocation (BCR-ABL) Negative; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Gastrointestinal Complications; Juvenile Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Childhood Rhabdomyosarcoma; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia

  9. Adoptive Transfer of Treg Cells Combined with Mesenchymal Stem Cells Facilitates Repopulation of Endogenous Treg Cells in a Murine Acute GVHD Model.

    PubMed

    Lee, Eun-Sol; Lim, Jung-Yeon; Im, Keon-Il; Kim, Nayoun; Nam, Young-Sun; Jeon, Young-Woo; Cho, Seok-Goo

    2015-01-01

    Therapeutic effects of combined cell therapy with mesenchymal stem cells (MSCs) and regulatory T cells (Treg cells) have recently been studied in acute graft-versus-host-disease (aGVHD) models. However, the underlying, seemingly synergistic mechanism behind combined cell therapy has not been determined. We investigated the origin of Foxp3+ Treg cells and interleukin 17 (IL-17+) cells in recipients following allogeneic bone marrow transplantation (allo-BMT) to identify the immunological effects of combined cell therapy. Treg cells were generated from eGFP-expressing C57BL/6 mice (Tregegfp cells) to distinguish the transferred Treg cells; recipients were then examined at different time points after BMT. Systemic infusion of MSCs and Treg cells improved survival and GVHD scores, effectively downregulating pro-inflammatory Th×and Th17 cells. These therapeutic effects of combined cell therapy resulted in an increased Foxp3+ Treg cell population. Compared to single cell therapy, adoptively transferred Tregegfp cells only showed prolonged survival in the combined cell therapy group on day 21 after allogeneic BMT. In addition, Foxp3+ Treg cells, generated endogenously from recipients, significantly increased. Significantly higher levels of Tregegfp cells were also detected in aGVHD target organs in the combined cell therapy group compared to the Treg cells group. Thus, our data indicate that MSCs may induce the long-term survival of transferred Treg cells, particularly in aGVHD target organs, and may increase the repopulation of endogenous Treg cells in recipients after BMT. Together, these results support the potential of combined cell therapy using MSCs and Treg cells for preventing aGVHD.

  10. Double Umbilical Cord Blood Transplantation with Reduced Intensity Conditioning and Sirolimus-Based GVHD Prophylaxis

    PubMed Central

    Cutler, Corey; Stevenson, Kristen; Kim, Haesook T.; Brown, Julia; McDonough, Sean; Herrera, Maria; Reynolds, Carol; Liney, Deborah; Kao, Grace; Ho, Vincent; Armand, Philippe; Koreth, John; Alyea, Edwin; Dey, Bimalangshu R.; Attar, Eyal; Spitzer, Thomas; Boussiotis, Vassiliki A.; Ritz, Jerome; Soiffer, Robert; Antin, Joseph H.; Ballen, Karen

    2010-01-01

    The main limitations to umbilical cord blood transplantation (UCBT) in adults are delayed engraftment, poor immunological reconstitution and high rates of non-relapse mortality (NRM). Double UCBT (DUCBT) has been used to circumvent the issue of low cell dose, but acute graft-vs.-host disease (GVHD) remains a significant problem. We describe our experience in 32 subjects who underwent DUCBT after reduced-intensity conditioning with fludarabine/melphalan/anti-thymocyte globulin and who received sirolimus and tacrolimus to prevent acute GVHD. Engraftment of neutrophils occurred in all patients at a median of 21 days, and platelet engraftment occurred at a median of 42 days. Three subjects had grade II-IV acute GVHD (9.4%) and chronic GVHD occurred in 4 subjects (cumulative incidence 12.5%). No deaths were caused by GVHD and NRM at 100 days was 12.5%. At two years, NRM, progression-free survival (PFS) and overall survival (OS) were 34.4%, 31.2% and 53.1%, respectively. As expected, immunologic reconstitution was slow, but PFS and OS were associated with reconstitution of CD4+ and CD8+ lymphocyte subsets, suggesting that recovery of adaptive immunity is required for prevention of infection and relapse after transplantation. In summary, sirolimus and tacrolimus provide excellent GVHD prophylaxis in DUCBT, and this regimen is associated with low NRM after DUCBT. PMID:20697368

  11. Rat acute GvHD is Th1-driven and characterized by predominant donor CD4(+) T cell infiltration of skin and gut.

    PubMed

    Boieri, Margherita; Shah, Pranali; Jalapothu, Dasaradha; Zaitseva, Olena; Walter, Lutz; Rolstad, Bent; Naper, Christian; Dressel, Ralf; Inngjerdingen, Marit

    2017-02-23

    Acute graft-versus-host disease (aGvHD) remains a significant hurdle to successful treatment of many hematological disorders. The disease is caused by infiltration of allo-activated donor T cells primarily into the gastrointestinal tract and skin. While cytotoxic T cells mediate direct cellular damage, T helper (Th) cells differentially secrete immunoregulatory cytokines. Acute GvHD is thought to be primarily initiated by Th1 cells but a consensus is still lacking regarding the role of Th2 and Th17 cells. The aim of this study was to determine the contribution of distinct T cell subsets to aGvHD in the rat. Acute GvHD was induced by transplanting irradiated rats with T-cell depleted MHC-mismatched bone marrow, followed two weeks later by donor lymphocyte infusion. Near complete donor T cell chimerism was achieved in the blood and lymphatic tissues, in contrast to mixed chimerism in the skin and gut. Skin and gut donor T cells were predominantly CD4(+), in contrast to T cells in blood and lymphatic tissues. Genes associated with Th1 cells were up-regulated in gut, liver, lung, and skin tissues affected by aGvHD. Increased serum levels of CXCL10 and IL-18 preceded symptoms of aGvHD, accompanied by increased responsiveness to CXCL10 by blood CD4(+) T cells. No changes in expression of Th2- or Th17-associated genes were observed, indicating that aGvHD in this rat model is mainly Th1-driven. The rat model of aGvHD could be instrumental for further investigations of donor T cell subsets in the skin and gut, and for exploring therapeutic options to ameliorate symptoms of aGvHD.

  12. Donor Atorvastatin Treatment in Preventing Severe Acute GVHD After Nonmyeloablative Peripheral Blood Stem Cell Transplant in Patients With Hematological Malignancies

    ClinicalTrials.gov

    2017-01-13

    Aggressive Non-Hodgkin Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm; Non-Hodgkin Lymphoma; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Aggressive Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Waldenstrom Macroglobulinemia

  13. International, multi-center standardization of acute graft-versus-host disease clinical data collection: a report from the MAGIC consortium

    PubMed Central

    Harris, Andrew C.; Young, Rachel; Devine, Steven; Hogan, William J.; Ayuk, Francis; Bunworasate, Udomsak; Chanswangphuwana, Chantiya; Efebera, Yvonne A.; Holler, Ernst; Litzow, Mark; Ordemann, Rainer; Qayed, Muna; Renteria, Anne S.; Reshef, Ran; Wölfl, Matthias; Chen, Yi-Bin; Goldstein, Steven; Jagasia, Madan; Locatelli, Franco; Mielke, Stephan; Porter, David; Schechter, Tal; Shekhovtsova, Zhanna; Ferrara, James L.M.; Levine, John E.

    2015-01-01

    Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and non-relapse mortality following allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed upon by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multi-center clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance was following discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture which may improve the reproducibility of GVHD clinical trials after further prospective validation. PMID:26386318

  14. Exploratory research for optimal GvHD prophylaxis after single unit CBT in adults: short-term methotrexate reduced the incidence of severe GvHD more than mycophenolate mofetil.

    PubMed

    Terakura, S; Wake, A; Inamoto, Y; Murata, M; Sakai, R; Yamaguchi, T; Takahashi, S; Uchida, N; Onishi, Y; Ohashi, K; Ozawa, Y; Kanamori, H; Yamaguchi, H; Fukuda, T; Ichinohe, T; Takanashi, M; Atsuta, Y; Teshima, T

    2017-03-01

    In order to examine GvHD prophylaxis in umbilical cord blood transplantation (UCBT) in more detail, we compared transplant outcomes after UCBT for acute leukemia among GvHD prophylaxes using registry data. We selected patients transplanted with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 1516 first myeloablative UCBT between 2000 and 2012 (Cyclosporine A (CyA) plus MTX, 824, Tacrolimus (Tac) plus MTX, 554, Tac plus MMF, 138) were included. With adjusted analyses, Tac plus MMF showed a significantly higher risk for grade II-IV and III-IV acute GvHD than CyA or Tac plus MTX. Although NRM was similar, Tac plus MMF showed a significantly lower risk of relapse than CyA or Tac plus MTX. A significant difference was observed in the risk of overall mortality (OM) between the MTX-containing group and MMF-containing group. In patients with standard-risk disease, there was no significant difference in the risk of OM in any GvHD prophylaxis. However, in patients with advanced-risk disease, Tac plus MMF showed a significantly lower risk of OM. Therefore, MTX-containing prophylaxis is preferred in UCBT for standard-risk disease, whereas MMF-containing prophylaxis is preferred for advanced-risk disease. A prospective study to identify optimal GvHD prophylaxis for UCBT is warranted.

  15. Longitudinal Assessment of Morbidity and Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation: Retrospective Analysis of a Multicenter Phase III Study

    PubMed Central

    Carnevale-Schianca, Fabrizio; Leisenring, Wendy; Martin, Paul J.; Furlong, Terry; Schoch, Gary; Anasetti, Claudio; Appelbaum, Frederick R.; Carpenter, Paul A.; Deeg, H. Joachim; Kiem, Hans-Peter; Storb, Rainer; McDonald, George B.; Nash, Richard A.

    2009-01-01

    Since morbidity early after HCT results in large part from the development of acute GVHD, we previously proposed that a longitudinal assessment of morbidity involving the skin, liver, and gastrointestinal tract might provide a more complete, objective approach for comparing two arms of open-label randomized clinical trials for acute GVHD prevention. In the current study, we determined both morbidity-across-time and GVHD-across-time in a retrospective analysis of a database from an open-label randomized clinical trial comparing tacrolimus/methotrexate versus cyclosporine/methotrexate after myeloablative conditioning and marrow transplantation from HLA-matched unrelated donors. The results confirmed differences in overall morbidity across time among patients with peak grades II-IV GVHD as compared to those with grades 0-I GVHD, but no significant differences were found between morbidity associated with grade II GVHD as compared to grades 0-I GVHD. We observed less skin and a trend towards less liver morbidity across time in the tacrolimus group (p=0.04; p= 0.09, respectively) but not for gastrointestinal or overall morbidity, despite significantly decreased skin and liver stages and overall grades of GVHD-across-time in the tacrolimus arm. In conclusion, an objective assessment of differences in morbidity (regardless of cause) as a measure of acute GVHD in a randomized clinical tria of acute GVHD prevention had limited utility. The difficulty of demonstrating clinical benefits from objective parameters such as survival and morbidity and the subjectivity of grading acute GVHD emphasize that blinded assessments are required in clinical trials of GVHD prevention. PMID:19450760

  16. Tacrolimus plus sirolimus with or without ATG as GVHD prophylaxis in HLA-mismatched unrelated donor allogeneic stem cell transplantation.

    PubMed

    Kharfan-Dabaja, M A; Parody, R; Perkins, J; Lopez-Godino, O; Lopez-Corral, L; Vazquez, L; Caballero, D; Falantes, J; Shapiro, J; Ortí, G; Barba, P; Valcárcel, D; Esquirol, A; Martino, R; Piñana, J L; Solano, C; Tsalatsanis, A; Pidala, J; Anasetti, C; Perez-Simón, J A

    2017-03-01

    HLA-matched related or unrelated donors are not universally available. Consequently, patients can be offered hematopoietic stem cell transplantation (HSCT) from alternative donors, including mismatched unrelated donors (MMURD), known to cause a higher incidence of acute GVHD (aGVHD) and chronic GVHD. In vivo T-cell-depletion strategies, such as antithymocyte globulin (ATG) therapy, significantly decrease the risk of GVHD. We performed a multicenter, retrospective study comparing tacrolimus (TAC) and sirolimus (SIR) with or without ATG in 104 patients (TAC-SIR=45, TAC-SIR-ATG=59) who underwent MMURD HSCT. Use of ATG was associated with a lower incidence, albeit not statistically significant, of grades 2-4 aGVHD (46% vs 64%, P=0.09), no difference in grades 3-4 aGVHD (10% vs 15%, P=0.43), a trend for a lower incidence of moderate/severe chronic GVHD (16% vs 37%, P=0.09) and more frequent Epstein-Barr virus reactivation (54% vs 18%, P=0.0002). There were no statistically significant differences in 3-year overall survival (OS) (TAC-SIR-ATG=40% (95% confidence interval (CI)=24-56%) vs TAC-SIR=54% (95% CI=37-70%), P=0.43) or 3-year cumulative incidence of relapse/progression (TAC-SIR-ATG=40% (95% CI=28-58%) vs TAC-SIR=22% (95% CI=13-39%), P=0.92). An intermediate Center for International Blood & Marrow Transplant Research disease risk resulted in a significantly lower non-relapse mortality and better OS at 3 years. Our study suggests that addition of ATG to TAC-SIR in MMURD HSCT does not affect OS when compared with TAC-SIR alone.

  17. The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation.

    PubMed

    Noriega, Víctor; Martínez-Laperche, Carolina; Buces, Elena; Pion, Marjorie; Sánchez-Hernández, Noemí; Martín-Antonio, Beatriz; Guillem, Vicent; Bosch-Vizcaya, Anna; Bento, Leyre; González-Rivera, Milagros; Balsalobre, Pascual; Kwon, Mi; Serrano, David; Gayoso, Jorge; de la Cámara, Rafael; Brunet, Salut; Rojas-Contreras, Rafael; Nieto, José B; Martínez, Carmen; Gónzalez, Marcos; Espigado, Ildefonso; Vallejo, Juan C; Sampol, Antonia; Jiménez-Velasco, Antonio; Urbano-Ispizua, Alvaro; Solano, Carlos; Gallardo, David; Díez-Martín, José L; Buño, Ismael

    2015-01-01

    The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08-0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients.

  18. The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation

    PubMed Central

    Buces, Elena; Pion, Marjorie; Sánchez-Hernández, Noemí; Martín-Antonio, Beatriz; Guillem, Vicent; Bosch-Vizcaya, Anna; Bento, Leyre; González-Rivera, Milagros; Balsalobre, Pascual; Kwon, Mi; Serrano, David; Gayoso, Jorge; de la Cámara, Rafael; Brunet, Salut; Rojas-Contreras, Rafael; Nieto, José B.; Martínez, Carmen; Gónzalez, Marcos; Espigado, Ildefonso; Vallejo, Juan C.; Sampol, Antonia; Jiménez-Velasco, Antonio; Urbano-Ispizua, Alvaro; Solano, Carlos; Gallardo, David; Díez-Martín, José L.; Buño, Ismael

    2015-01-01

    The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08–0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients. PMID:26473355

  19. 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

  20. Characterization of acute graft-versus-host disease following reduced-intensity stem-cell transplantation from an HLA-identical related donor.

    PubMed

    Murashige, Naoko; Kami, Masahiro; Mori, Shin-ichiro; Katayama, Yuta; Kobayashi, Kazuhiko; Onishi, Yasushi; Hori, Akiko; Kishi, Yukiko; Hamaki, Tamae; Tajima, Kinuko; Kanda, Yoshinobu; Tanosaki, Ryuji; Takaue, Yoichi

    2008-08-01

    To investigate clinical features of acute graft-versus-host disease (GVHD) following reduced intensity stem-cell transplantation (RIST), we retrospectively investigated medical records of 65 patients with hematologic malignancies who underwent RIST from a matched related donor. Preparative regimen comprised fludarabine 30 mg/m(2) (n = 53) or cladribine 0.11 mg/kg (n = 12) for 6 days plus busulfan 4 mg/kg for 2 days. Twelve patients received rabbit antithymocyte globulin 2.5 mg/kg/day for 2-4 consecutive days. Grade II to IV acute GVHD was diagnosed in 36 patients (55%). Its median onset was day 58 (range, 17-109), while it was bimodal, peaking day 15-29 (early-onset GVHD, n = 18) and day 75-89 days (late-onset GVHD, n = 18). Variables that were more common in early-onset GVHD than late-onset GVHD included skin rash (89% vs. 61%) and noninfectious fevers (33% vs. 11%). Desaturation, pulmonary infiltrates and hyperbilirubinemia (>2.0 mg/dL) were more common in late-onset GVHD (6% vs. 22%, 0% vs. 17%, and 6% vs. 33%, respectively). All of the patients with early-onset GVHD given corticosteroid responded to it, while 5 of the 18 patients with late-onset GVHD failed to respond it. Patients with either early-onset or late-onset GVHD tended to have better progression-free survival (PFS) than those without it; however, there was no significant difference in PFS between patients with early-onset GVHD and those with late-onset GVHD. This study suggests that several etiologies might have contributed to the development of acute GVHD following RIST.

  1. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect.

    PubMed

    Brunstein, Claudio G; Miller, Jeffrey S; McKenna, David H; Hippen, Keli L; DeFor, Todd E; Sumstad, Darin; Curtsinger, Julie; Verneris, Michael R; MacMillan, Margaret L; Levine, Bruce L; Riley, James L; June, Carl H; Le, Chap; Weisdorf, Daniel J; McGlave, Philip B; Blazar, Bruce R; Wagner, John E

    2016-02-25

    We studied the safety and clinical outcomes of patients treated with umbilical cord blood (UCB)-derived regulatory T cells (Tregs) that expanded in cultures stimulated with K562 cells modified to express the high-affinity Fc receptor (CD64) and CD86, the natural ligand of CD28 (KT64/86). Eleven patients were treated with Treg doses from 3-100 × 10(6) Treg/kg. The median proportion of CD4(+)FoxP3(+)CD127(-) in the infused product was 87% (range, 78%-95%), and we observed no dose-limiting infusional adverse events. Clinical outcomes were compared with contemporary controls (n = 22) who received the same conditioning regimen with sirolimus and mycophenolate mofetil immune suppression. The incidence of grade II-IV acute graft-versus-host disease (GVHD) at 100 days was 9% (95% confidence interval [CI], 0-25) vs 45% (95% CI, 24-67) in controls (P = .05). Chronic GVHD at 1 year was zero in Tregs and 14% in controls. Hematopoietic recovery and chimerism, cumulative density of infections, nonrelapse mortality, relapse, and disease-free survival were similar in the Treg recipients and controls. KT64/86-expanded UCB Tregs were safe and resulted in low risk of acute GVHD.

  2. Validation of National Institutes of Health global scoring system for chronic graft-versus-host disease (GVHD) according to overall and GVHD-specific survival.

    PubMed

    Moon, Joon Ho; Sohn, Sang Kyun; Lambie, Anna; Ellis, Laura; Hamad, Nada; Uhm, Jieun; Gupta, Vikas; Lipton, Jeffrey H; Messner, Hans A; Kuruvilla, John; Kim, Dennis

    2014-04-01

    A new severity grading system for graft-versus-host disease (GVHD) was established by the National Institutes of Health (NIH) consensus criteria (NCC). However, its prognostic value still needs to be validated. Four hundred twenty-five consecutive patients who survived beyond 100 days after allogeneic stem cell transplantation were reviewed and reclassified using NCC. GVHD-specific survival (GSS) and cumulative incidence of relapse were compared according to the NIH global score at the onset and peak of chronic GVHD (cGVHD). Of 346 patients with cGVHD diagnosed by the Revised Seattle Criteria, 317 patients were reclassified according to the NCC as classic cGVHD (n = 144) and overlap syndrome (n = 173). The NIH global scores at onset were mild (43.2%), moderate (42.3%), and severe (14.5%), whereas more moderate (55.5%) and severe (31.6%) cGVHD was observed at the peak of cGVHD. With a median follow-up duration of 34 months, the 5-year GSS was significantly worse for the severe group than the moderate/mild groups at onset and at peak: 50.9% ± 7.8% versus 89.7% ± 3.2% versus 93.5% ± 2.4% at onset (P < .001) and 69.1% ± 5.2% versus 93.2% ± 2.1% versus 97.3% ± 2.7% at peak (P < .001). Severe NIH global score at onset and peak were confirmed as a poor prognostic factor for GSS in multivariate analysis. The cumulative incidence of relapse did not differ among the severity groups at onset or peak. In conclusion, the new NIH global scoring system was shown to differentiate a high-risk group of patients (with severe grade cGVHD) in terms of long-term transplant outcomes.

  3. Role of the mycobiome in human acute graft-versus-host disease.

    PubMed

    van der Velden, Walter J F M; Netea, Mihai G; de Haan, Anton F J; Huls, Gerwin A; Donnelly, J Peter; Blijlevens, Nicole M A

    2013-02-01

    A role for gut bacteria in the pathogenesis of graft-versus-host disease (GVHD) has been firmly established; however, the role of Candida spp, which form part of the mycobiome, remains unknown. In a homogenous group of patients who underwent allogeneic stem cell transplantation (SCT), we found a significant impact of Candida colonization on the occurrence of acute GVHD. Patients colonized with Candida spp developed significantly more grade II-IV acute GVHD compared with noncolonized patients (50% vs 32%; P = .03), as well as more gastrointestinal (GI)-GVHD (33% vs 19%; P = .05). Colonization with Candida spp was more frequent in patients bearing the loss-of-function polymorphism Y238X, which results in dectin-1 dysfunction, compared with patients with the wild-type allele (73% vs 31%; P = .002). There was no direct effect of dectin-1 dysfunction on acute GVHD, although it did influence the occurrence of GVHD indirectly through Candida colonization. The exact mechanism of GVHD induction by Candida spp colonization of the mucosa is unknown, but the link might prove to be the induction of Th 17/IL-23 responses through activation of pattern recognition receptors by fungal motifs, including β-d-glucan and mannans. These data indicate a role for the mycobiome in the pathogenesis of GVHD and suggest that altering the mycobiome by antifungal drugs can help ameliorate GI-GVHD. In addition, given that the genetic constitution of patients affects susceptibility to both Candida colonization and GVHD, whether identifying gene polymorphisms will facilitate personalized treatment of SCT recipients remains to be determined.

  4. Rapid response to alefacept given to patients with steroid resistant or steroid dependent acute graft-versus-host disease: a preliminary report.

    PubMed

    Shapira, M Y; Resnick, I B; Bitan, M; Ackerstein, A; Tsirigotis, P; Gesundheit, B; Zilberman, I; Miron, S; Leubovic, A; Slavin, S; Or, R

    2005-12-01

    We evaluated the effect of alefacept (Amevive), a novel dimeric fusion protein, in steroid resistant/dependent acute graft-versus-host-disease (aGVHD). Seven patients were treated in eight aGVHD episodes. GVHD grade at treatment initiation and at peak ranged 2-4 (median 2.5) and 2-4 (median 4), respectively. System involvement at GVHD peak included skin (n=7), gastrointestinal tract (n=5) and liver (n=3). All patients responded. However, one patient with skin GVHD and two with gastrointestinal GVHD featuring an early initial response (IR) exacerbated and CR was not achieved. Skin GVHD responded rapidly with a median of 1 day to IR and 7 days to CR. Intestinal response was slower with median 7.5 days to IR. Of the four patients that achieved IR, CR was achieved in only one (40 days to CR). None of the patients had significant hepatic GVHD before treatment so no hepatic effect of alefacept could be determined. No immediate alefacept-related side effects were observed. Late side effects included infections (aspergillus sinusitis, pneumonia, bacteremia, pharyngeal thrush), pancytopenia and hemorrhagic cystitis. Three patients had CMV reactivation while on alefacept. We conclude that alefacept may have a beneficial effect in controlling aGVHD. Further investigations in larger cohorts of patients and controlled studies are warranted.

  5. Evidence that erythrocyte DARC-positive phenotype can affect the GVHD occurrence after HLA-identical sibling HSCT.

    PubMed

    Sellami, Mohamed Hichem; Chaabane, Manel; Kaabi, Houda; Torjemane, Lamia; Ladeb, Saloua; Othmane, Tarek Ben; Hmida, Slama

    2011-09-01

    Chemokine receptors are very important players in the pathogenesis of GVHD. The aim of this study is to test the hypothesis that the lack of expression of the DARC receptor on erythrocytes can affect the GVHD incidence. A total of 105 recipients and their 105 respective sibling donors of HSCs were enrolled in this study. All patients were evaluated for acute and chronic GVHD. The DARC genotyping assay was performed using the SSP-PCR method. The case-control analyses showed that the donor DARC 146G allele and T(-46)G(146) haplotype, coding for the FY2 version of DARC, are very significant in the GVHD paradigm because they are associated with the incidence of acute effects of this outcome in recipients (p=0.007, χ²=7.200). It seems that this version of DARC receptor is a powerful facilitator of chemokine transcytosis and subsequently leukocyte migration into GVHD target organs.

  6. Both high and low levels of cellular Epstein-Barr virus DNA in blood identify failure after hematologic stem cell transplantation in conjunction with acute GVHD and type of conditioning

    PubMed Central

    Li, Qin; Rane, Lalit; Poiret, Thomas; Zou, Jiezhi; Magalhaes, Isabelle; Ahmed, Raija; Du, Ziming; Vudattu, Nalini; Meng, Qingda; Gustafsson-Jernberg, Åsa; Winiarski, Jacek; Ringdén, Olle; Maeurer, Markus; Remberger, Mats; Ernberg, Ingemar

    2016-01-01

    The level of Epstein-Barr virus DNA in blood has proven to be a biomarker with some predictive value in allogeneic hematopoietic stem cell transplantation patients (HSCT). We evaluated the impact of EBV load on survival of 51 patients (32M/19F, median age: 32 years, from < 1 to 68 years old), who had received HSCT for different types of malignancies (49 cases) or non-malignancies (2 cases). The overall survival [1]was compared between patients with extreme and moderate cell bound EBV DNA levels. Different sources of stem-cells (peripheral blood stem, n = 39; bone marrow, n = 9; or umbilical cord blood, n = 3) were used. Twenty patients received reduced-intensity conditioning regimen while the other 31 received myeloablative conditioning. Patients with high or very low level of cell bound EBV-DNA levels had a shorter OS than those with moderate EBV load: OS at 5 years was 67% vs 90% (p < 0.03). There was a conspicuous relationship between EBV load and the reconstitution dynamics of total and EBV-specific T cells, CD4+ and CD4- CD8- (double negative) T cells in the few patients where it was analyzed. This was not statistically significant. Two other factors were associated to early mortality in addition to high or low EBV load: acute GVHD II-IV (p < 0.02) and pre-transplant conditioning with total body irradiation (TBI) ≥6 Gy, (p < 0.03). All the patients meeting all three criteria died within two years after transplantation. This points to a subgroup of HSCT patients which deserve special attention with improvement of future, personalized treatment. PMID:27102298

  7. [The impact of donor naive and memory T cell subsets on patient outcome following allogeneic stem cell transplantation: relationship between infused donor CD4+/CCR7+ T cell subsets and acute graft-versus-host disease].

    PubMed

    Choufi, B; Thiant, S; Trauet, J; Cliquennois, M; Cherrel, M; Boulanger, F; Coiteux, V; Magro, L; Labalette, M; Yakoub-Agha, I

    2014-06-01

    In a previous prospective study on 62 patients who underwent an HLA-matched allogeneic stem cell transplantation, we have observed that proportion of donor-derived CCR7(+)/CD4(+) T cells in the graft provided a predictive indicator of acute GVHD without interfering on chronic GVHD and relapse rate. Here we present our results on a confirmatory cohort of 137 consecutive patients. Indeed patients who received more than 76% of CCR7(+)/CD4(+) T cells in the graft developed more often acute GVHD be it of low or high grade than those who did not. Determination of the CCR7(+)/CCR7(neg) ratio of CD4(+) T cells in the graft provides a predictive indicator of acute GVHD and could help to define strategies of partial selective T cell depleted transplantation.

  8. High expression of heme oxygenase-1 in target organs may attenuate acute graft-versus-host disease through regulation of immune balance of TH17/Treg.

    PubMed

    Yu, Meisheng; Wang, Jishi; Fang, Qin; Liu, Ping; Chen, Shuya; Zhe, Nana; Lin, Xiaojing; Zhang, Yaming; Zhao, Jiangyuan; Zhou, Zhen

    2016-07-01

    The high incidence of acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Grades III and IV aGVHD are the leading causes of death in allo-HSCT recipients. Heme oxygenase-1(HO-1) has anti-inflammatory and immune-regulatory functions. In this study, we evaluated the none GVHD and grade I-IV patients samples which were collected at the first re-examination after successful allo-HSCT, we found that expressions of HO-1 mRNA in the bone marrow and peripheral blood mononuclear cells of allo-HSCT recipients who had subsequent non-GVHD and grade I aGVHD were significantly higher than those in patients with Grade III-IV aGVHD. We then demonstrated that enhanced expression of HO-1 in target organs by infusing HO-1-gene-modified Mesenchymal stem cells (MSCs) alleviated the clinical and histopathological severity of aGVHD in experimental mice. Flow cytometry revealed a higher expression of Treg cells and a lower expression of TH17 cells in splenic and lymph node tissues of mice with enhanced HO-1 expression, as compared to that in the aGVHD mice. This was further substantiated by lower expression levels of ROR-Υt and IL-17A mRNA, and higher levels of Foxp3 mRNA in the splenic tissue of mice with enhanced HO-1 expression. Our results indicate that high expression of HO-1 may reduce the severity of aGVHD by regulation of the TH17/Treg balance.

  9. Allogeneic nonmyeloablative hematopoietic cell transplantation in metastatic colon cancer: tumor-specific T cells directed to a tumor-associated antigen are generated in vivo during GVHD.

    PubMed

    Carnevale-Schianca, Fabrizio; Cignetti, Alessandro; Capaldi, Antonio; Vitaggio, Katiuscia; Vallario, Antonella; Ricchiardi, Alberto; Sperti, Elisa; Ferraris, Renato; Gatti, Marco; Grignani, Giovanni; Rota-Scalabrini, Delia; Geuna, Massimo; Fizzotti, Marco; Sangiolo, Dario; Sottile, Antonino; De Rosa, Giovanni; Bucci, Anna Rosa; Lambertenghi-Deliliers, Giorgio; Benedetti, Edoardo; Nash, Richard; Aglietta, Massimo

    2006-05-01

    A pilot study was conducted to evaluate safety and activity of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) in colorectal carcinoma (CRC) and to determine whether a T-cell response to a tumor-associated antigen (TAA) was induced. Fifteen patients with metastatic CRC underwent HCT from human leukocyte antigen (HLA)-matched siblings after a nonmyeloablative conditioning regimen. All patients engrafted with a median donor T-cell chimerism of 72% at day +56. Eight patients experienced grades II to IV acute graft-versus-host disease (GVHD). Despite progressive disease before HCT, partial remission and disease stabilization longer than 90 days were observed in 1 and 3 patients, respectively. Induction of TAA-specific T cells was evaluated with a carcinoembryonic antigen (CEA)-specific HLA-A(*)0201 pentamer in 6 patients with CRC. CEA-specific CD8(+) T cells were detected in 3 of 3 patients concomitant with GHVD onset, but not in 3 of 3 patients without GVHD. They were also not detected in 9 of 9 control patients with GVHD who received transplants for diagnoses other than CRC. Antitumor activity of CEA-specific T cells was also validated in vitro. In one patient, the induction of CEA-specific T cells was associated with a decrease of serum CEA levels and a partial response. Thus, graft-versus-host reactions associated with allogeneic HCT can trigger the generation of T cells specific for CEA, and this may be associated with a clinical response.

  10. 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.

  11. GVHD-associated, inflammasome-mediated loss of function in adoptively transferred myeloid-derived suppressor cells.

    PubMed

    Koehn, Brent H; Apostolova, Petya; Haverkamp, Jessica M; Miller, Jeffrey S; McCullar, Valarie; Tolar, Jakub; Munn, David H; Murphy, William J; Brickey, Willie June; Serody, Jonathan S; Gabrilovich, Dmitry I; Bronte, Vincenzo; Murray, Peter J; Ting, Jenny P-Y; Zeiser, Robert; Blazar, Bruce R

    2015-09-24

    Myeloid-derived suppressor cells (MDSCs) are a naturally occurring immune regulatory population associated with inhibition of ongoing inflammatory responses. In vitro generation of MDSCs from bone marrow has been shown to enhance survival in an acute model of lethal graft-versus-host disease (GVHD). However, donor MDSC infusion only partially ameliorates GVHD lethality. In order to improve the potential therapeutic benefit and ultimately survival outcomes, we set out to investigate the fate of MDSCs after transfer in the setting of acute GVHD (aGVHD). MDSCs transferred to lethally irradiated recipients of allogeneic donor hematopoietic grafts are exposed to an intense inflammatory environment associated with aGVHD, which we now show directly undermines their suppressive capacity. Under a conditioning regimen and GVHD inflammatory settings, MDSCs rapidly lose suppressor function and their potential to inhibit GVHD lethality, which is associated with their induced conversion toward a mature inflammasome-activated state. We find even brief in vitro exposure to inflammasome-activating mediators negates the suppressive potential of cultured murine and human-derived MDSCs. Consistent with a role for the inflammasome, donor MDSCs deficient in the adaptor ASC (apoptosis-associated speck-like protein containing a CARD), which assembles inflammasome complexes, conferred improved survival of mice developing GVHD compared with wild-type donor MDSCs. These data suggest the use of MDSCs as a therapeutic approach for preventing GVHD and other systemic inflammatory conditions will be more effective when combined with approaches limiting in vivo MDSC inflammasome activation, empowering MDSCs to maintain their suppressive potential.

  12. GVHD-associated, inflammasome-mediated loss of function in adoptively transferred myeloid-derived suppressor cells

    PubMed Central

    Koehn, Brent H.; Apostolova, Petya; Haverkamp, Jessica M.; Miller, Jeffrey S.; McCullar, Valarie; Tolar, Jakub; Munn, David H.; Murphy, William J.; Brickey, Willie June; Serody, Jonathan S.; Gabrilovich, Dmitry I.; Bronte, Vincenzo; Murray, Peter J.; Ting, Jenny P.-Y.; Zeiser, Robert

    2015-01-01

    Myeloid-derived suppressor cells (MDSCs) are a naturally occurring immune regulatory population associated with inhibition of ongoing inflammatory responses. In vitro generation of MDSCs from bone marrow has been shown to enhance survival in an acute model of lethal graft-versus-host disease (GVHD). However, donor MDSC infusion only partially ameliorates GVHD lethality. In order to improve the potential therapeutic benefit and ultimately survival outcomes, we set out to investigate the fate of MDSCs after transfer in the setting of acute GVHD (aGVHD). MDSCs transferred to lethally irradiated recipients of allogeneic donor hematopoietic grafts are exposed to an intense inflammatory environment associated with aGVHD, which we now show directly undermines their suppressive capacity. Under a conditioning regimen and GVHD inflammatory settings, MDSCs rapidly lose suppressor function and their potential to inhibit GVHD lethality, which is associated with their induced conversion toward a mature inflammasome-activated state. We find even brief in vitro exposure to inflammasome-activating mediators negates the suppressive potential of cultured murine and human-derived MDSCs. Consistent with a role for the inflammasome, donor MDSCs deficient in the adaptor ASC (apoptosis-associated speck-like protein containing a CARD), which assembles inflammasome complexes, conferred improved survival of mice developing GVHD compared with wild-type donor MDSCs. These data suggest the use of MDSCs as a therapeutic approach for preventing GVHD and other systemic inflammatory conditions will be more effective when combined with approaches limiting in vivo MDSC inflammasome activation, empowering MDSCs to maintain their suppressive potential. PMID:26265697

  13. GVHD (Graft-Versus-Host Disease): A Guide for Patients and Families After Stem Cell Transplant

    MedlinePlus

    ... the first 100 days after your transplant or infusion of T-cells (in a donor lymphocyte infusion, or DLI). Acute GVHD commonly affects your skin, ... mouth or put on your skin or an infusion through a vascular access device. Also, treatment may ...

  14. Fludarabine and busulfan as a reduced-toxicity myeloablative conditioning regimen in allogeneic hematopoietic stem cell transplantation for acute leukemia patients

    PubMed Central

    DAI, ZHIMING; LIU, JIE; ZHANG, WANG-GANG; CAO, XINGMEI; ZHANG, YANG; DAI, ZHIJUN

    2016-01-01

    The optimal conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute leukemia remains undefined. We evaluated the outcomes in 30 patients with acute leukemia who underwent allo-HSCT from human leukocyte antigen-matched donors after conditioning with busulfan and fludarabine (BuFlu). The regimen comprised injection of busulfan 3.2 mg/kg daily on 4 consecutive days and fludarabine 30 mg/m2 daily for 4 doses. All 30 patients achieved hematopoiesis reconstitution with full donor chimerism confirmed by short tandem repeat DNA analysis. The most common regimen-related toxicity was mucositis (86.7%), followed by cytomegalovirus infection (80%). Serious regimen-related toxicities were rare. Acute graft vs. host disease (aGVHD) was detected in 46.7% of the patients; 33.4% had grade I–II aGVHD and 13.3% had grade III–IV aGVHD. Chronic GVHD (cGVHD) was noted in 20% of the patients. The overall survival and disease-free survival rates were 66.7 and 53%, respectively, with a median follow-up of 25 months for surviving patients. Therefore, BuFlu was an effective conditioning regimen with a low rate of transplant-related adverse effects and increased antileukemic effects in patients with acute leukemia undergoing allo-HSCT. PMID:27073687

  15. Tocilizumab for steroid refractory acute graft-versus-host disease.

    PubMed

    Roddy, Julianna V F; Haverkos, Bradley M; McBride, Ali; Leininger, Kathryn M; Jaglowski, Samantha; Penza, Sam; Klisovic, Rebecca; Blum, William; Vasu, Sumithira; Hofmeister, Craig C; Benson, Don M; Andritsos, Leslie A; Devine, Steven M; Efebera, Yvonne A

    2016-01-01

    Acute graft-versus-host-disease (aGVHD) is a frequent and often lethal complication of allogeneic hematopoietic stem cell transplant despite prophylaxis. Tocilizumab is a humanized anti-IL-6 receptor monoclonal antibody that has evidence of activity in patients with steroid refractory (SR) GVHD. We retrospectively report on nine patients with grade 3 or 4 SR aGVHD who received tocilizumab. Eight mg/kg of tocilizumab was administered intravenously every 3-4 weeks. aGVHD grading and responses were based on consensus criteria. Median age at transplant was 48 years. Five patients had alternate donor sources. Median time from aGVHD onset to tocilizumab administration was 44 days. Two patients had complete responses and two had partial responses. Median survival from start of tocilizumab was 26 days (range 13-1054). Our limited experience demonstrated an overall response rate of 44% (CR + PR); however, this response was not durable. Further studies are needed to determine the optimal time for tocilizumab initiation.

  16. Tocilizumab for steroid refractory acute graft-versus-host disease

    PubMed Central

    Roddy, Julianna V. F.; Haverkos, Bradley M.; McBride, Ali; Leininger, Kathryn M.; Jaglowski, Samantha; Penza, Sam; Klisovic, Rebecca; Blum, William; Vasu, Sumithira; Hofmeister, Craig C.; Benson, Don M.; Andritsos, Leslie A.; Devine, Steven M.; Efebera, Yvonne A.

    2015-01-01

    Acute graft-versus-host-disease (aGVHD) is a frequent and often lethal complication of allogeneic hematopoietic stem cell transplant despite prophylaxis. Tocilizumab is a humanized anti-IL-6 receptor monoclonal antibody that has evidence of activity in patients with steroid refractory (SR) GVHD. We retrospectively report on nine patients with grade 3 or 4 SR aGVHD who received tocilizumab. Eight mg/kg of tocilizumab was administered intravenously every 3–4 weeks. aGVHD grading and responses were based on consensus criteria. Median age at transplant was 48 years. Five patients had alternate donor sources. Median time from aGVHD onset to tocilizumab administration was 44 days. Two patients had complete responses and two had partial responses. Median survival from start of tocilizumab was 26 days (range 13–1054). Our limited experience demonstrated an overall response rate of 44% (CR + PR); however, this response was not durable. Further studies are needed to determine the optimal time for tocilizumab initiation. PMID:26140610

  17. 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.

  18. High day 28 ST2 levels predict for acute graft-versus-host disease and transplant-related mortality after cord blood transplantation.

    PubMed

    Ponce, Doris M; Hilden, Patrick; Mumaw, Christen; Devlin, Sean M; Lubin, Marissa; Giralt, Sergio; Goldberg, Jenna D; Hanash, Alan; Hsu, Katharine; Jenq, Robert; Perales, Miguel-Angel; Sauter, Craig; van den Brink, Marcel R M; Young, James W; Brentjens, Renier; Kernan, Nancy A; Prockop, Susan E; O'Reilly, Richard J; Scaradavou, Andromachi; Paczesny, Sophie; Barker, Juliet N

    2015-01-01

    While cord blood transplantation (CBT) is an effective therapy for hematologic malignancies, acute graft-versus-host disease (aGVHD) is a leading cause of transplant-related mortality (TRM). We investigated if biomarkers could predict aGVHD and TRM after day 28 in CBT recipients. Day 28 samples from 113 CBT patients were analyzed. Suppressor of tumorigenicity 2 (ST2) was the only biomarker associated with grades II-IV and III-IV aGVHD and TRM. Day 180 grade III-IV aGVHD in patients with high ST2 levels was 30% (95% confidence interval [CI], 18-43) vs 13% (95% CI, 5-23) in patients with low levels (P = .024). The adverse effect of elevated ST2 was independent of HLA match. Moreover, high day 28 ST2 levels were associated with increased TRM with day 180 estimates of 23% (95% CI, 13-35) vs 5% (95% CI, 1-13) if levels were low (P = .001). GVHD was the most common cause of death in high ST2 patients. High concentrations of tumor necrosis factor receptor-1, interleukin-8, and regenerating islet-derived protein 3-α were also associated with TRM. Our results are consistent with those of adult donor allografts and warrant further prospective evaluation to facilitate future therapeutic intervention to ameliorate severe aGVHD and further improve survival after CBT.

  19. Decreased incidence of acute graft-versus-host disease by continuous infusion of cyclosporine with a higher target blood level.

    PubMed

    Oshima, Kumi; Kanda, Yoshinobu; Nakasone, Hideki; Arai, Shunya; Nishimoto, Nahoko; Sato, Hiroyuki; Watanabe, Takuro; Hosoya, Noriko; Izutsu, Koji; Asai, Takashi; Hangaishi, Akira; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo

    2008-03-01

    Cyclosporine A (CsA) is the mainstay of pharmacologic prevention of acute graft-versus-host disease (GVHD). We previously reported that continuous infusion of CsA with a target blood level between 250 and 400 ng/ml significantly increased the incidence of acute GVHD compared to twice-daily infusion with a target trough level between 150 and 300 ng/ml. Thus, we raised the target level of CsA continuous infusion to 450-550 ng/ml. We treated 33 patients with the higher target level (CsA500) and compared the efficacy and toxicity with those in the 33 historical control patients (CsA300 group). Other transplantation procedures were not changed. The patients' characteristics were equivalent. The average CsA concentration was adjusted around 500 ng/ml and the actual daily dose was maintained at the initial dose (CsA 3mg/kg/day). Toxicities were equivalently observed among the two groups. The incidence of grades II-IV acute GVHD was significantly lower in the CsA500 group (27 vs. 52%, P = 0.033). The target level of CsA was identified as an independent significant risk factor for grades II-IV acute GVHD (P = 0.039), adjusted for the presence of HLA mismatch. The incidence of chronic GVHD was also decreased in the CsA500 group (47 vs. 73%, P = 0.016). We conclude that the toxicity of the continuous CsA infusion with a target level of 450-550 ng/ml is acceptable and the efficacy to prevent acute GVHD is significant. A larger comparative study is warranted to confirm these findings.

  20. Circulating Angiogenic Factors Associated with Response and Survival in Patients with Acute Graft-Versus-Host Disease: Results from BMT CTN 0302 and 0802

    PubMed Central

    Holtan, Shernan G.; Verneris, Michael R.; Schultz, Kirk R.; Newell, Laura F.; Meyers, Gabrielle; He, Fiona; DeFor, Todd E.; Vercellotti, Gregory M.; Slungaard, Arne; MacMillan, Margaret L.; Cooley, Sarah A.; Blazar, Bruce R.; Panoskaltsis-Mortari, Angela; Weisdorf, Daniel J.

    2015-01-01

    Circulating angiogenic factors (AF) reflect tissue healing capacity, although some AF can also contribute to inflammation and are indicative of endothelial dysfunction. The AF milieu in acute graft-versus-host disease (aGVHD) has not been broadly characterized. We hypothesized that patients with abundant AF involved in repair/regeneration vs. those mediating damage/inflammation would have improved outcomes. Circulating AF known predominantly for repair/regeneration (epidermal growth factor [EGF], fibroblast growth factor-1 and -2, heparin binding-EGF-like growth factor, vascular endothelial growth factor-A, -C, and -D) and for damage/inflammation (angiopoietin-2, endothelin-1, soluble endoglin [sEng], follistatin [FS], leptin, placental growth factor [PlGF]) were measured in a discovery set of HCT recipients with grade III/IV aGVHD versus controls, then validated in two aGVHD cohorts enrolled in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials 0302 (N=105, serum) and 0802 (N=158, plasma) versus controls without aGVHD (N=53, serum). Levels of EGF and VEGF-A were lower than controls at the onset of aGVHD in both trials and higher with complete response to first-line aGVHD therapy in CTN 0802. FS and PlGF were elevated in aGVHD measured in either serum or plasma. At day 28 after initial aGVHD therapy, elevated FS was an independent negative prognostic factor for survival in both cohorts (hazard ratio 9.3 in CTN 0302, 2.8 in CTN 0802). These data suggest that circulating AF are associated with clinical outcomes after aGVHD and thus may contribute to both pathogenesis and recovery. PMID:25759146

  1. Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD.

    PubMed

    Jacoby, Elad; Yang, Yinmeng; Qin, Haiying; Chien, Christopher D; Kochenderfer, James N; Fry, Terry J

    2016-03-10

    Acute lymphoblastic leukemia (ALL) persisting or relapsing following bone marrow transplantation (BMT) has a dismal prognosis. Success with chimeric antigen receptor (CAR) T cells offers an opportunity to treat these patients with leukemia-redirected donor-derived T cells, which may be more functional than T cells derived from patients with leukemia but have the potential to mediate graft-versus-host disease (GVHD). We, together with others, have previously demonstrated tumor-specific T-cell dysfunction in the allogeneic environment. Here, we studied CAR T-cell function following BMT using an immunocompetent murine model of minor mismatched allogeneic transplantation followed by donor-derived CD19-CAR T cells. Allogeneic donor-derived CD19-CAR T cells eliminated residual ALL with equal potency to those administered after syngeneic BMT. Surprisingly, allogeneic CAR T cells mediated lethal acute GVHD with early mortality, which is atypical for this minor mismatch model. We demonstrated that both allogeneic and syngeneic CAR T cells show initial expansion as effector T cells, with a higher peak but rapid deletion of allogeneic CAR T cells. Interestingly, CAR-mediated acute GVHD was only seen in the presence of leukemia, suggesting CAR-target interactions induced GVHD. Indeed, serum interleukin (IL)-6 was elevated only in the presence of both leukemia and CAR T cells, and IL-6 neutralization ameliorated the severity of GVHD in a delayed donor lymphocyte infusion model. Finally, allogeneic CD4(+) CAR T cells were responsible for GVHD, which correlated with their ability to produce IL-6 upon CAR stimulation. Altogether, we demonstrate that donor-derived allogeneic CAR T cells are active but have the capacity to drive GVHD.

  2. Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions

    PubMed Central

    Liu, Hongtao; Rich, Elizabeth S.; Godley, Lucy; Odenike, Olatoyosi; Joseph, Loren; Marino, Susana; Kline, Justin; Nguyen, Vu; Cunningham, John; Larson, Richard A.; del Cerro, Paula; Schroeder, Linda; Pape, Lisa; Stock, Wendy; Wickrema, Amittha; Artz, Andrew S.

    2011-01-01

    We conducted a 45 patient prospective study of reduced-intensity conditioning (RIC) and transplantation of unrelated umbilical cord blood (UCB) and CD34+ stem cells from a haploidentical family member. Median age was 50 years; weight was 80 kg. Fifty-eight percent had active disease. Neutrophil engraftment occurred at 11 days (interquartile range [IQR], 9-15) and platelet engraftment at 19 days (IQR, 15-33). In the majority of patients, early haploidentical engraftment was replaced by durable engraftment of UCB by 100 days, with regular persistence of minor host and/or haplo-hematopoiesis. Percentage of haplochimerism at day 100 correlated with the haplo-CD34 dose (P = .003). Cumulative incidence of acute GVHD (aGVHD) was 25% and chronic GVHD (cGVHD) was 5%. Actuarial survival at 1 year was 55%, progression-free survival (PFS) was 42%, nonrelapse mortality (NRM) was 28%, and relapse was 30%. RIC and haplo-cord transplantation results in fast engraftment of neutrophils and platelets, low incidences of aGVHD and cGVHD, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay, and promising long-term outcomes. UCB cell dose had no impact on time to hematopoietic recovery. Therefore, UCB selection can prioritize matching, and better matched donors can be identified rapidly for most patients. This study is registered at http://clinicaltrials.gov as NCI clinical trial no. NCT00943800. PMID:21976674

  3. In Vivo T Cell Depletion with Myeloablative Regimens on Outcomes after Cord Blood Transplantation for Acute Lymphoblastic Leukemia in Children.

    PubMed

    Ponce, Doris M; Eapen, Mary; Sparapani, Rodney; O'Brien, Tracey A; Chan, Ka Wah; Chen, Junfang; Craddock, John; Schultz, Kirk R; Wagner, John E; Perales, Miguel-Angel; Barker, Juliet N

    2015-12-01

    The inclusion of antithymocyte globulin (ATG) in cord blood transplantation is controversial. We evaluated outcomes according to ATG inclusion in 297 children and adolescents with acute lymphoblastic leukemia (ALL) who received myeloablative total body irradiation-based conditioning and either single-unit (74%) or double-unit (26%) grafts. Ninety-two patients (31%) received ATG and 205 (69%) did not. ATG recipients were more likely to be cytomegalovirus seronegative. The incidences of day 100 grades II to IV acute graft-versus-host disease (GVHD; 30% versus 54%, P = .0002) and chronic GVHD (22% versus 43%, P = .0008) were lower with ATG compared with non-ATG regimens. However, day 100 grades III to IV acute GVHD was comparable (11% versus 17%, P = .15). The 3-year incidences of transplant-related mortality (16% versus 17%, P = .98), relapse (17% versus 27%, P = .12), and leukemia-free survival (66% versus 55%, P = .23) in ATG and non-ATG recipients were similar. There were no differences in viral reactivation between treatment groups (60% versus 58%, P = .83). Therefore, the data suggest that incorporation of ATG with myeloablative conditioning regimens may be useful in reducing the risk of acute and chronic GVHD without any deleterious effect on transplant-related mortality, relapse, or leukemia-free survival in children and adolescents with ALL.

  4. Circulating angiogenic factors associated with response and survival in patients with acute graft-versus-host disease: results from Blood and Marrow Transplant Clinical Trials Network 0302 and 0802.

    PubMed

    Holtan, Shernan G; Verneris, Michael R; Schultz, Kirk R; Newell, Laura F; Meyers, Gabrielle; He, Fiona; DeFor, Todd E; Vercellotti, Gregory M; Slungaard, Arne; MacMillan, Margaret L; Cooley, Sarah A; Blazar, Bruce R; Panoskaltsis-Mortari, Angela; Weisdorf, Daniel J

    2015-06-01

    Circulating angiogenic factors (AF) reflect tissue healing capacity, although some AF can also contribute to inflammation and are indicative of endothelial dysfunction. The AF milieu in acute graft-versus-host disease (aGVHD) has not been broadly characterized. We hypothesized that patients with abundant AF involved in repair/regeneration versus those mediating damage/inflammation would have improved outcomes. Circulating AF known predominantly for repair/regeneration (epidermal growth factor [EGF], fibroblast growth factor-1 and -2, heparin binding-EGF-like growth factor, and vascular endothelial growth factor-A [VEGF-A], -C, and -D) and for damage/inflammation (angiopoietin-2, endothelin-1, soluble endoglin [sEng], follistatin [FS], leptin, and placental growth factor [PlGF]) were measured in a discovery set of hematopoietic cell recipients with grade III and IV aGVHD and compared with controls, then validated in 2 aGVHD cohorts enrolled in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials 0302 (n = 105, serum) and 0802 (n = 158, plasma) versus controls without aGVHD (n = 53, serum). Levels of EGF and VEGF-A were lower than in controls at the onset of aGVHD in both trials and higher with complete response to first-line aGVHD therapy in CTN 0802. FS and PlGF were elevated in aGVHD measured in either serum or plasma. At day 28 after initial aGVHD therapy, elevated FS was an independent negative prognostic factor for survival in both cohorts (hazard ratio, 9.3 in CTN 0302; 2.8 in CTN 0802). These data suggest that circulating AF are associated with clinical outcomes after aGVHD and, thus, may contribute to both pathogenesis and recovery.

  5. In vivo T-cell depletion with myeloablative regimens on outcomes after cord blood transplantation for acute lymphoblastic leukemia in children

    PubMed Central

    Ponce, Doris M.; Eapen, Mary; Sparapani, Rodney; O'Brien, Tracey A.; Chan, Ka Wah; Chen, Junfang; Craddock, John; Schultz, Kirk R.; Wagner, John E.; Perales, Miguel-Angel; Barker, Juliet N.

    2015-01-01

    The inclusion of anti-thymocyte globulin (ATG) in cord blood transplantation is controversial. We evaluated outcomes according to ATG inclusion in 297 children and adolescents with acute lymphoblastic leukemia (ALL) who received myeloablative total body irradiation-based conditioning and either single (74%) or double-unit (26%) grafts. Ninety-two patients (31%) received ATG and 205 (69%) did not. ATG recipients were more likely to be cytomegalovirus seronegative. The incidence of day-100 grade II-IV acute GVHD (30% versus 54%, p = 0.0002), and chronic GVHD (22% versus 43%, p = 0.0008) were lower with ATG compared to non-ATG regimens. However, day 100 grade III-IV acute GVHD was comparable (11% versus 17%, p = 0.15). The 3-year incidences of transplant-related mortality (16% versus 17%, p = 0.98) and relapse (17% versus 27%, p = 0.12), and leukemia-free survival (66% versus 55%, p = 0.23) in ATG and non-ATG recipients were similar. There were no differences in viral reactivation between treatment groups (60% versus 58%, p=0.83). Therefore, the data suggest that incorporation of ATG with myeloablative conditioning regimens may be useful in reducing the risk of acute and chronic GVHD without any deleterious effect on transplant-related mortality, relapse or leukemia-free survival in children and adolescents with ALL. PMID:26327630

  6. Late-onset acute graft-versus-host disease mimicking hand, foot, and mouth disease

    PubMed Central

    Mahabal, Gauri; George, Leni; Bindra, Mandeep; George, Biju

    2016-01-01

    Acute skin graft-versus-host disease (GVHD) classically presents as a pruritic erythematous maculopapular rash. We describe a patient who underwent allogeneic hematopoietic stem cell transplantation and presented with a hand foot and mouth disease like clinical presentation. Histopathology was suggestive of acute GVHD. This case is being reported to make dermatologists aware of this unusual presentation of GVHD. PMID:27990387

  7. Topical tacrolimus and periodontal therapy in the management of a case of oral chronic GVHD characterized by specific gingival localization.

    PubMed

    Conrotto, Davide; Broccoletti, Roberto; Carcieri, Paola; Giaccone, Luisa; Arduino, Paolo G

    2014-01-01

    Background. Chronic graft versus host disease (cGVHD) is a complication following bone marrow transplantation. The oral lesions are difficult to control with a systemic pharmacological therapy. Case Description. A 63-year-old female patient, who underwent an allogeniec transplantation for acute myeloid leukemia, developed a chronic oral and cutaneous GVHD. The patient was treated with topical tacrolimus 0.1%, twice daily for two months, and underwent a protocol of oral hygiene characterized by 3 appointments of scaling, root planning, and daily oral hygiene instructions. The patient showed marked resolution of gingival lesions and a significant improvement of related pain and gingival inflammatory indexes. Clinical Implications. This case report suggests that treatment with topical tacrolimus and professional oral hygiene may be helpful in the management of chronic oral GVHD with severe gingival involvement.

  8. Comparison of Tacrolimus and Sirolimus (Tac/Sir) versus Tacrolimus, Sirolimus, and mini-methotrexate (Tac/Sir/MTX) as acute graft-versus-host disease prophylaxis after reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation.

    PubMed

    Ho, Vincent T; Aldridge, Julie; Kim, Haesook T; Cutler, Corey; Koreth, John; Armand, Philippe; Antin, Joseph H; Soiffer, Robert J; Alyea, Edwin P

    2009-07-01

    Previous studies have shown that adding sirolimus to a tacrolimus/mini-methotrexate regimen (Tac/Sir/MTX) as graft-versus-host disease (GVHD) prophylaxis produces low rates of acute GVHD (aGVHD) after reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). To assess whether posttransplantation methotrexate MTX can be safely eliminated altogether, we conducted a prospective clinical trial testing the combination of T and Sir alone (tac/sir) as GVHD prophylaxis after RIC SCT from matched related donors. We compared the results with patients who received (Tac/Sir/MTX) as GVHD prophylaxis after RIC SCT from matched related donors in a previous prospective study. Patients in both groups received i.v. fludarabine (Flu) 30 mg/m(2)/day and i.v. busulfan (Bu) 0.8 mg/kg/day on days -5 to -2 as conditioning, followed by transplantation of unmanipulated filgrastim-mobilized peripheral blood stem cells (PBSCS). After transplantation, patients in both groups received Tac and Sir orally starting on day -3, with doses adjusted to achieve trough serum levels of 5 to 10 ng/mL and 3 to 12 ng/mL, respectively. The patients in the Tac/Sir/MTX group also received mini-MTX therapy (5 mg/m(2) i.v.) on days +1, +3, and +6. Filgrastim 5 microg/kg/day s.c. was started on day +1 and continued until neutrophil engraftment. Twenty-nine patients received the Tac/Sir regimen, and 46 patients received the Tac/Sir/MTX regimen. The 2 groups were balanced in terms of age, sex, and disease characteristics. Engraftment was brisk and donor chimerism after transplantation robust in both groups. The cumulative incidence of grade II-IV aGVHD was similar in the 2 groups (17% for Tac/Sir versus 11% for Tac/Sir/MTX; P = .46). There also were no differences between the 2 groups in cumulative incidence of extensive chronic GVHD (cGVHD), treatment-related mortality (TRM), disease relapse, or survival. The Tac/Sir combination for GVHD prophylaxis is well tolerated and associated with a

  9. Pre-transplant donor CD4(-) invariant NKT cell expansion capacity predicts the occurrence of acute graft-versus-host disease.

    PubMed

    Rubio, M-T; Bouillié, M; Bouazza, N; Coman, T; Trebeden-Nègre, H; Gomez, A; Suarez, F; Sibon, D; Brignier, A; Paubelle, E; Nguyen-Khoc, S; Cavazzana, M; Lantz, O; Mohty, M; Urien, S; Hermine, O

    2017-04-01

    Clinically useful pre-transplant predictive factors of acute graft-versus-host-disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-SCT) are lacking. We prospectively analyzed HSC graft content in CD34(+), NK, conventional T, regulatory T and invariant natural killer T (iNKT) cells in 117 adult patients before allo-SCT. Results were correlated with occurrence of aGVHD and relapse. In univariate analysis, iNKT cells were the only graft cell populations associated with occurrence of aGVHD. In multivariate analysis, CD4(-) iNKT/T cell frequency could predict grade II-IV aGVHD in bone marrow and peripheral blood stem cell (PBSC) grafts, while CD4(-) iNKT expansion capacity was predictive in PBSC grafts. Receiver operating characteristic analyses determined the CD4(-) iNKT expansion factor as the best predictive factor of aGVHD. Incidence of grade II-IV aGVHD was reduced in patients receiving a graft with an expansion factor above versus below 6.83 (9.7 vs 80%, P<0.0001), while relapse incidence at two years was similar (P=0.5).The test reached 94% sensitivity and 100% specificity in the subgroup of patients transplanted with human leukocyte antigen 10/10 PBSCs without active disease. Analysis of this CD4(-) iNKT expansion capacity test may represent the first diagnostic tool allowing selection of the best donor to avoid severe aGVHD with preserved graft-versus-leukemia effect after peripheral blood allo-SCT.

  10. Increased incidence of acute graft-versus-host disease with the continuous infusion of cyclosporine A compared to twice-daily infusion.

    PubMed

    Ogawa, N; Kanda, Y; Matsubara, M; Asano, Y; Nakagawa, M; Sakata-Yanagimoto, M; Kandabashi, K; Izutsu, K; Imai, Y; Hangaishi, A; Kurokawa, M; Tsujino, S; Ogawa, S; Aoki, K; Chiba, S; Motokura, T; Hirai, H

    2004-03-01

    We retrospectively compared the incidence of acute graft-versus-host disease (GVHD) before and after September 1999, when we changed the mode of cyclosporine A (CsA) administration from twice-daily infusions (TD) (n=58) to continuous infusion (CIF) (n=71). The incidence of grade II-IV acute GVHD in the CIF group (56%) was significantly higher than that in the TD group (27%, P=0.00022). Multivariate analysis identified only two independent significant risk factors for the development of grade II-IV acute GVHD; CIF of CsA (relative risk 2.59, 95% CI 1.46-4.60, P=0.0011) and the presence of HLA mismatch (2.01, 95% CI 1.15-3.53, P=0.014). The incidence of relapse was significantly lower in the CIF group when adjusted for disease status before transplantation (0.41, 95% CI 0.18-0.95, P=0.038), which resulted in better disease-free survival in high-risk patients (43 vs 16% at 2 years, P=0.039), but not in standard-risk patients (72 vs 80%, P=0.45). CIF of CsA with a target level of 250-400 ng/ml may not be appropriate for GVHD prophylaxis in standard-risk patients.

  11. Acute graft-vs.-host disease correlates with the disparity for the PECAM-1 S536N polymorphism only in the HLA-B44-like positive Tunisian recipients of HSCs.

    PubMed

    Sellami, Mohamed Hichem; Ladeb, Saloua; Kaabi, Houda; Cherif, Ghaya; Torjemane, Lamia; Othman, Tarek Ben; Hmida, Slama

    2010-01-01

    GVHD is the major cause of mortality after HLA-identical HSCT. Such complication has been widely linked to donor/recipient disparity for minor histocompatibility antigens (MiHAgs). PECAM-1 is one of potential human MiHAgs but its effect on the GVHD occurrence remains not clear. In order to examine such association in the Tunisian cohort of HSCs recipients, we performed a retrospective study on patients who undergone HLA-identical HSCT between 2000 and 2009. Genotyping of the three selected PECAM-1 polymorphisms (rs668, rs12953 and rs1131012) was performed with SSP-PCR method. Univariate analyses showed that grades II-IV acute GVHD were considerably linked to the non-identity for rs12953 only in HLA-B44-like positive patients (p=0.010, OR=10.000). Multivariate analysis for chronic GVHD showed that this outcome may be affected only by the adulthood and the conditioning regimen. Our findings support the previously reported data suggesting a significant association between the PECAM-1 disparity and the risk of acute GVHD.

  12. Radiolabeled Anti-CD45 Antibody with Reduced-Intensity Conditioning and Allogeneic Transplantation for Younger Patients with Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome

    PubMed Central

    Mawad, Raya; Gooley, Ted A.; Rajendran, Joseph G.; Fisher, Darrell R.; Gopal, Ajay K.; Shields, Andrew T.; Sandmaier, Brenda M.; Sorror, Mohamed L.; Deeg, H. Joachim; Storb, Rainer; Green, Damian J.; Maloney, David G.; Appelbaum, Frederick R.; Press, Oliver W.; Pagel, John M.

    2014-01-01

    We treated patients under age 50 years with 131I-anti-CD45 antibody combined with fludarabine and 2 Gy total body irradiation to create an improved hematopoietic cell transplantation (HCT) strategy for advanced acute myeloid leukemia or high-risk myelodysplastic syndrome patients. Fifteen patients received 332–1,561 mCi of 131I, delivering an average of 27 Gy to bone marrow, 84 Gy to spleen, and 21 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no dose-limiting toxicity was observed. Marrow doses were arbitrarily capped at 43 Gy to avoid radiation-induced stromal damage; however no graft failure or evidence of stromal damage was observed. Twelve patients (80%) developed Grade II graft-versus-host disease (GVHD), one patient developed Grade III GVHD, and no patients developed Grade IV GVHD during the first 100 days after HCT. Of the 12 patients with chronic GVHD data, 10 developed chronic GVHD, generally involving the skin and mouth. Six patients (40%) are surviving after a median of 5.0 years (range, 4.2 to 8.3 years). The estimated survival at 1 year was 73% among the 15 treated patients. Eight patients relapsed, 7 of whom subsequently died. The median time to relapse among these 8 patients was 54 days (range, 26 to 1364 days). No cases of non-relapse mortality were observed in the first year after transplant. However, two patients died in remission from complications of chronic GVHD and cardiomyopathy, at 18 months and 14 months after transplant, respectively. This study suggests that patients may tolerate myeloablative doses >28 Gy delivered to the liver using 131I-anti-CD45 antibody in addition to standard reduced intensity conditioning. Moreover, the arbitrary limit of 43 Gy to the marrow may be unnecessarily conservative, and continued escalation of targeted radioimmunotherapy doses may be feasible to further reduce relapse. PMID:24858425

  13. α-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics.

    PubMed

    Marcondes, A Mario; Karoopongse, Ekapun; Lesnikova, Marina; Margineantu, Daciana; Welte, Tobias; Dinarello, Charles A; Hockenbery, David; Janciauskiene, Sabina; Deeg, H Joachim

    2014-10-30

    Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma α-1-antitrypsin (AAT) levels in human donors and the development of acute GVHD in the recipients (n = 111; P = .0006). In murine models, treatment of transplant donors with human AAT resulted in an increase in interleukin-10 messenger RNA and CD8(+)CD11c(+)CD205(+) major histocompatibility complex class II(+) dendritic cells (DCs), and the prevention or attenuation of acute GVHD in the recipients. Ablation of DCs (in AAT-treated CD11c-DTR donors) decreased CD4(+)CD25(+)FoxP3(+) regulatory T cells to one-third and abrogated the anti-GVHD effect. The graft-versus-leukemia (GVL) effect of donor cells (against A20 tumor cells) was maintained or even enhanced with AAT treatment of the donor, mediated by an expanded population of NK1.1(+), CD49B(+), CD122(+), CD335(+) NKG2D-expressing natural killer (NK) cells. Blockade of NKG2D significantly suppressed the GVL effect. Metabolic analysis showed a high glycolysis-high oxidative phosphorylation profile for NK1.1(+) cells, CD4(+)CD25(+)FoxP3(+) T cells, and CD11c(+) DCs but not for effector T cells, suggesting a cell type-specific effect of AAT. Thus, via altered metabolism, AAT exerts effective GVHD protection while enhancing GVL effects.

  14. Mismatch for the minor histocompatibility antigen HA-2 and GVHD occurrence in HLA-A*0201-positive Tunisian recipients of HSCs.

    PubMed

    Sellami, Mohamed Hichem; Torjemane, Lamia; Espadas de Arias, Alejandro; Kaabi, Houda; Ladeb, Saloua; Ben Othman, Tarek; Poli, Francesca; Hmida, Slama

    2010-01-01

    Graft-versus-Host disease (GVHD) has been widely linked to immunogenetic causes such as disparity between the recipient and its HLA geno-identical donor for some Non-HLA antigens called minor histocompatibility antigens (MiHAgs). HA-2 is one of potential human MiHAgs but its effect on the GVHD occurrence remains not clear. In order to examine such association in the Tunisian cohort of HSCs recipients, we performed a retrospective study on patients who received an HLA-identical HSCT between 2000 and 2009. The study was performed on 60 HLA-A2-positive patients who had received a haematopoietic stem cell transplant from an HLA-identical sibling. All patients received cyclosporine A and/or methotrexate for GVHD prophylaxis. HA-2 genotyping assay was performed with SSP-PCR method and HLA-A*0201 positive samples were identified mainly with Luminex HLA-Typing method. Luminex HLA-Typing assay showed that only 53 cases were positives for the HLA-A*0201 allele. Among these cases, only 3 pairs were mismatched for the MiHAg HA-2. Acute GVHD occurred in 01 HA-2-mismatched pair while chronic GVHD was detected in 02 disparate couples. Univariate and multivariate analyses showed that MiHAg HA-2 disparity does not have any significant effect on the occurrence of either acute or chronic GVHD. This last one appeared to be correlated only with the age of patient (adulthood) (p: 0.011, OR: 22.092). Our findings support the previously reported data denying the influence of the HA-2 disparity on the GVHD occurrence after HSCT.

  15. Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome.

    PubMed

    Pusic, Iskra; Choi, Jaebok; Fiala, Mark A; Gao, Feng; Holt, Matthew; Cashen, Amanda F; Vij, Ravi; Abboud, Camille N; Stockerl-Goldstein, Keith E; Jacoby, Meghan A; Uy, Geoffrey L; Westervelt, Peter; DiPersio, John F

    2015-10-01

    Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I, inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD), and facilitate a graft-versus-leukemia effect by enhancing the effect of T regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplantation started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10, and 15 mg/m(2)/day × 5 days every 6 weeks, for a maximum 8 cycles. The maximum tolerated dose (MTD) was defined as the maximum dose at which ≤ 25% of people experience dose-limiting toxicities during the first cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; 1 patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in the post-allotransplantation setting. Although the MTD was not reached, the dose of 10 mg/m(2) for 5 days every 6 weeks appeared to be the

  16. Efficacy of Mesenchymal Stem Cell Therapy for Steroid-Refractory Acute Graft-Versus-Host Disease following Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

    PubMed Central

    Chen, Xiaomei; Wang, Chunyan; Yin, Jin; Xu, Jinhuan; Wei, Jia; Zhang, Yicheng

    2015-01-01

    Background Mesenchymal stem cells (MSCs) have been broadly used experimentally in various clinical contexts. The addition of MSCs to initial steroid therapy for acute graft-versus-host disease (aGVHD) may improve patient outcomes. However, investigations regarding prognostic factors affecting the efficacy of MSC therapy for steroid-refractory aGVHD remain controversial. We thus conducted a systematic review and meta-analysis of published clinical trials to determine possible prognostic factors affecting the efficacy of MSCs in treating steroid-refractory aGVHD. Methods and Findings Clinical trials using MSC therapy for steroid-refractory aGVHD were identified by searching PubMed and EMBASE databases. A total of 6,963 citations were reviewed, and 13 studies met the inclusion criteria. A total of 301 patients from thirteen studies were included. Of these, 136 patients showed a complete response (CR), and 69 patients displayed a partial (PR) or mixed response (MR). In total, 205 patients exhibited overall response (ORR). Patients with skin steroid-refractory aGVHD showed a better clinical response than gastrointestinal (CR: odds ratio [OR] = 1.93, 95% confidence interval [95%CI]: 1.05–3.57, p < 0.05) and liver (CR: OR = 2.30, 95%CI: 1.12–4.69, p < 0.05, and ORR: OR = 2.93, 95%CI: 1.06–8.08, p < 0.05) steroid-refractory aGVHD. Those with grade II steroid-refractory aGVHD exhibited a better clinical response following MSC therapy than recipients with grade III–IV (CR: OR = 3.22, 95%CI: 1.24–8.34, p < 0.05). Completion therapy may improve the CR but reduce ORR compared with induction therapy (CR: OR = 0.20, 95%CI: 0.09–0.44, p < 0.05; ORR: OR = 2.18, 95%CI: 1.17–4.05, p = 0.01). There was also a trend towards a better clinical response in children compared with adults (CR: OR = 2.41, 95%CI: 1.01–5.73, p = 0.05). Conclusions Age, skin involvement, lower aGVHD grade, and the number of infusions are the main prognostic factors affecting the efficacy of MSC

  17. Lessons Learned With Laparoscopic Management of Complicated Grades of Acute Appendicitis

    PubMed Central

    Gomes, Carlos Augusto; Junior, Cleber Soares; Costa, Evandro de Freitas Campos; Alves, Paula de Assis Pereira; de Faria, Carolina Vieira; Cangussu, Igor Vitoi; Costa, Luisa Pires; Gomes, Camila Couto; Gomes, Felipe Couto

    2014-01-01

    Background Laparoscopy has not been consolidated as the approach of first choice in the management of complicated appendicitis. Methodological flaws and absence of disease stratification criteria have been implicated in that less evidence. The objective is to study the safe and effectiveness of laparoscopy in the management of complicated appendicitis according to laparoscopic grading system. Method From January 2008 to January 2011, 154 consecutive patients who underwent a laparoscopic appendectomy for complicated appendicitis were evaluated in the prospective way. The patient’s age ranged from 12 to 75 years old (31.7 ± 13.3) and 58.3% were male. Complicated appendicitis refers to gangrenous and/or perforated appendix and were graded as 3A (segmental necrosis), 3B (base necrosis), 4A (abscess), 4B (regional peritonitis) and 5 (diffuse peritonitis). The outcomes including operative time, infection complication, operative complications and conversion rate were chosen to evaluate the procedure. Results The grade 3A was the most frequent with 50 (32.4%) patients. The mean operative time was 69.4 ± 26.3 minutes. The grade 4A showed the highest mean operative time (80.1 ± 26.7 minutes). The wound and intra-abdominal infection rates were 2.6 and 4.6%, respectively. The base necrosis was the most important factor associated with the conversion (5.2%). The grades 4A and 5 were associated with greater possibility of intra-abdominal collection. There were no operative complications. Conclusion The laparoscopic management of all complicated grades of acute appendicitis is safe and effective and should be the procedure of first choice. The laparoscopic grading system allows us to assess patients in the same disease stage. PMID:24883151

  18. How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver

    PubMed Central

    2016-01-01

    Treatment of acute graft-versus-host disease (GVHD) has evolved from a one-size-fits-all approach to a more nuanced strategy based on predicted outcomes. Lower and time-limited doses of immune suppression for patients predicted to have low-risk GVHD are safe and effective. In more severe GVHD, prolonged exposure to immunosuppressive therapies, failure to achieve tolerance, and inadequate clinical responses are the proximate causes of GVHD-related deaths. This article presents acute GVHD-related scenarios representing, respectively, certainty of diagnosis, multiple causes of symptoms, jaundice, an initial therapy algorithm, secondary therapy, and defining futility of treatment. PMID:26729898

  19. GVHD-Related, Cytokine-Driven Apoptosis Depends on p73 in Cytokeratin 15-Positive Target Cells

    PubMed Central

    Zhan, Qian; Korngold, Robert; Lezcano, Cecilia; McKeon, Frank; Murphy, George F.

    2012-01-01

    Acute graft-versus-host disease (GVHD), a major complication of allogeneic stem cell transplantation, involves cytotoxic soluble and cellular effectors that induce apoptosis selectively in normally apoptosis-resistant, cytokeratin 15 (K15)-expressing epithelial stem cells that reside at tips of rete ridges of human epidermis and in analogous rete-like prominences (RLPs) of murine dorsal lingual epithelium. The mechanism(s) whereby epithelial stem cells are rendered vulnerable to apoptosis during allostimulation is unknown. We hypothesized that GVHD-induced target cell injury may relate to pathways involving the p53 family that are constitutively expressed by epithelial stem cells and designed to trigger physiological apoptosis as a result of environmental danger signals. Among the p53 family members, we found p73 protein and mRNA to be preferentially expressed in K15+ RLPs of murine lingual squamous epithelium. Upon in vitro exposure to recombinant TNF alpha (TNFα) and Il-1 in an organ culture model previously shown to replicate early GVHD-like target cell injury, apoptosis was selectively induced in K15+ stem cell regions and was associated with induction of phosphorylated p73, a marker for p73 activation, and apoptosis was abrogated in target tissue obtained from p73-deficient (p73−/−) mice. Evaluation of early in vivo lesions in experimental murine GVHD disclosed identical patterns of phosphorylated p73 expression that coincided with the onset of effector T cell infiltration and target cell apoptosis within K15+ RLPs. These data for the first time indicate that paradoxical apoptosis in GVHD of physiologically protected K15+ epithelial stem cells is explainable, at least in part, by cytokine-induced activation of suicide pathways designed to eliminate stem cells after exposure to deleterious factors perceived to be harmful to the host. PMID:22469882

  20. High CD3+ and CD34+ peripheral blood stem cell grafts content is associated with increased risk of graft-versus-host disease without beneficial effect on disease control after reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia — an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

    PubMed Central

    Czerw, Tomasz; Labopin, Myriam; Schmid, Christoph; Cornelissen, Jan J.; Chevallier, Patrice; Blaise, Didier; Kuball, Jürgen; Vigouroux, Stephane; Garban, Frédéric; Lioure, Bruno; Fegueux, Nathalie; Clement, Laurence; Sandstedt, Anna; Maertens, Johan; Guillerm, Gaëlle; Bordessoule, Dominique

    2016-01-01

    Inconsistent results have been reported regarding the influence of graft composition on the incidence of graft versus host disease (GVHD), disease control and survival after reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplantation (allo-PBSCT). These discrepancies may be at least in part explained by the differences in disease categories, disease status at transplant, donor type and conditioning. The current retrospective EBMT registry study aimed to analyze the impact of CD3+ and CD34+ cells dose on the outcome of RIC allo-PBSCT in patients with acute myelogenous leukemia (AML) in first complete remission, allografted from HLA-matched unrelated donors (10 of 10 match). We included 203 adults. In univariate analysis, patients transplanted with the highest CD3+ and CD34+ doses (above the third quartile cut-off point values, >347 × 10^6/kg and >8.25 × 10^6 /kg, respectively) had an increased incidence of grade III-IV acute (a) GVHD (20% vs. 6%, P = .003 and 18% vs. 7%, P = .02, respectively). There was no association between cellular composition of grafts and transplant-related mortality, AML relapse, incidence of chronic GVHD and survival. Neither engraftment itself nor the kinetics of engraftment were affected by the cell dose. In multivariate analysis, CD3+ and CD34+ doses were the only adverse predicting factors for grade III-IV aGVHD (HR = 3.6; 95%CI: 1.45-9.96, P = .006 and 2.65 (1.07-6.57), P = .04, respectively). These results suggest that careful assessing the CD3+ and CD34+ graft content and tailoring the cell dose infused may help in reducing severe acute GVHD risk without negative impact on the other transplantation outcomes. PMID:27036034

  1. Monitoring of TNFR1, IL-2Rα, HGF, CCL8, IL-8 and IL-12p70 following HSCT and their role as GVHD biomarkers in paediatric patients.

    PubMed

    Berger, M; Signorino, E; Muraro, M; Quarello, P; Biasin, E; Nesi, F; Vassallo, E; Fagioli, F

    2013-09-01

    No predictive factors are currently available to establish patient-specific GVHD risk. A panel of six serum cytokines (TNF receptor 1, IL-2 receptor alfa (IL-2Rα), hepatocyte growth factor (HGF), monocyte chemo-attractant protein-2, IL-8, IL-12p70) were monitored at established time points (days -1, +1, +7, +14, +21, +28 and +60) in 170 paediatric hematopoietic SCT (HSCT) recipients. We found that higher concentrations of IL-2Rα on days +14 and +21 together with HGF on days +14 and +21 were significantly associated at a higher probability of both grade II-IV GVHD (on day +14 it was: 60% vs 28%, P=0.007) and grade III-IV (on day +14 it was: 40% vs 15%, P=0.001). The higher IL-8 serum concentration on day +28 was associated with a lower probability of chronic GVHD being 4% vs 29% (P=0.01) for patients with higher vs lower IL-8 serum concentration. These findings were confirmed when the analysis was restricted to the the matched unrelated donor group. In conclusion, even if the serum cytokine levels were related to several variables associated with HSCT, we identified two cytokines as predictors of GVHD II-IV and III-IV, translating into a higher TRM risk (17% vs 3%, P=0.004).

  2. Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

    PubMed Central

    Ye, YongBin; Wang, Jing; Huang, YuXian; Weng, GuangYang; Zhang, MingWan

    2016-01-01

    Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a major cause of nonrelapse mortality after allo-HSCT. A conditioning regimen plays a pivotal role in the development of aGVHD. To provide a platform for studying aGVHD and evaluating the impact of different conditioning regimens, we established a murine aGVHD model that simulates the clinical situation and can be conditioned with Busulfan-Cyclophosphamide (Bu-Cy) and Fludarabine-Busulfan (Flu-Bu). In our study, BALB/c mice were conditioned with Bu-Cy or Flu-Bu and transplanted with 2 × 107 bone marrow cells and 2 × 107 splenocytes from either allogeneic (C57BL/6) or syngeneic (BALB/c) donors. The allogeneic recipients conditioned with Bu-Cy had shorter survivals (P < 0.05), more severe clinical manifestations, and higher hepatic and intestinal pathology scores, associated with increased INF-γ expression and diminished IL-4 expression in serum, compared to allogeneic recipients conditioned with Flu-Bu. Moreover, higher donor-derived T-cell infiltration and severely impaired B-cell development were seen in the bone marrow of mice, exhibiting aGVHD and conditioned with Flu-Bu. Our study showed that the conditioning regimen with Bu-Cy resulted in more severe aGVHD while the Flu-Bu regimen was associated with more extensive and long standing bone marrow damage. PMID:27843940

  3. Sequential chemotherapy followed by reduced-intensity conditioning and allogeneic haematopoietic stem cell transplantation in adult patients with relapse or refractory acute myeloid leukaemia: a survey from the Acute Leukaemia Working Party of EBMT.

    PubMed

    Ringdén, Olle; Labopin, Myriam; Schmid, Christoph; Sadeghi, Behnam; Polge, Emmanuelle; Tischer, Johanna; Ganser, Arnold; Michallet, Mauricette; Kanz, Lothar; Schwerdtfeger, Rainer; Nagler, Arnon; Mohty, Mohamad

    2017-02-01

    This study analysed the outcome of 267 patients with relapse/refractory acute myeloid leukaemia (AML) who received sequential chemotherapy including fludarabine, cytarabine and amsacrine followed by reduced-intensity conditioning (RIC) and allogeneic haematopoietic stem cell transplantation (HSCT). The transplants in 77 patients were from matched sibling donors (MSDs) and those in 190 patients were from matched unrelated donors. Most patients (94·3%) were given anti-T-cell antibodies. The incidence of acute graft-versus-host disease (GVHD) of grades II-IV was 32·1% and that of chronic GVHD was 30·2%. The 3-year probability of non-relapse mortality (NRM) was 25·9%, that of relapse was 48·5%, that of GVHD-free and relapse-free survival (GRFS) was 17·8% and that of leukaemia-free survival (LFS) was 25·6%. In multivariate analysis, unrelated donor recipients more frequently had acute GVHD of grades II-IV [hazard ratio (HR) = 1·98, P = 0·017] and suffered less relapses (HR = 0·62, P = 0·01) than MSD recipients. Treatment with anti-T-cell antibodies reduced NRM (HR = 0·35, P = 0·01) and improved survival (HR = 0·49, P = 0·01), GRFS (HR = 0·37, P = 0·0004) and LFS (HR = 0·46, P = 0·005). Thus, sequential chemotherapy followed by RIC HSCT and use of anti-T-cell antibodies seems promising in patients with refractory AML.

  4. Histopathological Findings in Brains of Patients Who Died in the Acute Stage of Poor-grade Subarachnoid Hemorrhage

    PubMed Central

    SATOMI, Junichiro; HADEISHI, Hiromu; YOSHIDA, Yasuji; SUZUKI, Akifumi; NAGAHIRO, Shinji

    2016-01-01

    Patients with poor-grade aneurysmal subarachnoid hemorrhage (SAH) are likely to die due to irreversible acute-stage primary brain damage. However, the mechanism(s) and pathology responsible for their high mortality rate remain unclear. We report our findings on the brains of individuals who died in the acute stage of SAH. An autopsy was performed on the brains of 11 SAH patients (World Federation of Neurosurgical Societies grade 5) who died within 3 days of admission and who did not receive respiratory assistance. All brains were free of intracranial hematoma and hydrocephalus; all harbored ruptured aneurysms. In all brains, multiple infarcts with perifocal edema were scattered throughout the cortex and subcortical white matter of the whole brain. Infarcts with a patchy – were more often seen than infarcts with a wedge-shaped pattern. Microscopic examination revealed multiple areas with cytotoxic edema and neuronal death indicative of acute ischemic changes. Edema and congestion were more obvious in areas where the subarachnoid clot tightly adhered to the pia mater. Pathologically, the brains of deceased patients with acute poor-grade SAH were characterized by edema and multifocal infarcts spread throughout the whole brain; they were thought to be attributable to venous ischemia. Diffuse disturbance in venous drainage attributable to an abrupt increase in the intracranial pressure and focal disturbances due to tight adhesion of the subarachnoid clot to the pia mater, may contribute strongly to irreversible brain damage in the acute stage of SAH. PMID:27357086

  5. Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: considerations for the allogeneic transplantation therapy of leukemia and lymphoma.

    PubMed

    Fowler, D H; Gress, R E

    2000-07-01

    Allogeneic stem cell transplantation (SCT) represents a curative treatment option for patients with leukemia and lymphoma. T lymphocytes contained in the allograft mediate a graft-versus-leukemia (GVL) effect and prevent graft rejection; however, T cells also initiate graft-versus-host disease (GVHD). Identification of T cell populations which mediate a GVL effect and prevent rejection with reduced GVHD will likely improve transplantation outcome. T cells exist in four functionally-defined populations, the CD4+, Th1/Th2 and CD8+, Tc1/Tc2 subsets. Th1-type CD4 cells primarily secrete type I cytokines (IL-2 and IFN-gamma), whereas Th2 cells secrete type II cytokines (IL-4, IL-5, and IL-10). Similarly, the CD8+ Tc1 and Tc2 cells differentially secrete the type I and type II cytokines, respectively. In addition to cytokine secretion, Tc1 and Tc2 populations mediate cytolytic effects, with Tc1 cells utilizing both perforin- and fas-based killing pathways, whereas Tc2 cells primarily utilize perforin-mediated cytolysis. In murine transplantation models of graft rejection, GVHD, and GVL effects, we have evaluated such functional T cell subsets for their ability to differentially mediate and regulate transplantation responses. These studies demonstrate that donor Th2 cells do not initiate acute GVHD, and can regulate the GVHD mediated by unmanipulated donor T cells without impairing alloengraftment. Additional experiments have shown that allospecific donor Tc2 cells result in reduced GVHD, and mediate a significant GVL effect. Thirdly, we have demonstrated that non-host reactive Tc2 cells with veto-like activity can potently abrogate marrow rejection independent of GVHD. Together, these results demonstrate that functionally-defined donor Th2 and Tc2 populations play an important role in the regulation of GVHD, the prevention of graft rejection, and the mediation of GVL effects, and suggest that utilization of Th2 and Tc2 cells in clinical allogeneic SCT may have potential

  6. Serum proteomic profiling and haptoglobin polymorphisms in patients with GVHD after allogeneic hematopoietic cell transplantation

    PubMed Central

    McGuirk, Joseph; Hao, Gang; Hou, Weijian; Abhyankar, Sunil; Williams, Casey; Yan, Weisi; Yuan, Jianda; Guan, Xiuqin; Belt, Robert; Dejarnette, Shaun; Wieman, Jeffery; Yan, Ying

    2009-01-01

    We studied serum proteomic profiling in patients with graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) by two-dimensional gel electrophoresis (2-DE) and mass spectrometry analysis. The expression of a group of proteins, haptoglobin (Hp), alpha-1-antitrypsin, apolipoprotein A-IV, serum paraoxonase and Zn-alpha-glycoprotein were increased and the proteins, clusterin precursor, alpha-2-macroglobulin, serum amyloid protein precursor, sex hormone-binding globulin, serotransferrin and complement C4 were decreased in patients with extensive chronic GVHD (cGVHD). Serum haptoglobin (Hp) levels in patients with cGVHD were demonstrated to be statistically higher than in patients without cGVHD and normal controls (p < 0.01). We used immunoblotting and PCR in combination with 2-DE gel image analysis to determine Hp polymorphisms in 25 allo-HCT patients and 16 normal donors. The results demonstrate that patients with cGVHD had a higher incidence of HP 2-2 phenotype (43.8%), in comparison to the patients without cGVHD (0%) and normal donors (18.7%), suggesting the possibility that specific Hp polymorphism may play a role in the development of cGVHD after allo-HCT. In this study, quantitative serum Hp levels were shown to be related to cGVHD development. Further, the data suggest the possibility that specific Hp polymorphisms may be associated with cGVHD development and warrant further investigation. PMID:19379511

  7. Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes.

    PubMed

    Martino, Rodrigo; Caballero, María Dolores; Pérez-Simón, José Antonio; Simón, José Antonio Pérez; Canals, Carmen; Solano, Carlos; Urbano-Ispízua, Alvaro; Bargay, Joan; Léon, Angel; Sarrá, Josep; Sanz, Guillermo F; Moraleda, José María; Brunet, Salut; San Miguel, Jesús; Sierra, Jorge

    2002-09-15

    We report the results of a prospective study of a reduced-intensity conditioning (RIC) regimen followed by allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical sibling in 37 patients with acute myeloid leukemia (AML; n = 17) or myelodysplastic syndrome (MDS; n = 20). The median age was 57 years, and 22 (59%) were beyond the early phase of their disease. The incidence of grade II to IV acute graft-versus-host disease (GVHD) was 19% (5% grade III-IV), and the 1-year incidence of chronic extensive GVHD was 46%. With a median follow-up of 297 days (355 days in 24 survivors), the 1-year probability of transplant-related mortality was 5%, and the 1-year progression-free survival was 66%. The 1-year incidence of disease progression in patients with and without GVHD was 13% (95% CI, 4%-34%) and 58% (95% CI, 36%-96%), respectively (P =.008). These results suggest that a graft-versus-leukemia effect plays a crucial role in reducing the risk of relapse after a RIC allograft in AML and MDS.

  8. Acute and subchronic oral toxicity studies in rats with nanoscale and pigment grade titanium dioxide particles.

    PubMed

    Warheit, D B; Brown, S C; Donner, E M

    2015-10-01

    Data generated using standardized testing protocols for toxicity studies generally provide reproducible and reliable results for establishing safe levels and formulating risk assessments. The findings of three OECD guideline-type oral toxicity studies of different duration in rats are summarized in this publication; each study evaluated different titanium dioxide (TiO2) particles of varying sizes and surface coatings. Moreover, each study finding demonstrated an absence of any TiO2 -related hazards. To briefly summarize the findings: 1) In a subchronic 90-day study (OECD TG 408), groups of young adult male and female rats were dosed with rutile-type, surface-coated pigment-grade TiO2 test particles (d50 = 145 nm - 21% nanoparticles by particle number criteria) by oral gavage for 90 days. The no-adverse-effect level (NOAEL) for both male and female rats in this study was 1000 mg/kg bw/day, the highest dose tested. The NOAEL was determined based on a lack of TiO2 particle-related adverse effects on any in-life, clinical pathology, or anatomic/microscopic pathology parameters; 2) In a 28-day repeated-dose oral toxicity study (OECD TG 407), groups of young adult male rats were administered daily doses of two rutile-type, uncoated, pigment-grade TiO2 test particles (d50 = 173 nm by number) by daily oral gavage at a dose of 24,000 mg/kg bw/day. There were no adverse effects measured during or following the end of the exposure period; and the NOAEL was determined to be 24,000 mg/kg bw/day; 3) In an acute oral toxicity study (OECD TG 425), female rats were administered a single oral exposure of surface-treated rutile/anatase nanoscale TiO2 particles (d50 = 73 nm by number) with doses up to 5000 mg/kg and evaluated over a 14-day post-exposure period. Under the conditions of this study, the oral LD50 for the test substance was >5000 mg/kg bw. In summary, the results from these three toxicity studies - each with different TiO2 particulate-types, demonstrated an absence of

  9. High-Grade Acute Organ Toxicity as a Positive Prognostic Factor in Primary Radiochemotherapy for Anal Carcinoma

    SciTech Connect

    Wolff, Hendrik Andreas; Raus, Ismene; Jung, Klaus; Schueler, Phillip; Herrmann, Markus Karl; Hennies, Steffen; Vorwerk, Hilke; Hille, Andrea; Hess, Clemens Friedrich; Christiansen, Hans

    2011-04-01

    Purpose: To test for a possible correlation between high-grade acute organ toxicity during primary radiochemotherapy and treatment outcome for patients with anal carcinoma. Methods and Materials: From 1991 to 2009, 72 patients with anal carcinoma were treated at our department (10 patients had stage I, 28 patients had stage II, 11 patients had stage IIIA, and 13 patients had stage IIIB cancer [Union Internationale Contre le Cancer criteria]). All patients received normofractionated (1.8 Gy/day, five times/week) whole-pelvis irradiation including iliac and inguinal lymph nodes with a cumulative dose of 50.4 Gy. Concomitant chemotherapy regimen consisted of two cycles of 5-fluorouracil (1,000 mg/m{sup 2}total body surface area (TBSA)/day as continuous intravenous infusion on days 1-4 and 29-32) and mitomycin C (10 mg/m{sup 2}/TBSA, intravenously on days 1 and 29). Toxicity during treatment was monitored weekly, and any incidence of Common Toxicity Criteria (CTC) grade of {>=}3 for skin reaction, cystitis, proctitis, or enteritis was assessed as high-grade acute organ toxicity for later analysis. Results: We found significant correlation between high-grade acute organ toxicity and overall survival, locoregional control, and stoma-free survival, which was independent in multivariate analysis from other possible prognostic factors: patients with a CTC acute organ toxicity grade of {>=}3 had a 5-year overall survival rate of 97% compared to 30% in patients without (p < 0.01, multivariate analysis; 97% vs. 48%, p = 0.03 for locoregional control, and 95% vs. 59%, p = 0.05 for stoma-free survival). Conclusions: Our data indicate that normal tissue and tumor tissue may behave similarly with respect to treatment response, since high-grade acute organ toxicity during radiochemotherapy showed itself to be an independent prognostic marker in our patient population. This hypothesis should be further analyzed by using biomolecular and clinical levels in future clinical trials.

  10. A high migratory capacity of donor T-cells in response to the lymph node homing receptor CCR7 increases the incidence and severity of GvHD.

    PubMed

    Portero-Sainz, I; Gómez-García de Soria, V; Cuesta-Mateos, C; Fernández-Arandojo, C; Vega-Piris, L; Royg, M; Colom-Fernández, B; Marcos-Jiménez, A; Somovilla-Crespo, B; Ramírez-Mengíbar, A; López-Huete, V; de Rosendo-Serrano, A; Kreutzman, A; Muñoz-Calleja, C

    2017-01-23

    The pathogenesis of GvHD involves migration of donor T-cells into the secondary lymphoid organs in the recipient, which is steered by two homing molecules, CD62L and CCR7. Therefore, we investigated whether the migratory capacity of donor T-cells is associated with GvHD. This single center prospective study included 85 donor-recipient pairs. In vitro chemotaxis assays of the lymphocytes of the apheresis product were performed in parallel to the analysis of CD62L and CCR7 by flow cytometry. The migratory index to the CCR7 ligands, CCL19 and CCL21, was higher in T-cells from donors whose recipients will develop GvHD. Similarly, the acute GvHD (aGvHD) group received higher percentage of CD4+CCR7+ T-cells, whereas chronic GvHD (cGvHD) patients were transplanted with higher percentages of CD8+CCR7+ T-cells compared with the non-GvHD group. These results were confirmed when patients were subdivided according to degrees of severity. Further, multivariate analysis confirmed that the proportions of CCR7+ CD4+ and CCR7+ CD8+ T-cells are risk factors for the development and severity of aGvHD and cGvHD, respectively. Functional experiments demonstrated that CCR7+ T-cells exhibited higher potential for activation than CCR7- T-cells did. We therefore propose that the selective depletion of CCR7-expressing T-cells may be an effective preventive therapy for GvHD.Bone Marrow Transplantation advance online publication, 23 January 2017; doi:10.1038/bmt.2016.342.

  11. Total Body Irradiation without Chemotherapy as Conditioning for an Allogeneic Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia

    PubMed Central

    Altouri, Sultan; Allan, David; Atkins, Harry; Huebsch, Lothar; Maze, Dawn; Samant, Rajiv; Bredeson, Christopher

    2016-01-01

    Current therapies for acute myeloid leukemia (AML), failing induction, are rarely effective. We report our experience in 4 patients with AML who received 16 Gy TBI prior to allogeneic hematopoietic cell transplantation (alloHCT), between June 2010 and May 2011. Patients were 20 to 55 years of age, 2 with relapsed disease and 2 with AML failing induction. An HLA-matched graft from related or unrelated donor was infused on day 0. All but one, who received a CD34+-selected graft, received methotrexate and tacrolimus +/− antithymocyte globulin, as GVHD prophylaxis. The other patient received tacrolimus alone. Neutrophil and platelet engraftment occurred at a median of 18 and 14 days, respectively. Patients were discharged at a median of 28 days. There were no unexpected toxicities in the first 30 days. One patient had cytomegalovirus (CMV) viremia and anorexia, at two months. One patient had grade 2 acute GVHD of the skin. One patient developed chronic GVHD of the eyes, mouth, skin, joints, and lung at 4 months. Two patients died from relapse of their leukemia at days 65 and 125. Two patients remain in remission beyond day 1500. 16 Gy TBI followed by an alloHCT for AML, failing induction, is feasible and tolerable. PMID:27957357

  12. Staffing in acute hospital wards: part 2. Relationships between grade mix, staff stability and features of ward organizational environment.

    PubMed

    Adams, Ann; Bond, Senga

    2003-09-01

    This paper explores relationships between grade mix, staff stability, care organization and nursing practice. The data were collected in the mid-1990s from a nationally representative sample of 100 acute hospital wards and 825 nurses. Analyses provides important insights for managers seeking to achieve the strategic aims set out in consecutive National Health Service (NHS) human resource management policies. Hypotheses about ward clinical grade mix were not well supported. Where there was rich grade mix, nurses reported better collaborative working with other disciplines and greater influence. However, it was expected that wards practising 'devolved' nursing would have a richer grade mix and that the latter would lead to more innovative practice and nurses experiencing greater job satisfaction. No evidence to support any of these hypotheses was found although the opposite scenario - a link between poor grade mix, unprogressive practice and perceived lower standards of care - was supported. Wards practising the 'devolved' system rely on adequate numbers of nurses rather than a rich grade mix, and do not necessarily provide a more stable, retentive work environment for nurses. By contrast, findings about staff stability were largely as expected. A strong link between staff stability and standards of professional nursing practice was found, indicating that staff stability is more important than a rich grade mix for achieving innovative, research-based practice. However, staff instability undermined cohesion with nurse colleagues, collaborative working with doctors, and nurses' ability to cope with the workload. Overall, both the papers demonstrate that staffing resources and prevailing ethos of care are more important predictors of care processes and job satisfaction than organizational systems. They identify the detrimental effects on nurses and their work of having few staff and a weak grade mix, and the importance of staff stability. Higher standards of nursing

  13. Diagnosis and differential diagnosis of hepatic graft versus host disease (GVHD)

    PubMed Central

    Matsukuma, Karen E.; Wei, Dongguang; Sun, Kai; Ramsamooj, Rajendra

    2016-01-01

    Graft versus host disease (GVHD) is a common complication following allogeneic hematopoietic cell transplantation (HCT) that typically manifests as injury to the skin, gastrointestinal mucosa, and liver. In some cases, hepatic GVHD may be histologically indistinguishable from other disorders such as infection and drug-induced liver injury (DILI). Additionally, clinical signs and symptoms are frequently confounded by the superimposed effects of pretransplant chemoradiotherapy, immunotherapy (IT) (targeted to the underlying malignancy), GVHD prophylaxis, and infection. Thus, careful attention to and correlation with clinical findings, laboratory values, and histologic features is essential for diagnosis. This review, aimed at the practicing pathologist, will discuss current clinical and histologic criteria for GVHD, the approach to diagnosis of hepatic GVHD, and features helpful for distinguishing it from other entities in the differential diagnosis. PMID:27034810

  14. Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome.

    PubMed

    Mawad, Raya; Gooley, Ted A; Rajendran, Joseph G; Fisher, Darrell R; Gopal, Ajay K; Shields, Andrew T; Sandmaier, Brenda M; Sorror, Mohamed L; Deeg, Hans Joachim; Storb, Rainer; Green, Damian J; Maloney, David G; Appelbaum, Frederick R; Press, Oliver W; Pagel, John M

    2014-09-01

    We treated patients under age 50 years with iodine-131 ((131)I)-anti-CD45 antibody combined with fludarabine and 2 Gy total body irradiation to create an improved hematopoietic cell transplantation (HCT) strategy for advanced acute myeloid leukemia or high-risk myelodysplastic syndrome patients. Fifteen patients received 332 to 1561 mCi of (131)I, delivering an average of 27 Gy to bone marrow, 84 Gy to spleen, and 21 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no dose-limiting toxicity was observed. Marrow doses were arbitrarily capped at 43 Gy to avoid radiation-induced stromal damage; however, no graft failure or evidence of stromal damage was observed. Twelve patients (80%) developed grade II graft-versus-host disease (GVHD), 1 patient developed grade III GVHD, and no patients developed grade IV GVHD during the first 100 days after HCT. Of the 12 patients with chronic GVHD data, 10 developed chronic GVHD, generally involving the skin and mouth. Six patients (40%) are surviving after a median of 5.0 years (range, 4.2 to 8.3 years). The estimated survival at 1 year was 73% among the 15 treated patients. Eight patients relapsed, 7 of whom subsequently died. The median time to relapse among these 8 patients was 54 days (range, 26 to 1364 days). No cases of nonrelapse mortality were observed in the first year after transplantation. However, 2 patients died in remission from complications of chronic GVHD and cardiomyopathy, at 18 months and 14 months after transplantation, respectively. This study suggests that patients may tolerate myeloablative doses >28 Gy delivered to the liver using (131)I-anti-CD45 antibody in addition to standard reduced-intensity conditioning. Moreover, the arbitrary limit of 43 Gy to the marrow may be unnecessarily conservative, and continued escalation of targeted radioimmunotherapy doses may be feasible to further reduce relapse.

  15. Acute gastrointestinal effects of graded levels of copper in drinking water.

    PubMed

    Pizarro, F; Olivares, M; Uauy, R; Contreras, P; Rebelo, A; Gidi, V

    1999-02-01

    The objective of this study was to determine the acute gastrointestinal effects caused by the consumption of drinking water containing graded levels of added copper. Sixty healthy, adult women were randomly assigned to receive copper [Cu(II)] at four concentrations in their drinking water following a Latin-square design. Each group (n = 15) received tap water with no added copper, 1, 3, and 5 mg Cu/l of added copper sulfate for a 2-week study period, followed by 1 week of standard tap water. The subjects recorded their water consumption and gastrointestinal symptoms daily on a special form. The average daily consumption of water was 1.64 liters per subject, regardless of the amount of copper added. Final serum copper, ceruloplasmin, and liver enzymes were measured in all subjects and were not different from baseline concentrations. Twenty-one subjects (35%) recorded gastrointestinal disturbances sometime during the study, 9 had diarrhea, some with abdominal pain and vomiting, and 12 subjects presented abdominal pain, nausea, or vomiting. There was no association between copper levels in drinking water and diarrhea. However, nausea, abdominal pain, or vomiting were significantly related to copper concentrations in water. The recorded incidence rate of these symptoms was 5, 2, 17, and 15% while ingesting water with 0, 1, 3, and 5 mg Cu/l, respectively (overall [chi]2 = 11.3, p<0.01; Cu [less than/equal to]1 mg/l versus Cu [Greater than/equal to]3 mg/l, [chi]2, p<0.01). When subjects interrupted their consumption of drinking water with added copper, most symptoms disappeared. We conclude that under the conditions of the study, there was no association between aggregate copper in drinking water within the range of 0-5 mg/l and diarrhea, but a [Greater than/equal to]3 mg Cu/l level of ionized copper was associated with nausea, abdominal pain, or vomiting. Additional studies with sufficient numbers of subjects are needed to define thresholds for specific gastrointestinal

  16. Low risk of chronic graft-versus-host disease and relapse associated with T cell-depleted peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission: results of the blood and marrow transplant clinical trials network protocol 0303.

    PubMed

    Devine, Steven M; Carter, Shelly; Soiffer, Robert J; Pasquini, Marcelo C; Hari, Parameswaran N; Stein, Anthony; Lazarus, Hillard M; Linker, Charles; Stadtmauer, Edward A; Alyea, Edwin P; Keever-Taylor, Carolyn A; O'Reilly, Richard J

    2011-09-01

    Graft-versus-host disease (GVHD) is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft, but its role in the treatment of patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) in complete remission (CR) remains unclear. We performed a phase 2 single-arm multicenter study to evaluate the role of TCD in AML patients in CR1 or CR2 up to age 65 years. The primary objective was to achieve a disease-free survival (DFS) rate of >75% at 6 months posttransplantation. A total of 44 patients with AML in CR1 (n = 37) or CR2 (n = 7) with a median age of 48.5 years (range, 21-59 years) received myeloablative chemotherapy and fractionated total body irradiation (1375 cGy) followed by immunomagnetically selected CD34-enriched, T cell‒depleted allografts from HLA-identical siblings. No pharmacologic GVHD prophylaxis was given. All patients engrafted. The incidence of acute GVHD grade II-IV was 22.7%, and the incidence of extensive chronic GVHD was 6.8% at 24 months. The relapse rate for patients in CR1 was 17.4% at 36 months. With a median follow-up of 34 months, DFS for all patients was 82% at 6 months, and DFS for patients in CR1 was 72.8% at 12 months and 58% at 36 months. HCT after myeloablative chemoradiotherapy can be performed in a multicenter setting using a uniform method of TCD, resulting in a low risk of extensive chronic GVHD and relapse for patients with AML in CR1.

  17. Unrelated Cord Blood Transplantation for Acute Leukemia Diagnosed in the First Year of Life: Outcomes and Risk Factor Analysis.

    PubMed

    Ruggeri, Annalisa; Volt, Fernanda; Locatelli, Franco; Michel, Gerard; Diaz de Heredia, Cristina; Abecasis, Manuel; Zecca, Marco; Vora, Ajay; Yakouben, Karima; O'Brien, Tracey A; Giardino, Stefano; Cornish, Jacqueline; Rocha, Vanderson; Peters, Christina; Bader, Peter; Gluckman, Eliane; Dalle, Jean Hugues

    2017-01-01

    Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n = 157) or acute myelogenous leukemia (AML; n = 95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40% ± 3% and of 4-year chronic GVHD was 13% ± 2%. CIF of 1-year transplant-related mortality was 23% ± 3% and of 4-year relapse was 27% ± 3%. Leukemia-free-survival (LFS) at 4 years was 50% ± 3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P = .001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P = .001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P = .012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL.

  18. Pathophysiology of GvHD and Other HSCT-Related Major Complications

    PubMed Central

    Ghimire, Sakhila; Weber, Daniela; Mavin, Emily; Wang, Xiao nong; Dickinson, Anne Mary; Holler, Ernst

    2017-01-01

    For over 60 years, hematopoietic stem cell transplantation has been the major curative therapy for several hematological and genetic disorders, but its efficacy is limited by the secondary disease called graft versus host disease (GvHD). Huge advances have been made in successful transplantation in order to improve patient quality of life, and yet, complete success is hard to achieve. This review assimilates recent updates on pathophysiology of GvHD, prophylaxis and treatment of GvHD-related complications, and advances in the potential treatment of GvHD. PMID:28373870

  19. Indium-111-labeled autologous leukocyte scanning in gastrointestinal graft versus host disease (GVHD)

    SciTech Connect

    Saverymuttu, S.H.; Peters, A.M.; O'Brien, C.; Chadwick, V.S.; Lavender, J.P.; Goldman, J.M.; Gordon-Smith, E.C.; Hodgson, H.J.

    1986-08-01

    The technique of scanning with indium-111 autologous leukocytes has been used to assess gastrointestinal graft-versus-host disease (GVHD) following allogenic marrow transplantation. In patients with active disease, abdominal scans showed extensive abnormal localization in the bowel, while in those whose disease was quiescent after responding to treatment, scans showed localized ileocecal involvement. Rectal histology showed excellent agreement with scanning in the diagnosis of GVHD, but in three of six cases with active disease underestimated disease severity. Indium-111 leukocyte scanning is a useful noninvasive technique for the diagnosis and assessment of gut GVHD.

  20. Improved accuracy of acute graft-versus-host disease staging among multiple centers.

    PubMed

    Levine, John E; Hogan, William J; Harris, Andrew C; Litzow, Mark R; Efebera, Yvonne A; Devine, Steven M; Reshef, Ran; Ferrara, James L M

    2014-01-01

    The clinical staging of acute graft-versus-host disease (GVHD) varies significantly among bone marrow transplant (BMT) centers, but adherence to long-standing practices poses formidable barriers to standardization among centers. We have analyzed the sources of variability and developed a web-based remote data entry system that can be used by multiple centers simultaneously and that standardizes data collection in key areas. This user-friendly, intuitive interface resembles an online shopping site and eliminates error-prone entry of free text with drop-down menus and pop-up detailed guidance available at the point of data entry. Standardized documentation of symptoms and therapeutic response reduces errors in grade assignment and allows creation of confidence levels regarding the diagnosis. Early review and adjudication of borderline cases improves consistency of grading and further enhances consistency among centers. If this system achieves widespread use it may enhance the quality of data in multicenter trials to prevent and treat acute GVHD.

  1. Nutritional support in patients with GVHD of the digestive tract: state of the art.

    PubMed

    van der Meij, B S; de Graaf, P; Wierdsma, N J; Langius, J A E; Janssen, J J W M; van Leeuwen, P A M; Visser, O J

    2013-04-01

    An important complication of allo-SCT is GVHD, which commonly affects the skin, liver and digestive tract. Clinical symptoms of GVHD of the digestive tract (GVHD-DT) include excessive diarrhoea, abdominal pain and cramps, nausea and vomiting, gastrointestinal bleeding, dysphagia, and weight loss. Treatment is complicated and regarding nutritional support, only a few guidelines are available. Our aim was to critically appraise the literature on nutritional assessment, nutritional status and nutritional support for patients with GVHD-DT. Evidence shows that GVHD-DT is often associated with malnutrition, protein losing enteropathy, magnesium derangements, and deficiencies of zinc, vitamin B12 and vitamin D. Limited evidence exists on derangements of magnesium, resting energy expenditure, bone mineral density and pancreatic function, and some beneficial effects of n-3 polyunsaturated fatty acids and pancreatic enzyme replacement therapy. Expert opinions recommend adequate amounts of energy, at least 1.5 g protein/kg body weight, supplied by total parenteral nutrition in cases of severe diarrhoea. When diarrhoea is <500 mL a day, a stepwise oral upgrade diet can be followed. No studies exist on probiotics, prebiotics, dietary fibre and immunonutrition in GVHD-DT patients. Future research should focus on absorption capacity, vitamin and mineral status, and nutritional support strategies.

  2. Curcumin Attenuates Acute Graft-versus-Host Disease Severity via In Vivo Regulations on Th1, Th17 and Regulatory T Cells

    PubMed Central

    Lee, Sung-Hee; Yang, Eun-Ji; Min, Jun-Ki; Cho, Seok-Goo; Yang, Chul-Woo; Park, Sung-Hwan; Kim, Ho-Youn; Cho, Mi-La

    2013-01-01

    Background In this study we examined the in vivo and in vitro effects and mechanisms of action of curcumin on the development of acute graft-versus-host disease (GVHD) using a murine model. Methodology/Principal Findings Mixed lymphocyte reactions were used to determine the in vitro effects of curcumin. Treatment with curcumin attenuated alloreactive T cell proliferation and inhibited the production of interferon (IFN)-γ and interleukin (IL)-17. In a murine acute GVHD model, transplantation of curcumin-treated allogeneic splenocytes into irradiated recipient mice significantly reduced the clinical severity scores of acute GVHD manifested in the liver, skin, colon and lung as compared with animals receiving vehicle-treated splenocytes. c-Fos and c-Jun expression levels in the skin and intestine, which are major target organs, were analyzed using immunohistochemical staining. Expression of both proteins was reduced in epithelial tissues of skin and intestine from curcumin-treated GVHD animals. The IFN-γ-expressing CD4+ splenocytes and IFN-γ-expressing lymph node cells were dramatically decreased in curcumin-treated mice. In contrast, CD4+Foxp3+ splenocytes were increased in the curcumin-treated acute GVHD animals. Flow cytometric analysis revealed that animals transplanted with curcumin-treated allogeneic splenocytes showed increased populations of CD4+ regulatory T cells (Tregs) as well as CD8+ Treg cells, compared to animals administered vehicle-treated splenocytes. Curcumin-treated acute GVHD animals could have a change in B cell subpopulations. Conclusion/Significance In the present study, we investigated the efficacy and mechanism of action of curcumin treatment against acute GVHD. The acute GVHD mice administered with curcumin-treated splenocytes showed significantly reduced severity of acute GVHD. Curcumin exerted in vivo preventive effects on acute GVHD by reciprocal regulation of T helper 1 (Th1) and Treg (both CD4+ and CD8+ Treg) cell lineages as well as

  3. Acute graft-versus-host disease in pancreas transplantation: a comparison of two case presentations and a review of the literature.

    PubMed

    Weinstein, Adam; Dexter, David; KuKuruga, Debra L; Philosophe, Benjamin; Hess, John; Klassen, David

    2006-07-15

    As a complication of solid organ transplantation, acute graft-versus-host disease (GVHD) is most associated with small bowel and liver transplants. We present two cases of acute GVHD following pancreas transplantation. Case 1 was a 27-year-old female who underwent cadaveric pancreas transplant 9 months after a successful live donor kidney transplant. Case 2 was a 38-year-old male who received a simultaneous cadaveric pancreas and live donor kidney transplant. Both patients presented within 30 days of transplant with nonspecific symptoms. Rejection and infection were ruled out. Both subjects had progressive decline in mentation associated with pancytopenia and hyperbilirubinemia. Rash was not present until late in their hospital course. Skin biopsies demonstrated mixed chimerism with pancreas donor DNA diagnostic of GVHD. Acute GVHD is a rare, often fatal, complication of pancreas transplantation, and its presentation appears to differ from acute GVHD associated with stem cell transplantation.

  4. World Health Organization Grade II Oligodendroglioma Occurring after Successful Treatment for Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Yoon, Sang-In; Park, Dong-Hyuk; Kang, Shin-Hyuk; Park, Jung-Yul; Chung, Yong-Gu

    2016-01-01

    When treating childhood acute lymphoblastic leukemia (ALL), secondary neoplasms are a significant long term problem. Radiation is generally accepted to be a major cause of the development of secondary neoplasms. Following treatment for ALL, a variety of secondary tumors, including brain tumors, hematologic malignancies, sarcomas, thyroid cancers, and skin cancers have been reported. However, oligodendroglioma as a secondary neoplasm is extremely rare. Herein we present a case of secondary oligodendroglioma occurring 13 years after the end of ALL treatment. PMID:27867928

  5. T-cell-replete haploidentical stem cell transplantation is highly efficacious for relapsed and refractory childhood acute leukaemia

    PubMed Central

    Kobayashi, S; Ito, M; Sano, H; Mochizuki, K; Akaihata, M; Waragai, T; Ohara, Y; Hosoya, M; Ohto, H; Kikuta, A

    2014-01-01

    Background Despite improvements in first-line therapies, the outcomes of relapsed or refractory childhood acute leukaemia that has not achieved complete remission after relapse, has relapsed after stem cell transplantation (SCT), has primary induction failure and has relapsed with a very unfavourable cytogenetic risk profile, are dismal. Objectives and Methods We evaluated the feasibility and efficacy of T-cell-replete haploidentical peripheral blood stem cell transplantation (haplo-SCT) with low-dose anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate and prednisolone (PSL) in 14 paediatric patients with high-risk childhood acute leukaemia. Results All patients achieved complete engraftment. The median time to reaching an absolute neutrophil count of more than 0.5 × 109 L−1 was 14 days. Acute graft-vs-host disease (aGVHD) of grades II–IV and III–IV developed in 10 (71%) and 2 (14%) patients, respectively. Treatment-related mortality and relapse occurred in one (7%) patient and six (43%) patients, respectively. Eleven patients were alive and seven of them were disease-free with a median follow-up of 36 months (range: 30–159 months). The probability of event-free survival after 2 years was 50%. Conclusion These findings indicate that T-cell-replete haplo-SCT, with low-dose ATG and PSL, provides sustained remission with an acceptable risk of GVHD in paediatric patients with advanced haematologic malignancies. PMID:25224311

  6. Assessment of dry eye in a GVHD murine model: Approximation through tear osmolarity measurement.

    PubMed

    Martínez-Carrasco, Rafael; Sánchez-Abarca, Luis Ignacio; Nieto-Gómez, Cristina; García, Elisabet Martín; Ramos, Teresa L; Velasco, Almudena; Sánchez-Guijo, Fermín; Aijón, José; Hernández-Galilea, Emiliano

    2017-01-01

    Dry eye disease is one of the most frequent pathological events that take place in the course of the graft versus host disease (GVHD), and is the main cause of deterioration in quality of life for patients. Thus, demonstration of dry eye signs in murine models of oGVHD is crucial for the validation of these models for the study of the disease. Given the increasing evidence that tear osmolarity is an important player of dry eye disease, our purpose in this study was to validate the use of a reliable method to assess tear osmolarity in mice: the electrical impedance method. Then, we wanted to test its utility with an oGVHD model. Tear volume assessment was also performed, using the phenol red thread test. We found differences in tear osmolarity in mice that received a transplant with cells from bone marrow and spleen (the GVHD group) when compared with mice that only received bone marrow cells (the BM group) at day 7 (362 ± 8 mOsm/l and 345 ± 9 mOsm/l respectively; P < 0.01) and day 21 (348 ± 19 mOsm/l vs. 326 ± 15 mOsm/l; P < 0.05). We found also differences in tear volume at day 14 (2.30 ± 0.61 mm in oGVHD group and 2.89 ± 0.62 mm in BM group; P = 0.06) and at day 21 (2.10 ± 0.30 mm in oGVHD group and 2.89 ± 0.32 mm in BM group; P < 0.01). Besides this, we observed reduction in epithelial thickness between the GVHD and BM groups (37.0 ± 6.2 μm and 43.6 ± 3.3 μm respectively; P < 0.05). These data show the usefulness of the electrical impedance method to measure tear osmolarity in mice. We can also conclude that this oGVHD model mimics the tear film alterations found in human dry eye disease, what contributes to give relevance to this model for the study of GVHD.

  7. Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity

    PubMed Central

    Ghosh, Arnab; Dogan, Yildirim; Moroz, Maxim; Holland, Amanda M.; Yim, Nury L.; Rao, Uttam K.; Young, Lauren F.; Tannenbaum, Daniel; Masih, Durva; Velardi, Enrico; Tsai, Jennifer J.; Jenq, Robert R.; Penack, Olaf; Hanash, Alan M.; Smith, Odette M.; Piersanti, Kelly; Lezcano, Cecilia; Murphy, George F.; Liu, Chen; Palomba, M. Lia; Sauer, Martin G.; Sadelain, Michel; Ponomarev, Vladimir; van den Brink, Marcel R.M.

    2013-01-01

    Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL+ T cells into mouse models of allo-HSCT. We found that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL+ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL+ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro–generated TRAIL+ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD. PMID:23676461

  8. Apoptotic signaling through Fas and TNF receptors ameliorates GVHD in mobilized peripheral blood grafts.

    PubMed

    Mizrahi, K; Yaniv, I; Ash, S; Stein, J; Askenasy, N

    2014-05-01

    Mobilized peripheral blood (mPB) is a prevalent source of hematopoietic progenitors for transplantation; however, allogeneic and haploidentical transplants are often accompanied by severe GVHD. Following the observation that murine GVHD is ameliorated by pretransplant donor cell exposure to Fas-ligand (FasL) without host-specific sensitization, we assessed the susceptibility of mPB cells to spontaneous and receptor-induced apoptosis as a possible approach to GVHD prophylaxis. Short incubation for 4 h resulted in spontaneous apoptosis of 50% of the T and B lymphocytes and 60% myeloid cells. Although expression of Fas and TNF-R1 was proportionate to fractional apoptosis, cell death was dominated by spontaneous apoptosis. Functional assays revealed that the death receptors modulated mPB graft composition as compared with incubation in medium, without detectable quantitative variations. Removal of dead cells increased the frequency of mPB myeloid progenitors (P<0.001 vs medium), and recipients of mPB exposed to death ligands displayed reduced GVHD (P<0.01 vs medium) and improved survival following lipopolysacharide stimulation. mPB grafts exposed to the apoptotic challenge retained SCID reconstituting potential and graft versus tumor activity. These data emphasize that short-term exposure of mPB grafts to an apoptotic challenge is effective in reduction of GVHD effector activity.

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

    PubMed Central

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

    2015-01-01

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

  10. Vorinostat, Tacrolimus, and Methotrexate in Preventing GVHD After Stem Cell Transplant in Patients With Hematological Malignancies

    ClinicalTrials.gov

    2015-10-13

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Graft Versus Host Disease; Intraocular Lymphoma; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous

  11. Preengraftment serum C-reactive protein (CRP) value may predict acute graft-versus-host disease and nonrelapse mortality after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Fuji, Shigeo; Kim, Sung-Won; Fukuda, Takahiro; Mori, Shin-ichiro; Yamasaki, Satoshi; Morita-Hoshi, Yuriko; Ohara-Waki, Fusako; Heike, Yuji; Tobinai, Kensei; Tanosaki, Ryuji; Takaue, Yoichi

    2008-05-01

    In a mouse model, inflammatory cytokines play a primary role in the development of acute graft-versus-host disease (aGVHD). Here, we retrospectively evaluated whether the preengraftment C-reactive protein (CRP) value, which is used as a surrogate marker of inflammation, could predict posttransplant complications including GVHD. Two hundred twenty-four adult patients (median age, 47 years; range: 18-68 years) underwent conventional stem cell transplantation (CST, n = 105) or reduced-intensity stem cell transplantation (RIST, n = 119). Patients were categorized according to the maximum CRP value during neutropenia: the "low-CRP" group (CRP < 15 mg/dL, n = 157) and the "high-CRP" group (CRP >or= 15 mg/dL, n = 67). The incidence of documented infections during neutropenia was higher in the high-CRP group (34% versus 17%, P = .004). When patients with proven infections were excluded, the CRP value was significantly lower after RIST than after CST (P = .017) or after related than after unrelated transplantation (P < .001). A multivariate analysis showed that male sex, unrelated donor, and HLA-mismatched donor were associated with high CRP values. The high-CRP group developed significantly more grade II-IV aGVHD (P = .01) and nonrelapse mortality (NRM) (P < .001), but less relapse (P = .02). The present findings suggest that the CRP value may reflect the net degree of tissue damage because of the conditioning regimen, infection, and allogeneic immune reactions, all of which lead to subsequent aGVHD and NRM.

  12. Return to Sports after Acute Simultaneous Reconstruction of Anterior Cruciate Ligament Injury and Grade III Medial Collateral Ligament Injury

    PubMed Central

    Bertona, Agustin; Zicaro, Juan Pablo; Viescas, Juan Manuel Gonzalez; Atala, Nicolas; Yacuzzi, Carlos; Costa-Paz, Matias

    2017-01-01

    Objectives: Combined Anterior Cruciate Ligament (ACL) injury and Medial Collateral Ligament (MCL) injury account for 20% of knee ligament lesions. Conservative treatment of MCL and surgical ACL reconstruction are generally recommended. Significant medial instability after non-surgical management of MCL can lead to ACL reconstruction failure. The optimal management for athletes with combined ACL-MCL injuries remains controversial. The purpose of this study was to analyze the functional and clinical evolution of patients who underwent combined ACL-MCL surgery and their return-to-sport level with minimum 2-years follow-up. Methods: A total of 20 athletes with acute simultaneous ACL/Grade III MCL reconstructions were treated between March 2006 and January 2014. The minimum follow-up time was 24 months. Subjective functional results (IKDC, Lysholm), range of motion, anterior-medial and rotational stability (Lachmann, Pivot Shift, valgus stress) were evaluated. The ability to return to sport (Tegner) and the level achieved was recorded. Results: All patients significantly improved functional scores and stability tests. The mean subjective IKDC score improved from 37.7 ± 12.9 (range 21-69) preoperatively to 88.21 ± 4.47 (range 80-96) postoperatively (P <0.05). The average Lysholm score was 40.44 ± 10.58 (range 27-65) preoperatively and 90.83 ± 3.38 (range 84-95) postoperatively (P <0.05). Valgus and sagittal laxity was not observed (IKDC A 92% B 8%) at final follow-up. All patients had normal/nearly normal (IKDC A or B) mobility. All patients returned to sports; 90% reached the level they had prior to the ligamentous injury. Of all competitive athletes, 66% achieved the same level of sport. Conclusion: In athletes with acute ACL-Grade III MCL lesions, an early simultaneous reconstruction can significantly improve the medial and sagittal stability of the knee. This procedure resulted in excellent functional outcomes, with return to the same level of sports in the

  13. [Research Progress on Notch Signal Pathway in Acute Graft-Versus-Host Disease -Review].

    PubMed

    Guo, Dong-Mei; Li, Ban-Ban; Li, Chun-Pu; Teng, Qing-Liang

    2017-02-01

    The Notch signaling pathway is a highly conserved cell signaling system that plays an essential role in many biological processes. Notch signaling regulates multiple aspects of hematopoiesis, especially during T cell develop-ment. Recent data suggest that Notch also regulates mature T cell differentiation and function. The latest data show that Notch also plays an essential role in alloreactive T cells mediating acute graft-versus-host disease (aGVHD), the most severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Notch inhibition in donor-derived T cells or blockade of individual Notch ligands and receptors after transplantation can reduce GVHD severity and mortality in mouse models of allo-HSCT, without causing global immunosuppression. These findings indicate Notch in T cells as an attractive therapeutic target to control aGVHD. In this article, the pathophysiology of aGVHD, the Notch signal pathway and aGVHD are reviewed.

  14. Kinetic and organ-specific patterns of cytokine expression in acute graft-versus-host disease.

    PubMed

    Baker, K S; Allen, R D; Roths, J B; Sidman, C L

    1995-04-01

    Although many cytokines have been previously implicated in graft-versus-host disease (GVHD), no study to date has comprehensively evaluated their expression over time or in different tissues affected by GVHD. Using a semi-quantitative reverse transcriptase-PCR technique and a murine model of acute GVHD, we have evaluated the expression levels of mRNA for a wide range of cytokines in spleen, gut and liver tissues at weekly intervals after bone marrow transfer. The earliest cytokine responses seen were increases in IL-2, IL-10, IFN-gamma, MIP-1 alpha and TNF-alpha in the spleen, suggesting a primarily Th1 pathway. Other cytokines (IL-1 alpha, IL-10 and MIP-1 alpha) were persistently elevated in GVHD mice, but were variable depending on the tissue. These data demonstrate that a wide range of cytokines are involved in the GVHD response and that their kinetic pattern of expression is different in various affected tissues.

  15. IL-22 promoted CD3+ T cell infiltration by IL-22R induced STAT3 phosphorylation in murine acute graft versus host disease target organs after allogeneic bone marrow transplantation.

    PubMed

    Zhao, Kai; Ruan, Suhong; Tian, Yu; Zhao, Dongmei; Chen, Chong; Pan, Bin; Yan, Zhiling; Yin, Lingling; Zhu, Shengyun; Xu, Kailin

    2016-10-01

    Graft versus host disease (GVHD) is a life threatening complication of bone marrow stem cell transplantation, in which considerable numbers of proinflammatory cytokines secreted by allo-reactive donor T cells are involved. We and other previous studies have found that interleukin-22 (IL-22) was able to aggravate the target organs damage of GVHD. However, the mechanism and the signal pathway of IL-22 in murine acute GVHD was not clear. Here, we observed that compared with GVHD group, more serious pathological damage and more CD3(+) T cells infiltrated in GVHD target organs were detected in the mice injected with IL-22. Meanwhile, transcription factor T-bet, RORγt and AhR respectively associated with Th1, Th17 and Th22 cells changed in varying degrees in different GVHD target organs. Furthermore, the increased expression of IL-22R and its downstream protein P-STAT3 were detected in GVHD mice with IL-22 treated. These results suggested that the pathological role of IL-22 in GVHD target organs contribute to exogenous injected IL-22 as well as secreted IL-22 from the infiltrated allo-reactive effector T cells. In addition, the IL-22R-STAT3 pathway may play important role in GVHD tissue injury and target this way may yield new approaches for reduction of GVHD.

  16. Fecal calprotectin and α1-antitrypsin dynamics in gastrointestinal GvHD.

    PubMed

    O'Meara, A; Kapel, N; Xhaard, A; Sicre de Fontbrune, F; Manéné, D; Dhedin, N; de Latour, R P; Socié, G; Robin, M

    2015-08-01

    In a previous study, the fecal biomarkers calprotectin and α1-antitrypsin (α1-AT) at symptom onset were reported to be significantly associated with the response to steroids in gastrointestinal GvHD (GI-GvHD). The purpose of this trial was to evaluate the dynamics of the fecal biomarkers calprotectin and α1-AT throughout the course of GvHD. Patients who were refractory to steroids had initially higher biomarker levels and in the course of GvHD demonstrated a continuous increase in fecal biomarkers. In contrast, the dynamics of calprotectin and α1-AT demonstrated low and decreasing levels in cortico-sensitive GvHD. In steroid-refractory patients who received a second line of treatment, the biomarker levels at the beginning of second-line treatment did not predict the subsequent response. Nevertheless, calprotectin levels progressively decreased in subsequent responders, whereas non-responders demonstrated continuously high levels of calprotectin. α1-AT values correlated to a lesser extent with the response to second-line treatment and remained elevated in both non-responders and responders. In conclusion, calprotectin monitoring can be of use in the management of immunosuppressive treatment in GI-GvHD.

  17. Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone

    PubMed Central

    Weisdorf, Daniel J.; Burns, Linda J.; Slungaard, Arne; Wagner, John E.; Verneris, Michael R.; Cooley, Sarah; Wangen, Rosanna; Fautsch, Susan K.; Nicklow, Roby; DeFor, Todd; Blazar, Bruce R.

    2007-01-01

    Donor lymphocyte infusions (DLIs) can produce lasting remissions in patients with relapsed chronic myeloid leukemia (CML), but are less effective in non-CML diseases. We hypothesized that lymphodepletion, achieved with cyclophosphamide (Cy) and fludarabine (Flu), would promote in vivo expansion of the infused lymphocytes enhancing their immunologic effects. Fifteen patients with relapsed non-CML disease who received Cy/Flu/DLI were compared with 63 controls who received DLI without chemotherapy. Only the patients receiving Cy/Flu/DLI became lymphopenic at the time of DLI. Compared with controls, patients who received Cy/Flu/DLI developed significantly more grades II to IV (60% vs 24%, P = .01) and grades III to IV acute graft-versus-host disease (GVHD) (47% vs 14%, P = .01) with greater GVHD lethality. In Cy/Flu/DLI patients, T-cell proliferation was elevated at 14 days after DLI. Although these data suggest that chemotherapy-induced lymphodepletion enhances activation of donor lymphocytes, the toxicity needs to be managed before testing whether better disease control can be achieved. This trial was registered at www.clinicaltrials.gov as no. NCT00303693 and www.cancer.gov/clinicaltrials as no. NCT00167180. PMID:17579184

  18. Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone.

    PubMed

    Miller, Jeffrey S; Weisdorf, Daniel J; Burns, Linda J; Slungaard, Arne; Wagner, John E; Verneris, Michael R; Cooley, Sarah; Wangen, Rosanna; Fautsch, Susan K; Nicklow, Roby; Defor, Todd; Blazar, Bruce R

    2007-10-01

    Donor lymphocyte infusions (DLIs) can produce lasting remissions in patients with relapsed chronic myeloid leukemia (CML), but are less effective in non-CML diseases. We hypothesized that lymphodepletion, achieved with cyclophosphamide (Cy) and fludarabine (Flu), would promote in vivo expansion of the infused lymphocytes enhancing their immunologic effects. Fifteen patients with relapsed non-CML disease who received Cy/Flu/DLI were compared with 63 controls who received DLI without chemotherapy. Only the patients receiving Cy/Flu/DLI became lymphopenic at the time of DLI. Compared with controls, patients who received Cy/Flu/DLI developed significantly more grades II to IV (60% vs 24%, P = .01) and grades III to IV acute graft-versus-host disease (GVHD) (47% vs 14%, P = .01) with greater GVHD lethality. In Cy/Flu/DLI patients, T-cell proliferation was elevated at 14 days after DLI. Although these data suggest that chemotherapy-induced lymphodepletion enhances activation of donor lymphocytes, the toxicity needs to be managed before testing whether better disease control can be achieved. This trial was registered at www.clinicaltrials.gov as no. NCT00303693 and www.cancer.gov/clinicaltrials as no. NCT00167180.

  19. MHC Class I Chain-Related Gene A (MICA) Donor-Recipient Mismatches and MICA-129 Polymorphism in Unrelated Donor Hematopoietic Cell Transplantations Has No Impact on Outcomes in Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome: A Center for International Blood and Marrow Transplant Research Study.

    PubMed

    Askar, Medhat; Sobecks, Ronald; Wang, Tao; Haagenson, Mike; Majhail, Navneet; Madbouly, Abeer; Thomas, Dawn; Zhang, Aiwen; Fleischhauer, Katharina; Hsu, Katharine; Verneris, Michael; Lee, Stephanie J; Spellman, Stephen R; Fernández-Viña, Marcelo

    2017-03-01

    Single-center studies have previously reported associations of MHC Class I Chain-Related Gene A (MICA) polymorphisms and donor-recipient MICA mismatching with graft-versus-host disease (GVHD) after unrelated donor hematopoietic cell transplantation (HCT). In this study, we investigated the association of MICA polymorphism (MICA-129, MM versus MV versus VV) and MICA mismatches after HCT with 10/10 HLA-matched (n = 552) or 9/10 (n = 161) unrelated donors. Included were adult patients with a first unrelated bone marrow or peripheral blood HCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome that were reported to the Center for International Blood and Marrow Transplant Research between 1999 and 2011. Our results showed that neither MICA mismatch nor MICA-129 polymorphism were associated with any transplantation outcome (P < .01), with the exception of a higher relapse in recipients of MICA-mismatched HLA 10/10 donors (hazard ratio [HR], 1.7; P = .003). There was a suggestion of association between MICA mismatches and a higher risk of acute GVHD grades II to IV (HR, 1.4; P = .013) There were no significant interactions between MICA mismatches and HLA matching (9/10 versus 10/10). In conclusion, the findings in this cohort did not confirm prior studies reporting that MICA polymorphism and MICA mismatches were associated with HCT outcomes.

  20. No influence of chromosome Y haplogroup variation in acute graft-versus-host disease in sardinia.

    PubMed

    Orofino, Maria Grazia; Contu, Daniela; Argiolu, Francesca; Sanna, Maria Adele; Gaziev, Javid; La Nasa, Giorgio; Vacca, Adriana; Cao, Antonio; Cucca, Francesco

    2006-12-15

    The donor-recipient sex-related mismatch has been reported as a risk factor for acute graft-versus-host disease (GVHD). However, the results obtained in previous studies appear to be contradictory. Here we evaluate the impact of donor-recipient sex-related mismatch in a series of 204 Sardinian individuals (92.1% of them affected by Beta- Thalassemia major) who underwent bone marrow transplantation (BMT) from human leukocyte antigen (HLA) identical siblings. In all, 78 of these patients had acute GVHD (aGVHD). We found that also in this homogenous group of patients from a homogenous population, the donor-female/recipient-male pair provided an increased risk for aGVHD when compared with a reference donor-male/recipient-male pair (POR=2.3, P=0.042). This data could be consistent with a role of variation in the male-specific portion of the Y chromosome in aGVHD. To assess this, we compared the distribution of the main Y-chromosome haplogroups in 28 male patients, who had aGVHD and underwent BMT from HLA-identical sisters, and 366 ethnically-matched controls. No significant differences were observed. These findings do not support the presence of Y chromosome founder variants contributing significantly to aGVHD in the Sardinian population.

  1. Clinical and Dosimetric Predictors of Acute Severe Lymphopenia During Radiation Therapy and Concurrent Temozolomide for High-Grade Glioma

    SciTech Connect

    Huang, Jiayi; DeWees, Todd A.; Badiyan, Shahed N.; Speirs, Christina K.; Mullen, Daniel F.; Fergus, Sandra; Tran, David D.; Linette, Gerry; Campian, Jian L.; Chicoine, Michael R.; Kim, Albert H.; Dunn, Gavin; Simpson, Joseph R.; Robinson, Clifford G.

    2015-08-01

    Purpose: Acute severe lymphopenia (ASL) frequently develops during radiation therapy (RT) and concurrent temozolomide (TMZ) for high-grade glioma (HGG) and is associated with decreased survival. The current study was designed to identify potential predictors of ASL, with a focus on actionable RT-specific dosimetric parameters. Methods and Materials: From January 2007 to December 2012, 183 patients with HGG were treated with RT+TMZ and had available data including total lymphocyte count (TLC) and radiation dose-volume histogram parameters. ASL was defined as TLC of <500/μL within the first 3 months from the start of RT. Stepwise logistic regression analysis was used to determine the most important predictors of ASL. Results: Fifty-three patients (29%) developed ASL. Patients with ASL had significantly worse overall survival than those without (median: 12.5 vs 20.2 months, respectively, P<.001). Stepwise logistic regression analysis identified female sex (odds ratio [OR]: 5.30; 95% confidence interval [CI]: 2.46-11.41), older age (OR: 1.05; 95% CI: 1.02-1.09), lower baseline TLC (OR: 0.92; 95% CI: 0.87-0.98), and higher brain volume receiving 25 Gy (V{sub 25Gy}) (OR: 1.03; 95% CI: 1.003-1.05) as the most significant predictors for ASL. Brain V{sub 25Gy} <56% appeared to be the optimal threshold (OR: 2.36; 95% CI: 1.11-5.01), with an ASL rate of 38% versus 20% above and below this threshold, respectively (P=.006). Conclusions: Female sex, older age, lower baseline TLC, and higher brain V{sub 25Gy} are significant predictors of ASL during RT+TMZ therapy for HGG. Maintaining the V{sub 25Gy} of brain below 56% may reduce the risk of ASL.

  2. Strong associations among rumen endotoxin and acute phase proteins with plasma minerals in lactating cows fed graded amounts of concentrate.

    PubMed

    Zebeli, Q; Dunn, S M; Ametaj, B N

    2010-04-01

    The objective of this investigation was to determine associations among rumen endotoxin, plasma serum amyloid A (SAA), and C-reactive protein (CRP) with plasma Ca, Fe, Zn, and Cu in lactating cows challenged with graded amounts of rolled barley grain in the diet (i.e., 0, 15, 30, and 45% of DMI). Correlative relationships among variables were determined by linear and nonlinear regression procedures adjusted for the effects of day, animal, and experimental period. Increasing the amount of grain in the diet was successful in inducing an acute phase response, as assessed by augmentation of rumen endotoxin and plasma CRP and SAA (P < 0.01). The correlative analysis revealed inverse, nonlinear relationships of rumen endotoxin and plasma SAA with circulating Ca. Interestingly, plasma Ca reached the asymptotic plateau at 10.6 mg/dL. The increase in rumen endotoxin was associated with an abrupt decrease in plasma Fe (R(2) = 0.91; P < 0.001). A similar relationship, although at a reduced estimation accuracy (R(2) = 0.21; P < 0.01), was observed between rumen endotoxin and plasma Zn. Augmentation of rumen endotoxin and plasma CRP resulted in a positive, biphasic response of plasma Cu. In conclusion, the increase in rumen endotoxin in response to high-grain diets, and the resulting increases in plasma SAA and CRP, were strongly correlated with fluctuations of plasma minerals. Results suggest that new feeding strategies should be developed to curb the release of endotoxin in the rumen fluid to prevent perturbing minerals in the plasma.

  3. Allo-SCT conditioning for myelodysplastic syndrome and acute myeloid leukemia with clofarabine, cytarabine and ATG.

    PubMed

    Martin, M G; Uy, G L; Procknow, E; Stockerl-Goldstein, K; Cashen, A; Westervelt, P; Abboud, C N; Augustin, K; Luo, J; DiPersio, J F; Vij, R

    2009-07-01

    The application of myeloablative Allo-SCT is limited by its associated morbidity and mortality. Reduced-intensity conditioning regimens attempt to diminish these, but are associated with a higher risk of disease relapse. Given the evidence of activity of clofarabine and cytarabine in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), we explored a novel reduced-intensity conditioning regimen based on this backbone. Patients received clofarabine 40 mg/m(2) i.v. on days -6 to -2, cytarabine 1 g/m(2) i.v. on days -6 to -2 and anti-thymocyte globulin (ATG) 1 mg/kg on day -4 and 2.5 mg/kg x 2 days on days -3 and -2. Seven patients were enrolled. Their median age was 54 years; three were with MDS and four with AML. The median duration of neutropenia was 14 days and that of thrombocytopenia was 22 days. Toxicities included hand-foot syndrome (57% grade 2), elevated alanine aminotransferase (ALT) (57% grade 3), elevated aspartate aminotransferase (AST) (86% grade 3) and hyperbilirubinemia (29% grade 3-5). No acute GVHD was observed. Enrollment to the trial was halted after three of the first seven patients expired on days +15, +26 and +32. Three of the four surviving patients have relapsed with a median TTP of 152 days. This regimen was not sufficiently immunosuppressive to ensure engraftment, and was associated with substantial morbidity and mortality.

  4. Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice.

    PubMed

    Li, Yue; Chen, Hung-Lin; Bannick, Nadine; Henry, Michael; Holm, Adrian N; Metwali, Ahmed; Urban, Joseph F; Rothman, Paul B; Weiner, George J; Blazar, Bruce R; Elliott, David E; Ince, M Nedim

    2015-02-01

    Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor [GVT]) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation called graft-versus-host disease (GVHD). High-dose steroids or other immunosuppressive drugs are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT, and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT, and prevent mortality in BMT. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected BALB/c recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation and reduced GVHD-related mortality, but maintained GVT. H. polygyrus colonization promoted the survival of TGF-β-generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGF-β-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD when T cells unresponsive to TGF-β-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD using Tregs and TGF-β-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT.

  5. A Validated System for Centralized Grading of Retinopathy of Prematurity: Telemedicine Approaches to Evaluating Acute Phase ROP (e-ROP) Study

    PubMed Central

    Daniel, Ebenezer; Quinn, Graham E.; Hildebrand, P. Lloyd; Ells, Anna; Hubbard, Baker; Capone, Antonio; Martin, Revell W.; Ostroff, Candace P.; Smith, Eli; Pistilli, Maxwell; Ying, Gui-Shuang

    2016-01-01

    Importance Measurable competence derived from comprehensive and advanced training in grading digital images is critical in studies using a Reading Center to evaluate retinal fundus images from infants at risk for Retinopathy of Prematurity (ROP). Details of certification for non-physician Trained Readers (TR) have not yet been described. Objective Describe a centralized system for grading ROP digital images by TRs in the “Telemedicine Approaches to evaluating acute-phase Retinopathy of Prematurity (e-ROP) Study”. Design Multi-center observational cohort study. Setting TRs were trained by experienced ROP specialists and certified to detect ROP morphology in digital retinal images under supervision of an ophthalmologist Reading Center Director (RCD). An ROP Reading Center was developed with standard hardware, secure Internet access and customized image viewing software with an electronic grading form. A detailed protocol for grading was developed. Based on results of TR gradings, a computerized algorithm determined whether Referral-Warranted ROP (RW-ROP, defined as presence of plus disease, zone I ROP, and stage 3 or worse ROP) was present. Independent double grading was done by the TRs with adjudication of discrepant fields performed by the RCD. Participants Infants with birth weights <1251g. Interventions/Exposures Digital retinal images Main Outcome Measure(s) Intra- and inter-grader variability, and monitoring for temporal drift. Results Four TRs underwent rigorous training and certification. 5,520 image sets were double graded with 25% requiring adjudication for at least one component of RW-ROP. The weighted kappas for inter-grader agreement (N= 80 image sets) were 0.72 (0.52 – 0.93) for RW-ROP, 0.57(95% CI: 0.37 – 0.77) for plus disease, 0.43 (0.24 – 0.63) for zone I ROP and 0.67(0.47 – 0.88) for Stage 3 or worse ROP. The weighted kappa for grade re-grade agreement were 0.77(0.57 – 0.97) for RW- ROP, 0.87(0.67 – 1.00) for plus disease, 0

  6. Outcomes of acute leukemia patients transplanted with naive T cell–depleted stem cell grafts

    PubMed Central

    Bleakley, Marie; Heimfeld, Shelly; Loeb, Keith R.; Jones, Lori A.; Chaney, Colette; Seropian, Stuart; Gooley, Ted A.; Sommermeyer, Franziska; Riddell, Stanley R.; Shlomchik, Warren D.

    2015-01-01

    BACKGROUND. Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HCT). In mice, naive T cells (TN) cause more severe GVHD than memory T cells (TM). We hypothesized that selective depletion of TN from human allogeneic peripheral blood stem cell (PBSC) grafts would reduce GVHD and provide sufficient numbers of hematopoietic stem cells and TM to permit hematopoietic engraftment and the transfer of pathogen-specific T cells from donor to recipient, respectively. METHODS. In a single-arm clinical trial, we transplanted 35 patients with high-risk leukemia with TN-depleted PBSC grafts following conditioning with total body irradiation, thiotepa, and fludarabine. GVHD prophylactic management was with tacrolimus immunosuppression alone. Subjects received CD34-selected PBSCs and a defined dose of TM purged of CD45RA+ TN. Primary and secondary objectives included engraftment, acute and chronic GVHD, and immune reconstitution. RESULTS. All recipients of TN-depleted PBSCs engrafted. The incidence of acute GVHD was not reduced; however, GVHD in these patients was universally corticosteroid responsive. Chronic GVHD was remarkably infrequent (9%; median follow-up 932 days) compared with historical rates of approximately 50% with T cell–replete grafts. TM in the graft resulted in rapid T cell recovery and transfer of protective virus-specific immunity. Excessive rates of infection or relapse did not occur and overall survival was 78% at 2 years. CONCLUSION. Depletion of TN from stem cell allografts reduces the incidence of chronic GVHD, while preserving the transfer of functional T cell memory. TRIAL REGISTRATION. ClinicalTrials.gov (NCT 00914940). FUNDING. NIH, Burroughs Wellcome Fund, Leukemia and Lymphoma Society, Damon Runyon Cancer Research Foundation, and Richard Lumsden Foundation. PMID:26053664

  7. Phase I Trial of Total Marrow and Lymphoid Irradiation Transplantation Conditioning in Patients with Relapsed/Refractory Acute Leukemia.

    PubMed

    Stein, Anthony; Palmer, Joycelynne; Tsai, Ni-Chun; Al Malki, Monzr M; Aldoss, Ibrahim; Ali, Haris; Aribi, Ahmed; Farol, Len; Karanes, Chatchada; Khaled, Samer; Liu, An; O'Donnell, Margaret; Parker, Pablo; Pawlowska, Anna; Pullarkat, Vinod; Radany, Eric; Rosenthal, Joseph; Sahebi, Firoozeh; Salhotra, Amandeep; Sanchez, James F; Schultheiss, Tim; Spielberger, Ricardo; Thomas, Sandra H; Snyder, David; Nakamura, Ryotaro; Marcucci, Guido; Forman, Stephen J; Wong, Jeffrey

    2017-04-01

    Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age range, 16 to 57 years) with relapsed/refractory acute leukemia undergoing HSCT (matched related, matched unrelated, or 1-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range, 1200 to 2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy, as TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post-transplantation nonrelapse mortality (NRM) rate was only 3.9% (95% confidence interval [CI], .7 to 12.0) at day +100 and 8.1% (95% CI, 2.5 to 18.0) at 1 year. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 43.1% (95% CI, 29.2 to 56.3) and for grade III and IV, it was 13.7% (95% CI, 6.9 to 27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall 1-year survival was 55.5% (95% CI, 40.7 to 68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100-day and 1-year NRM rate and no increased risk of GVHD with higher doses of radiation.

  8. Results of a prospective multicentre myeloablative double-unit cord blood transplantation trial in adult patients with acute leukaemia and myelodysplasia.

    PubMed

    Barker, Juliet N; Fei, Mingwei; Karanes, Chatchada; Horwitz, Mitchell; Devine, Steven; Kindwall-Keller, Tamila L; Holter, Jennifer; Adams, Alexia; Logan, Brent; Navarro, Willis H; Riches, Marcie

    2015-02-01

    Double-unit cord blood (CB) grafts may improve engraftment and relapse risk in adults with haematological malignancies. We performed a prospective high-dose myeloablative double-unit CB transplantation (CBT) trial in adults with high-risk acute leukaemia or myelodysplasia (MDS) between 2007 and 2011. The primary aim was to establish the 1-year overall survival in a multi-centre setting. Fifty-six patients (31 acute myeloid leukaemia, 19 acute lymphoblastic leukaemia, 4 other acute leukaemias, 2 myelodysplastic syndrome [MDS]) were transplanted at 10 centres. The median infused total nucleated cell doses were 2·62 (larger unit) and 2·02 (smaller unit) x 10(7) /kg. The cumulative incidence of day 100 neutrophil engraftment was 89% (95% confidence interval [CI]: 80-96). Day 180 grade II-IV acute graft-versus-host disease (GVHD) incidence was 64% (95%CI: 51-76) and 36% (95%CI: 24-49) of patients had chronic GVHD by 3-years. At 3-years post-transplant, the transplant-related mortality (TRM) was 39% (95%CI: 26-52), and the 3-year relapse incidence was 11% (95%CI: 4-21). With a median 37-month (range 23-71) follow-up of survivors, the 3-year disease-free survival was 50% (95%CI: 37-63). Double-unit CBT is a viable alternative therapy for high-risk acute leukaemia/ MDS in patients lacking a matched unrelated donor. This is especially important for minority patients. The relapse incidence was low but strategies to ameliorate TRM are needed.

  9. 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.

  10. Shared biology of GVHD and GVT effects: potential methods of separation.

    PubMed

    Fowler, Daniel H

    2006-03-01

    The difficult separation of clinical graft-versus-tumor (GVT) effects from graft-versus-host disease (GVHD) reflects their shared biology. Experimental approaches to mediate GVT effects while limiting GVHD include: (1) allograft T cell depletion followed by immune enhancement; (2) modulation of T cell dose or T cell subset composition; (3) donor lymphocyte infusion; (4) reduced-intensity host preparation; (5) modulation of Th1/Th2 and Tc1/Tc2 cell balance; (6) cytokine therapy or neutralization; (7) T regulatory cell therapy; (8) co-stimulatory pathway modulation; (9) chemokine pathway modulation; (10) induction of antigen-specific T cells; (11) alloreactive NK cell therapy; and (12) targeted pharmaceutical inhibition of proteosome, mammalian target of rapamycin, and histone deacetylase pathways. Clearly, a multitude of approaches exist that hold promise for separating GVT effects from GVHD. Future success in this endeavor will require a strong commitment towards translational research and continued advances in cell, vaccine, cytokine, monoclonal antibody, and targeted molecular therapy.

  11. Validation of the National Institutes of Health chronic GVHD Oral Mucosal Score using component-specific measures.

    PubMed

    Bassim, C W; Fassil, H; Mays, J W; Edwards, D; Baird, K; Steinberg, S M; Williams, K M; Cowen, E W; Mitchell, S A; Cole, K; Taylor, T; Avila, D; Zhang, D; Pulanic, D; Grkovic, L; Fowler, D; Gress, R E; Pavletic, S Z

    2014-01-01

    Oral chronic GVHD (cGVHD) is a common, late complication of alloSCT that is associated with significant patient morbidity. The NIH Oral Mucosal Score (NIH OMS) was developed to assess oral cGVHD therapeutic response, but has not been fully validated. This study's purpose was to conduct a rigorous construct validity and internal consistency analysis of this score and its components (erythema, lichenoid, ulcers, mucoceles) using established measures of oral pain, oral function, oral-related quality-of-life, nutrition and laboratory parameters in 198 patients with cGVHD. The construct validity of the NIH OMS was supported: a moderate correlation was observed between NIH OMS and mouth pain (rho=0.43), while a weaker correlation was observed with low albumin (rho=-0.26). Total NIH OMS, erythema and lichenoid components were associated with malnutrition, oral pain and impaired oral QOL, while ulcers were only associated with oral pain. No associations were found between mucoceles and any indicator evaluated, including salivary function or xerostomia. Kappa determined between scale components was low overall (all 0.35), supporting a conclusion that each component measures a distinct manifestation of oral cGVHD. This study supports the use of the NIH OMS and its components (erythema, lichenoid and ulcerations) to measure clinician-reported severity of oral cGVHD.

  12. Validation of the National Institutes of Health chronic GVHD Oral Mucosal Score using component-specific measures

    PubMed Central

    Bassim, CW; Fassil, H; Mays, JW; Edwards, D; Baird, K; Steinberg, SM; Williams, KM; Cowen, EW; Mitchell, SA; Cole, K; Taylor, T; Avila, D; Zhang, D; Pulanic, D; Grkovic, L; Fowler, D; Gress, RE; Pavletic, SZ

    2016-01-01

    Oral chronic GVHD (cGVHD) is a common, late complication of alloSCT that is associated with significant patient morbidity. The NIH Oral Mucosal Score (NIH OMS) was developed to assess oral cGVHD therapeutic response, but has not been fully validated. This study’s purpose was to conduct a rigorous construct validity and internal consistency analysis of this score and its components (erythema, lichenoid, ulcers, mucoceles) using established measures of oral pain, oral function, oral-related quality-of-life, nutrition and laboratory parameters in 198 patients with cGVHD. The construct validity of the NIH OMS was supported: a moderate correlation was observed between NIH OMS and mouth pain (rho =0.43), while a weaker correlation was observed with low albumin (rho = −0.26). Total NIH OMS, erythema and lichenoid components were associated with malnutrition, oral pain and impaired oral QOL, while ulcers were only associated with oral pain. No associations were found between mucoceles and any indicator evaluated, including salivary function or xerostomia. Kappa determined between scale components was low overall (all ≤0.35), supporting a conclusion that each component measures a distinct manifestation of oral cGVHD. This study supports the use of the NIH OMS and its components (erythema, lichenoid and ulcerations) to measure clinician-reported severity of oral cGVHD. PMID:23995099

  13. The Relationship between STR-PCR Chimerism Analysis and Chronic GvHD Following Hematopoietic Stem Cell Transplantation

    PubMed Central

    Mousavi, Seyed Asadollah; Javadimoghadam, Mina; Ghavamzadeh, Ardeshir; Alimoghaddam, Kamran; Sayarifard, Azadeh; Ghaffari, Seyed-Hamidollah; Chahardouli, Bahram; Basi, Ali

    2017-01-01

    Background: The study attempts to assess the relationship between chimerism analysis using polymerase chain reaction of short tandem repeat (STR) and the incidence of chronic graft versus host disease (GvHD) as well as survival. Subjects and Methods: The retrospective cohort included all patients who received allo-HSCT during 2005-2013. Data collected by day +100 were reviewed in terms of the incidence of chronic GvHD and survival. Chimerism was evaluated for whole blood, T-cell and PMN cells on days 15, 30 and 60, respectively using polymerase chain reaction of short tandem repeat (STR). Results: Forty (69%) patients developed chronic GvHD, 11 (19%) relapsed and 22 (39.7%) expired during the study. There was a significant relationship between chronic GvHD and chimerism analysis including whole blood on day 60 (p=0.001), Polymorphonuclear neutrophil (PMN) on day 60 (p=0.05), T-cell on days 15 (p=0.028), 30 (p=0.01) and 60 (p=0.004). Patients with chronic GvHD showed a long-term survival as compared with those without chronic GvHD (p=0.0013). Conclusion: Conducting continuous analysis of chimerism provides an opportunity to initiate immediate measures in order to prevent complications. PMID:28286611

  14. Predicting Grade 3 Acute Diarrhea During Radiation Therapy for Rectal Cancer Using a Cutoff-Dose Logistic Regression Normal Tissue Complication Probability Model

    SciTech Connect

    Robertson, John M.; Soehn, Matthias; Yan Di

    2010-05-01

    Purpose: Understanding the dose-volume relationship of small bowel irradiation and severe acute diarrhea may help reduce the incidence of this side effect during adjuvant treatment for rectal cancer. Methods and Materials: Consecutive patients treated curatively for rectal cancer were reviewed, and the maximum grade of acute diarrhea was determined. The small bowel was outlined on the treatment planning CT scan, and a dose-volume histogram was calculated for the initial pelvic treatment (45 Gy). Logistic regression models were fitted for varying cutoff-dose levels from 5 to 45 Gy in 5-Gy increments. The model with the highest LogLikelihood was used to develop a cutoff-dose normal tissue complication probability (NTCP) model. Results: There were a total of 152 patients (48% preoperative, 47% postoperative, 5% other), predominantly treated prone (95%) with a three-field technique (94%) and a protracted venous infusion of 5-fluorouracil (78%). Acute Grade 3 diarrhea occurred in 21%. The largest LogLikelihood was found for the cutoff-dose logistic regression model with 15 Gy as the cutoff-dose, although the models for 20 Gy and 25 Gy had similar significance. According to this model, highly significant correlations (p <0.001) between small bowel volumes receiving at least 15 Gy and toxicity exist in the considered patient population. Similar findings applied to both the preoperatively (p = 0.001) and postoperatively irradiated groups (p = 0.001). Conclusion: The incidence of Grade 3 diarrhea was significantly correlated with the volume of small bowel receiving at least 15 Gy using a cutoff-dose NTCP model.

  15. Antibiotic-Induced Depletion of Anti-Inflammatory Clostridia is Associated with the Development of GVHD in Pediatric Stem Cell Transplant Patients.

    PubMed

    Simms-Waldrip, Tiffany R; Sunkersett, Gauri; Coughlin, Laura A; Savani, Milan R; Arana, Carlos; Kim, Jiwoong; Kim, Minsoo; Zhan, Xiaowei; Greenberg, David E; Xie, Yang; Davies, Stella M; Koh, Andrew Y

    2017-02-09

    Adult stem cell transplantation (SCT) patients with graft-versus-host-disease (GVHD) exhibit significant disruptions in gut microbial communities. These changes are associated with higher overall mortality and appear to be driven by specific antibiotic therapies. It is unclear whether pediatric SCT patients who develop GVHD exhibit similar antibiotic-induced gut microbiota community changes. Here, we show that pediatric SCT patients (from Children's Medical Center Dallas, n=8, and Cincinnati Children's Hospital, n=7) who develop GVHD show a significant decline, up to 10-log fold, in gut anti-inflammatory Clostridia (AIC), compared to those without GVHD. In fact, the development of GVHD is significantly associated with this AIC decline and with cumulative antibiotic exposure, particularly antibiotics effective against anaerobic bacteria (p= 0.003, Firth logistic regression analysis). Using metagenomic shotgun sequencing analysis, we were able to identify specific commensal bacterial species, including AIC, that were significantly depleted in GVHD patients. We then used a preclinical GVHD model to verify our clinical observations. Clindamycin depleted AIC and exacerbated GVHD in mice, whereas oral AIC supplementation increased gut AIC levels and mitigated GVHD in mice. Together, these data suggest that an antibiotic-induced AIC depletion in the gut microbiota is associated with the development of GVHD in pediatric SCT patients.

  16. Administration Of Anti-CD20 mAb Is Highly Effective In Preventing But Ineffective In Treating Chronic GVHD While Preserving Strong GVL Effects

    PubMed Central

    Johnston, Heather F.; Xu, Yajing; Racine, Jeremy J.; Cassady, Kaniel; Ni, Xiong; Wu, Tao; Chan, Andrew; Forman, Stephen; Zeng, Defu

    2014-01-01

    Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome, and donor B cells play important roles in augmenting its pathogenesis. B cell-depleting anti-CD20 mAb has been administered before or after cGVHD onset for preventing or treating cGVHD in clinic. Although administration before onset appeared to be more effective, the effect is variable and sometimes minimal. Here, we used two mouse cGVHD models to evaluate the preventive and therapeutic effect of anti-CD20 mAb. With the model of DBA/2 donor to MHC-matched BALB/c recipient, one intravenous injection of anti-CD20 mAb (40 mg/kg) the following day or on day 7 after HCT when serum autoantibodies were undetectable effectively prevented induction of cGVHD and preserved strong graft-versus-leukemia (GVL) effect. The separation of GVL effect from GVHD was associated with a significant reduction of donor CD4+ T cell proliferation and expansion, and protection of host thymic medullary epithelial cells. Anti-CD20 mAb administration also prevented expansion of donor T cells and induction of cGVHD in another mouse model of C57BL/6 donor to MHC-mismatched BALB/c recipients. In contrast, administration of anti-CD20 mAb after GVHD onset was not able to effectively deplete donor B cells or ameliorate cGVHD in either model. These results indicate that administration of anti-CD20 mAb prior to signs of cGVHD can prevent induction of autoimmune-like cGVHD while preserving GVL effect; there is little effect if administered after cGVHD onset. This provides new insights into clinical prevention and therapy of cGVHD with B cell-depleting reagents. PMID:24796279

  17. Transplant Outcomes for Children with T-Cell Acute Lymphoblastic Leukemia in Second Remission: A Report of the CIBMTR®

    PubMed Central

    Burke, Michael J.; Verneris, Michael R.; Le Rademacher, Jennifer; He, Wensheng; Abdel-Azim, Hisham; Abraham, Allistair A.; Auletta, Jeffery J.; Ayas, Mouhab; Brown, Valerie I.; Cairo, Mitchell S.; Chan, Ka Wah; Diaz Perez, Miguel A.; Dvorak, Christopher C.; Egeler, R. Maarten; Eldjerou, Lamis; Frangoul, Haydar; Guilcher, Gregory M. T.; Hayashi, Robert J.; Ibrahim, Ahmed; Kasow, Kimberly A.; Leung, Wing H.; Olsson, Richard F.; Pulsipher, Michael A.; Shah, Niketa; Shah, Nirali N.; Thiel, Elizabeth; Talano, Julie-An; Kitko, Carrie L.

    2015-01-01

    Survival for children with relapsed T-ALL is poor when treated with chemotherapy alone and outcomes after allogeneic hematopoietic cell transplantation (HCT) is not well described. Two hundred and twenty-nine children with T-ALL in second complete remission (CR2) received a HCT following myeloablative conditioning between 2000–2011 and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Median age was 10 (range, 2–18) years. Donor source was umbilical cord blood (26%), matched sibling bone marrow (38%) or unrelated bone marrow/peripheral blood (36%). Acute GVHD (grade 2–4) and chronic GVHD occurred in 35% (95% CI, 27–45) and 26% (95% CI, 20–33) of patients. Transplant related mortality at day 100 and 3-year relapse rates were 13% (95% CI, 9–18) and 30% (95% CI, 24–37) respectively. Three year overall survival and disease-free survival were 48% (95% CI, 41–55) and 46% (95% CI, 39–52%) respectively. In multivariate analysis, patients with bone marrow relapse, with or without concurrent extramedullary relapse prior to HCT, were most likely to relapse (HR=3.94, p=0.005) as compared to isolated extramedullary disease. In conclusion, HCT for pediatric T-ALL in CR2 demonstrates reasonable and durable outcomes and consideration for HCT is warranted. PMID:26327632

  18. Narrow-Band Ultraviolet B Phototherapy Ameliorates Acute Graft-Versus-Host Disease of the Intestine by Expansion of Regulatory T Cells.

    PubMed

    Hashimoto, Akari; Sato, Tsutomu; Iyama, Satoshi; Yoshida, Masahiro; Ibata, Soushi; Tatekoshi, Ayumi; Kamihara, Yusuke; Horiguchi, Hiroto; Murase, Kazuyuki; Kawano, Yutaka; Takada, Kohichi; Miyanishi, Koji; Kobune, Masayoshi; Ichimiya, Shingo; Kato, Junji

    2016-01-01

    Narrowband ultraviolet B (NB-UVB) has been widely used in dermatological phototherapy. As for the application of NB-UVB phototherapy to graft-versus-host disease (GVHD), we previously reported that it was highly efficacious for cutaneous lesions of acute GVHD (aGVHD) and that expansion of regulatory T (Treg) cells induced by NB-UVB might be one of the mechanisms. In order to examine whether NB-UVB irradiation through expansion of Treg cells is effective for the treatment of not only cutaneous aGVHD but also aGVHD of inner organs such as the intestine or liver, we conducted experiments in which a murine lethal aGVHD model, characterized by severe involvement of the intestine, was irradiated with NB-UVB. We found that NB-UVB irradiation improved the clinical score and survival rate. The pathological score of aGVHD was improved in all affected organs: intestine, liver, and skin. In the serum of mice irradiated with NB-UVB, the levels of Treg cells-associated cytokines such as transforming growth factor beta (TGFβ) and interleukin-10 (IL-10) were elevated. The numbers of infiltrating Treg cells in inflamed tissue of the intestine and those in spleen were increased in mice treated with NB-UVB. This is the first report demonstrating that NB-UVB phototherapy has the ability to ameliorate intestinal aGVHD through the expansion of Treg cells.

  19. Development of Three Different NK Cell Subpopulations during Immune Reconstitution after Pediatric Allogeneic Hematopoietic Stem Cell Transplantation: Prognostic Markers in GvHD and Viral Infections.

    PubMed

    Huenecke, Sabine; Cappel, Claudia; Esser, Ruth; Pfirrmann, Verena; Salzmann-Manrique, Emilia; Betz, Sibille; Keitl, Eileen; Banisharif-Dehkordi, Julia; Bakhtiar, Shahrzad; Königs, Christoph; Jarisch, Andrea; Soerensen, Jan; Ullrich, Evelyn; Klingebiel, Thomas; Bader, Peter; Bremm, Melanie

    2017-01-01

    Natural killer (NK) cells play an important role following allogeneic hematopoietic stem cell transplantation (HSCT) exerting graft-versus-leukemia/tumor effect and mediating pathogen-specific immunity. Although NK cells are the first donor-derived lymphocytes reconstituting post-HSCT, their distribution of CD56(++)CD16(-) (CD56(bright)), CD56(++)CD16(+) (CD56(intermediate=int)), and CD56(+)CD16(++) (CD56(dim)) NK cells is explicitly divergent from healthy adults, but to some extent comparable to the NK cell development in early childhood. The proportion of CD56(bright)/CD56(int)/CD56(dim) changed from 15/8/78% in early childhood to 6/4/90% in adults, respectively. Within this study, we first compared the NK cell reconstitution post-HSCT to reference values of NK cell subpopulations of healthy children. Afterward, we investigated the reconstitution of NK cell subpopulations post-HSCT in correlation to acute graft versus host disease (aGvHD) and chronic graft versus host disease (cGvHD) as well as to viral infections. Interestingly, after a HSCT follow-up phase of 12 months, the distribution of NK cell subpopulations largely matched the 50th percentile of the reference range for healthy individuals. Patients suffering from aGvHD and cGvHD showed a delayed reconstitution of NK cells. Remarkably, within the first 2 months post-HSCT, patients suffering from aGvHD had significantly lower levels of CD56(bright) NK cells compared to patients without viral infection or without graft versus host disease (GvHD). Therefore, the amount of CD56(bright) NK cells might serve as an early prognostic factor for GvHD development. Furthermore, a prolonged and elevated peak in CD56(int) NK cells seemed to be characteristic for the chronification of GvHD. In context of viral infection, a slightly lower CD56 and CD16 receptor expression followed by a considerable reduction in the absolute CD56(dim) NK cell numbers combined with reoccurrence of CD56(int) NK cells was observed. Our

  20. Development of Three Different NK Cell Subpopulations during Immune Reconstitution after Pediatric Allogeneic Hematopoietic Stem Cell Transplantation: Prognostic Markers in GvHD and Viral Infections

    PubMed Central

    Huenecke, Sabine; Cappel, Claudia; Esser, Ruth; Pfirrmann, Verena; Salzmann-Manrique, Emilia; Betz, Sibille; Keitl, Eileen; Banisharif-Dehkordi, Julia; Bakhtiar, Shahrzad; Königs, Christoph; Jarisch, Andrea; Soerensen, Jan; Ullrich, Evelyn; Klingebiel, Thomas; Bader, Peter; Bremm, Melanie

    2017-01-01

    Natural killer (NK) cells play an important role following allogeneic hematopoietic stem cell transplantation (HSCT) exerting graft-versus-leukemia/tumor effect and mediating pathogen-specific immunity. Although NK cells are the first donor-derived lymphocytes reconstituting post-HSCT, their distribution of CD56++CD16− (CD56bright), CD56++CD16+ (CD56intermediate=int), and CD56+CD16++ (CD56dim) NK cells is explicitly divergent from healthy adults, but to some extent comparable to the NK cell development in early childhood. The proportion of CD56bright/CD56int/CD56dim changed from 15/8/78% in early childhood to 6/4/90% in adults, respectively. Within this study, we first compared the NK cell reconstitution post-HSCT to reference values of NK cell subpopulations of healthy children. Afterward, we investigated the reconstitution of NK cell subpopulations post-HSCT in correlation to acute graft versus host disease (aGvHD) and chronic graft versus host disease (cGvHD) as well as to viral infections. Interestingly, after a HSCT follow-up phase of 12 months, the distribution of NK cell subpopulations largely matched the 50th percentile of the reference range for healthy individuals. Patients suffering from aGvHD and cGvHD showed a delayed reconstitution of NK cells. Remarkably, within the first 2 months post-HSCT, patients suffering from aGvHD had significantly lower levels of CD56bright NK cells compared to patients without viral infection or without graft versus host disease (GvHD). Therefore, the amount of CD56bright NK cells might serve as an early prognostic factor for GvHD development. Furthermore, a prolonged and elevated peak in CD56int NK cells seemed to be characteristic for the chronification of GvHD. In context of viral infection, a slightly lower CD56 and CD16 receptor expression followed by a considerable reduction in the absolute CD56dim NK cell numbers combined with reoccurrence of CD56int NK cells was observed. Our results suggest that a precise

  1. Impact of graft-versus-host disease on outcomes after unrelated cord blood transplantation.

    PubMed

    Kanda, J; Morishima, Y; Terakura, S; Wake, A; Uchida, N; Takahashi, S; Ono, Y; Onishi, Y; Kanamori, H; Aotsuka, N; Ozawa, Y; Ogawa, H; Sakura, T; Ohashi, K; Ichinohe, T; Kato, K; Atsuta, Y; Teshima, T; Murata, M

    2017-03-01

    The effect of graft-versus-host disease (GVHD) on transplant outcomes after unrelated cord blood transplantation (UCBT) has not been fully elucidated. We analyzed the impact of acute and chronic GVHD on outcomes in adult patients with acute leukemia or myelodysplastic syndrome who underwent their first UCBT (n=2558). The effect of GVHD on outcomes was analyzed after adjusting for other significant variables. The occurrence of GVHD was treated as a time-dependent covariate. The occurrence of grade 1-2 or 3-4 acute GVHD was significantly associated with a lower relapse rate. Grade 3-4 acute GVHD was associated with a higher risk of non-relapse and overall mortality than no acute GVHD, whereas grade 1-2 acute GVHD was associated with a lower risk of non-relapse and overall mortality than no acute GVHD. Limited or extensive chronic GVHD was significantly associated with a lower relapse rate. Limited chronic GVHD was associated with a lower overall and non-relapse mortality than no chronic GVHD. In conclusion, mild acute or chronic GVHD was associated not only with a low risk of relapse but also with a low risk of non-relapse mortality, and provides a survival benefit in UCBT.

  2. Tac, Mini-MTX, MMF Versus Tac, MTX for GVHD Prevention

    ClinicalTrials.gov

    2016-09-29

    Chronic Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Acute Biphenotypic Leukemia; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Non-Hodgkin Lymphoma; Hodgkins Disease; Chronic Lymphocytic Leukemia; Multiple Myeloma

  3. The Role of Animal Models in the Study of Hematopoietic Stem Cell Transplantation and GvHD: A Historical Overview.

    PubMed

    Boieri, Margherita; Shah, Pranali; Dressel, Ralf; Inngjerdingen, Marit

    2016-01-01

    Bone marrow transplantation (BMT) is the only therapeutic option for many hematological malignancies, but its applicability is limited by life-threatening complications, such as graft-versus-host disease (GvHD). The last decades have seen great advances in the understanding of BMT and its related complications; in particular GvHD. Animal models are beneficial to study complex diseases, as they allow dissecting the contribution of single components in the development of the disease. Most of the current knowledge on the therapeutic mechanisms of BMT derives from studies in animal models. Parallel to BMT, the understanding of the pathophysiology of GvHD, as well as the development of new treatment regimens, has also been supported by studies in animal models. Pre-clinical experimentation is the basis for deep understanding and successful improvements of clinical applications. In this review, we retrace the history of BMT and GvHD by describing how the studies in animal models have paved the way to the many advances in the field. We also describe how animal models contributed to the understanding of GvHD pathophysiology and how they are fundamental for the discovery of new treatments.

  4. The Role of Animal Models in the Study of Hematopoietic Stem Cell Transplantation and GvHD: A Historical Overview

    PubMed Central

    Boieri, Margherita; Shah, Pranali; Dressel, Ralf; Inngjerdingen, Marit

    2016-01-01

    Bone marrow transplantation (BMT) is the only therapeutic option for many hematological malignancies, but its applicability is limited by life-threatening complications, such as graft-versus-host disease (GvHD). The last decades have seen great advances in the understanding of BMT and its related complications; in particular GvHD. Animal models are beneficial to study complex diseases, as they allow dissecting the contribution of single components in the development of the disease. Most of the current knowledge on the therapeutic mechanisms of BMT derives from studies in animal models. Parallel to BMT, the understanding of the pathophysiology of GvHD, as well as the development of new treatment regimens, has also been supported by studies in animal models. Pre-clinical experimentation is the basis for deep understanding and successful improvements of clinical applications. In this review, we retrace the history of BMT and GvHD by describing how the studies in animal models have paved the way to the many advances in the field. We also describe how animal models contributed to the understanding of GvHD pathophysiology and how they are fundamental for the discovery of new treatments. PMID:27625651

  5. Grading criteria for chronic ocular graft-versus-host disease: Comparing the NIH eye score, Japanese dry eye score, and DEWS 2007 score

    PubMed Central

    Tatematsu, Yukako; Ogawa, Yoko; Abe, Takayuki; Kamoi, Mizuka; Uchino, Miki; Saijo-Ban, Yumiko; Yaguchi, Saori; Mukai, Shin; Mori, Takehiko; Okamoto, Shinichiro; Tsubota, Kazuo

    2014-01-01

    Ocular graft-versus-host disease (GVHD) is a common complication after hematopoietic stem cell transplantation (HSCT). Here we compared the diagnostic rates of ocular GVHD, including its severity, prognosis and the agreement, obtained using three grading scales: the National Institutes of Health (NIH) eye score, Japanese dry eye score, and dry eye workshop score, by retrospectively reviewing the records of 82 patients who underwent HSCT. Tear dynamics and ocular surface assessments made 6–9 months after HSCT were used to determine ocular GVHD severity with the three scales. By the three scales, ocular GVHD was diagnosed in 56 patients (68.3%), 51 patients (62.2%), and 52 patients (63.4%), respectively. The Kappa coefficient was calculated to determine the agreement between scales for diagnosing ocular GVHD. The severity progression within two years after onset was also assessed by tear dynamics and ocular surface examination. The patients were categorized as no change, improved, or progressive. The three grading scales showed good agreement (Kappa = 0.87 to 0.97) in diagnosing patients with ocular GVHD, and the scores by all three were significantly associated with the patients' prognosis (p < 0.01). We recommend that multi-center research is needed for further validation and investigation. PMID:25338290

  6. Radiation-induced World Health Organization grade II meningiomas in young patients following prophylactic cranial irradiation for acute lymphoblastic leukemia in childhood. Three case reports.

    PubMed

    Oda, Keiko; Sato, Taku; Watanabe, Tadashi; Ichikawa, Masahiro; Ito, Eiji; Matsumoto, Yuka; Ando, Hitoshi; Sakuma, Jun; Kikuta, Atsushi; Hojo, Hiroshi; Saito, Kiyoshi

    2012-01-01

    Current chemotherapeutic regimens have been used to successfully treat many children with acute lymphoblastic leukemia (ALL), but have resulted in an increased risk of late central nervous system tumors, most commonly meningioma, particularly in patients who have received cranial irradiation. We treated 3 young patients with World Health Organization grade II meningiomas who had previously received cranial irradiation for the treatment of childhood ALL: a cerebellopontine angle tumor in a 19-year-old woman, a petroclival tumor in a 28-year-old man, and a frontal parasagittal tumor in a 19-year-old woman. These cases were difficult to treat due to the aggressive and invasive biology of the tumors. Therefore, we recommend systematic cranial imaging and long follow-up periods for leukemia survivors to detect brain tumors before progression.

  7. GTI-2040 in Treating Patients With Relapsed, Refractory, or High-Risk Acute Leukemia, High-Grade Myelodysplastic Syndromes, or Refractory or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-12-03

    Acute Undifferentiated Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  8. Amelioration of acute graft-versus-host disease by NKG2A engagement on donor T cells.

    PubMed

    Kawamura, Hiroki; Yagita, Hideo; Nisizawa, Tetsuro; Izumi, Nakako; Miyaji, Chikako; Vance, Russell E; Raulet, David H; Okumura, Ko; Abo, Toru

    2005-08-01

    Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic bone marrow transplantation, which is caused by donor T cells specific for host alloantigens. In a murine model, we found that donor T cells expressed a natural killer cell inhibitory receptor, CD94/NKG2A, during the course of aGVHD. Administration of an anti-NKG2A mAb markedly inhibited the expansion of donor T cells and ameliorated the aGVHD pathologies. These results suggested that the CD94/NKG2A inhibitory receptor expressed on host-reactive donor T cells can be a novel target for the amelioration of aGVHD.

  9. Acute ascorbic acid ingestion increases skeletal muscle blood flow and oxygen consumption via local vasodilation during graded handgrip exercise in older adults.

    PubMed

    Richards, Jennifer C; Crecelius, Anne R; Larson, Dennis G; Dinenno, Frank A

    2015-07-15

    Human aging is associated with reduced skeletal muscle perfusion during exercise, which may be a result of impaired endothelium-dependent dilation and/or attenuated ability to blunt sympathetically mediated vasoconstriction. Intra-arterial infusion of ascorbic acid (AA) increases nitric oxide-mediated vasodilation and forearm blood flow (FBF) during handgrip exercise in older adults, yet it remains unknown whether an acute oral dose can similarly improve FBF or enhance the ability to blunt sympathetic vasoconstriction during exercise. We hypothesized that 1) acute oral AA would improve FBF (Doppler ultrasound) and oxygen consumption (V̇o2) via local vasodilation during graded rhythmic handgrip exercise in older adults (protocol 1), and 2) AA ingestion would not enhance sympatholysis in older adults during handgrip exercise (protocol 2). In protocol 1 (n = 8; 65 ± 3 yr), AA did not influence FBF or V̇o2 during rest or 5% maximal voluntary contraction (MVC) exercise, but increased FBF (199 ± 13 vs. 248 ± 16 ml/min and 343 ± 24 vs. 403 ± 33 ml/min; P < 0.05) and V̇o2 (26 ± 2 vs. 34 ± 3 ml/min and 43 ± 4 vs. 50 ± 5 ml/min; P < 0.05) at both 15 and 25% MVC, respectively. The increased FBF was due to elevations in forearm vascular conductance (FVC). In protocol 2 (n = 10; 63 ± 2 yr), following AA, FBF was similarly elevated during 15% MVC (∼ 20%); however, vasoconstriction to reflex increases in sympathetic activity during -40 mmHg lower-body negative pressure at rest (ΔFVC: -16 ± 3 vs. -16 ± 2%) or during 15% MVC (ΔFVC: -12 ± 2 vs. -11 ± 4%) was unchanged. Our collective results indicate that acute oral ingestion of AA improves muscle blood flow and V̇o2 during exercise in older adults via local vasodilation.

  10. Notch pathway plays a novel and critical role in regulating responses of T and antigen-presenting cells in aGVHD.

    PubMed

    Luo, Xiaodan; Xu, Lihua; Li, Yangqiu; Tan, Huo

    2017-04-01

    Graft-versus-host disease (GVHD) induced by host antigen-presenting cells (APCs) and donor-derived T cells remains the major limitation of allogeneic bone marrow transplantation (allo-BMT). Notch signaling pathway is a highly conserved cell-cell communication that is important in T cell development. Recently, Notch signaling pathway is reported to be involved in regulating GVHD. To investigate the role of Notch inhibition in modulating GVHD, we established MHC-mismatched murine allo-BMT model. We found that inhibition of Notch signaling pathway by γ-secretase inhibitor in vivo could reduce aGVHD, which was shown by the onset time of aGVHD, body weight, clinical aGVHD scores, pathology aGVHD scores, and survival. Inhibition of Notch signaling pathway by DAPT ex vivo only reduced pathology aGVHD scores in the liver and intestine and had no impact on the onset time and clinical aGVHD scores. We investigated the possible mechanism by analyzing the phenotype of host APCs and donor-derived T cells. Notch signaling pathway had a broad effect on both host APCs and donor-derived T cells. The expressions of CD11c, CD40, and CD86 as the markers of activated dendritic cells (DCs) were decreased. The proliferative response of CD8+ T cell decreased, while CD4(+) Notch-deprived T cells had preserved expansion with increased expressions of CD25 and Foxp3 as markers of regulatory T cells (Tregs). In conclusion, Notch inhibition may minimize aGVHD by decreasing proliferation and activation of DCs and CD8(+) T cells while preserving Tregs expansion.

  11. Characterization of oral involvement in acute graft-versus-host disease.

    PubMed

    Ion, Daniela; Stevenson, Kristen; Woo, Sook-Bin; Ho, Vincent T; Soiffer, Robert; Antin, Joseph H; Treister, Nathaniel S

    2014-11-01

    Acute graft-versus-host-disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). The purpose of this study was to characterize the oral features associated with aGVHD in patients who underwent HSCT between 1995 and 2010 and developed prominent oral aGVHD. Data was collected from patient medical records and analyzed descriptively. Twenty-one cases were identified, of which 5 (24%) demonstrated only oral features; the remaining 16 had variable involvement of skin (n = 14), liver (n = 7), and gut (n = 5). The median time to onset of any sign of aGVHD was 22 days (range, 8 to 154 days), and that for onset of oral aGVHD was 35 days (range, 11 to 159 days). Sites affected by nonspecific erythema and ulcerations included buccal mucosa (19 of 21; 90%) tongue (18 of 21; 86%; dorsum in 8), labial mucosa (16 of 21; 76%), palatal mucosa (15 of 21; 71%; hard palate in 7), and floor of mouth (7 of 21; 33%). Eight cases (38%) presented with lip ulceration and crusting. In addition to systemic therapies, topical solutions of dexamethasone, tacrolimus, and morphine were used for ancillary support. Oral features of aGVHD may be the initial manifestation and include nonspecific erythema and ulcerations of keratinized and nonkeratinized mucosa and lips. Intensive topical therapies may help reduce symptoms and promote healing.

  12. PKCtheta is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice.

    PubMed

    Valenzuela, Javier O; Iclozan, Cristina; Hossain, Mohammad S; Prlic, Martin; Hopewell, Emily; Bronk, Crystina C; Wang, Junmei; Celis, Esteban; Engelman, Robert W; Blazar, Bruce R; Bevan, Michael J; Waller, Edmund K; Yu, Xue-Zhong; Beg, Amer A

    2009-12-01

    When used as therapy for hematopoietic malignancies, allogeneic BM transplantation (BMT) relies on the graft-versus-leukemia (GVL) effect to eradicate residual tumor cells through immunologic mechanisms. However, graft-versus-host disease (GVHD), which is initiated by alloreactive donor T cells that recognize mismatched major and/or minor histocompatibility antigens and cause severe damage to hematopoietic and epithelial tissues, is a potentially lethal complication of allogeneic BMT. To enhance the therapeutic potential of BMT, we sought to find therapeutic targets that could inhibit GVHD while preserving GVL and immune responses to infectious agents. We show here that T cell responses triggered in mice by either Listeria monocytogenes or administration of antigen and adjuvant were relatively well preserved in the absence of PKC isoform theta (PKCtheta), a key regulator of TCR signaling. In contrast, PKCtheta was required for alloreactivity and GVHD induction. Furthermore, absence of PKCtheta raised the threshold for T cell activation, which selectively affected alloresponses. Most importantly, PKCtheta-deficient T cells retained the ability to respond to virus infection and to induce GVL effect after BMT. These findings suggest PKCtheta is a potentially unique therapeutic target required for GVHD induction but not for GVL or protective responses to infectious agents.

  13. Anti-CD13 Abs in children with extensive chronic GVHD and their relation to soluble CD13 after allogeneic blood and marrow transplantation from a Children's Oncology Groups Study, ASCT0031.

    PubMed

    Cuvelier, G D E; Kariminia, A; Fujii, H; Aslanian, S; Wall, D; Goldman, F; Grupp, S A; Dunn, S E; Krailo, M; Shapiro, L H; Gilman, A; Schultz, K R

    2010-11-01

    Our group previously demonstrated a strong association between elevated plasma soluble CD13 enzyme activity and newly diagnosed extensive chronic GVHD (cGVHD) in children. As cytotoxic anti-CD13 Abs have been documented after blood and marrow transplant (BMT) in association with CMV infection and cGVHD, we hypothesized that soluble CD13 contributes to cGVHD pathogenesis by induction of CD13 reactive Abs and that anti-CD13 Abs could be additional biomarkers for newly diagnosed pediatric extensive cGVHD. Using prospectively collected plasma samples from pediatric allogeneic BMT (allo-BMT) subjects with cGVHD and controls without cGVHD enrolled in a large multi-institution Children's Oncology Group cGVHD therapeutic trial, we evaluated whether soluble CD13 correlates with induction of anti-CD13 Abs. We found that CD13 reactive Abs are present in a proportion of patients after allo-BMT, but did not seem to correlate with the presence of soluble CD13. Anti-CD13 Abs also did not meet our criteria as a diagnostic biomarker for cGVHD. These data do not confirm that induction of CD13 reactive Abs is a mechanism for cGVHD in children nor are part of the pathogenesis of cGVHD associated with elevated soluble CD13. The exact role of CD13 in cGVHD remains to be determined.

  14. Low Dose IL-2, Hematopoietic Stem Cell Transplantation, IL2 for GVHD

    ClinicalTrials.gov

    2016-01-11

    Acute Lymphoblastic Leukemia; ALL; Acute Myelogenous Leukemia; AML; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome; Myeloproliferative Disorder; Hodgkin Lymphoma; Non-Hodgkin Lymphoma; Non-malignant Diseases Requiring Allogeneic HSCT

  15. In-Vivo Activated T-Cell Depletion to Prevent GVHD

    ClinicalTrials.gov

    2014-09-26

    Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Myelodysplasia; Lymphoma, Non-Hodgkin's; Mantle-Cell Lymphoma; Hodgkin's Disease; Multiple Myeloma; Myelofibrosis

  16. Modulation of GvHD by suicide-gene transduced donor T lymphocytes: clinical applications in mismatched transplantation.

    PubMed

    Ciceri, F; Bonini, C; Gallo-Stampino, C; Bordignon, C

    2005-01-01

    In allogeneic hematopoietic cell transplantation (allo-HCT), donor lymphocytes play a central therapeutic role in both GvL and immune reconstitution. However, the full exploitation of these therapeutic properties is limited by the occurrence of GvHD. Different strategies have been investigated to obtain all the benefits derived from donor lymphocytes while avoiding the risk of GvHD. The genetic engineering of donor lymphocytes with the herpes simplex virus-thymidine kinase (HSV-TK) suicide gene confers the ability to modulate GvHD by invivo ganciclovir-induced elimination of the transduced cells. The suicide-gene strategy has applications in both donor lymphocyte infusion (DLI) for disease relapse and in add-back infusions after T-cell depleted allo-HCT. TK cell DLI resulted in anti-tumor activity in a relevant proportion of treated patients. Haplo-identical stem cell transplantation (haplo-HCT) is a promising therapeutic option for patients with high risk hematologic malignancies lacking an HLA-matched donor. However, the profound T-cell depletion required to overcome the risk of lethal GvHD has been associated with a marked delayed T-cell recovery with a prolonged risk of post-transplant viral, fungal and other opportunistic infections. TK cell add-backs efficiently promote early immune reconstitution after haplo-HCT and prevent disease relapse, providing a unique tool for the control of GvHD. The genetic manipulation of donor lymphocytes with a suicide gene is a promising strategy to increase feasibility and safety of allo-HCT.

  17. miR-153-3p, a new bio-target, is involved in the pathogenesis of acute graft-versus-host disease via inhibition of indoleamine- 2,3-dioxygenase

    PubMed Central

    Lv, Meng; Kong, Yuan; Luo, Hong-xue; Ye, Xiao-yang; Wu, Qi; Zhao, Tong-feng; Hu, Yue-huan; Zhang, Hong-yu; Huo, Ming-Rui; Wan, Jun; Huang, Xiao-jun

    2016-01-01

    Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Therefore, seeking reliable biomarkers and delineating the potential biological mechanism are important for optimizing treatment strategies and improving their curative effect. In this study, using a microRNA polymerase chain reaction (PCR)-based chip assay, microRNA-153-3p (miR-153-3p) was screened and selected as a potential biomarker of aGVHD. The elevated plasma miR-153-3p levels at +7 d after transplant could be used to predict the upcoming aGVHD. The area under the receiver operating characteristic curve for aGVHD+/aGVHD- patients receiving haploidentical transplant was 0.808 (95% confidence interval, 0.686-0.930) in a training set and 0.809 (95% confidence interval, 0.694-0.923) in a validation set. Interestingly, bioinformatics analysis indicated that indoleamine-2,3-dioxygenase (IDO) is a potential target of miR-153-3p. In vitro study confirmed that IDO could be directly inhibited by miR-153-3p. In a GVHD model, recipient mice injected with a miR-153-3p antagomir exhibited higher IDO expression levels at the early stage after transplantation, as well as delayed aGVHD and longer survival, indicating that the miR-153-3p level at +7 d post-transplant is a good predictor of aGVHD. miR-153-3p participates in aGVHD development by inhibiting IDO expression and might be a novel bio-target for aGVHD intervention. PMID:27340781

  18. Outcome of conditioning intensity in acute myeloid leukemia with monosomal karyotype in patients over 45 year-old: A study from the acute leukemia working party (ALWP) of the European group of blood and marrow transplantation (EBMT).

    PubMed

    Poiré, Xavier; Labopin, Myriam; Cornelissen, Jan J; Volin, Liisa; Richard Espiga, Carlos; Veelken, J Hendrik; Milpied, Noël; Cahn, Jean-Yves; Yacoub-Agha, Ibrahim; van Imhoff, Gustaaf W; Michallet, Mauricette; Michaux, Lucienne; Nagler, Arnon; Mohty, Mohamad

    2015-08-01

    Acute myeloid leukemia with monosomal karyotype (MK AML) carries a very poor prognosis, even after allogeneic stem cell transplantation (SCT). However, SCT remains the only curative option in this high-risk population. Because myeloablative conditioning regimen (MAC) is associated with less relapse, we hypothesized that more intensive conditioning regimen might be beneficial for MK AML patients. We reviewed 303 patients over age 45 diagnosed with either de novo or secondary MK AML. One hundred and five patients received a MAC and 198 a reduced-intensity conditioning (RIC). The median age at SCT was 57-year-old, significantly lower in the MAC (53-year-old) than in the RIC group (59-year-old). The median follow-up was 42 months (range, 3 - 156 months). The 3-year overall survival (OS), leukemia-free survival (LFS), and relapse rate (RR) were not significantly different between both groups with overall values of 34%, 29%, and 51%, respectively. On the contrary, the 3-year nonrelapse mortality (NRM) was significantly higher in MAC recipients (28%) compared with RIC patients (16%, P = 0.004). The incidence of Grades II to IV acute graft-versus-host disease (GvHD) was significantly higher after a MAC (30.5%) than after a RIC (19.3%, P = 0.02). That of chronic GvHD was comparable between both groups (35%) and did not impact on LFS. Interestingly, within our MK AML cohort, hypodiploidy was significantly associated with worse outcomes. Due to reduced toxicity and comparable OS, LFS, and RR, RIC appears as a good transplant option in the very high-risk population, including older patients, diagnosed with MK AML.

  19. Hematopoietic stem cell transplantation in children and young adults with secondary myelodysplastic syndrome and acute myelogenous leukemia after aplastic anemia.

    PubMed

    Yoshimi, Ayami; Strahm, Brigitte; Baumann, Irith; Furlan, Ingrid; Schwarz, Stephan; Teigler-Schlegel, Andrea; Walther, Joachim-Ulrich; Schlegelberger, Brigitte; Göhring, Gudrun; Nöllke, Peter; Führer, Monika; Niemeyer, Charlotte M

    2014-03-01

    Secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/sAML) are the most serious secondary events occurring after immunosuppressive therapy in patients with aplastic anemia. Here we evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in 17 children and young adults with sMDS/sAML after childhood aplastic anemia. The median interval between the diagnosis of aplastic anemia and the development of sMDS/sAML was 2.9 years (range, 1.2 to 13.0 years). At a median age of 13.1 years (range, 4.4 to 26.7 years), patients underwent HSCT with bone marrow (n = 6) or peripheral blood stem cell (n = 11) grafts from HLA-matched sibling donors (n = 2), mismatched family donors (n = 2), or unrelated donors (n = 13). Monosomy 7 was detected in 13 patients. The preparative regimen consisted of busulfan, cyclophosphamide, and melphalan in 11 patients and other agents in 6 patients. All patients achieved neutrophil engraftment. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and that of chronic GVHD was 70%. Relapse occurred in 1 patient. The major cause of death was transplant-related complication (n = 9). Overall survival and event-free survival at 5 years after HSCT were both 41%. In summary, this study indicates that HSCT is a curative therapy for some patients with sMDS/sAML after aplastic anemia. Future efforts should focus on reducing transplantation-related mortality.

  20. Efficacy and safety of intra-arterial steroid infusions in patients with steroid-resistant gastrointestinal acute graft-versus-host disease.

    PubMed

    Nishimoto, Mitsutaka; Koh, Hideo; Hirose, Asao; Nakamae, Mika; Nakane, Takahiko; Hayashi, Yoshiki; Okamura, Hiroshi; Yoshimura, Takuro; Koh, Shiro; Nanno, Satoru; Nakashima, Yasuhiro; Takeshita, Toru; Yamamoto, Akira; Sakai, Yukimasa; Nishida, Norifumi; Matsuoka, Toshiyuki; Miki, Yukio; Hino, Masayuki; Nakamae, Hirohisa

    2015-12-01

    There is no established second-line treatment for steroid-resistant acute graft-versus-host disease (GVHD). We prospectively assessed the safety and efficacy of intra-arterial steroid infusions (IASIs) for steroid-resistant acute gastrointestinal (GI) GVHD and compared the outcomes with those of historical controls at our institution. Nineteen consecutive, allogeneic hematopoietic stem cell transplantation subjects aged 31-67 years (median 52) were enrolled between October, 2008, and November, 2012. Acute GVHD was confirmed by biopsy in all cases. The enrolled patients were treated with infusions of methylprednisolone into the mesenteric arteries and/or gastroduodenal and left gastric arteries. Fourteen consecutive patients who developed steroid-resistant acute GI GVHD between 2001 and 2008 were used as controls. For the primary endpoint at day 28, the overall and complete responses in the IASI group trended higher (79% vs. 42%, p = 0.066) and were significantly higher (63% vs. 21%, p = 0.033) than those in the control group. Although not statistically significant, owing to the small population, the crude day-180-nonrelapse mortality rate was about 20% lower and the day-180-overall-survival rate tended to be higher than the control (11% vs. 29%, p = 0.222; 79% vs. 50%, p = 0.109, respectively). There were no serious IASI-related complications. Our results suggest that IASI can safely provide excellent efficacy for refractory acute GI GVHD without increasing infection-related complications and may improve prognosis.

  1. Acute renal graft-versus-host disease in a murine model of allogeneic bone marrow transplantation.

    PubMed

    Schmid, Peter M; Bouazzaoui, Abdellatif; Schmid, Karin; Birner, Christoph; Schach, Christian; Maier, Lars S; Holler, Ernst; Endemann, Dierk H

    2017-03-23

    Acute kidney injury (AKI) is a very common complication after allogeneic bone marrow transplantation (BMT) and associated with poor prognosis. Generally kidneys are assumed to be no direct target of Graft-versus-Host Disease (GvHD), and renal impairment is often attributed to several other factors occurring in the early phase after BMT. Our study aimed to prove the existence of renal GvHD in a fully MHC-mismatched model of BALB/c mice conditioned and transplanted according to two different intensity protocols. Syngeneically transplanted and untreated animals served as controls. 4 weeks after transplantation, allogeneic animals developed acute GvHD that was more pronounced in the high-intensity protocol (HIP) group than in the low-intensity protocol (LIP) group. Urea and creatinine as classic serum markers of renal function could not verify renal impairment 4 weeks after BMT. Creatinine levels were even reduced as a result of catabolic metabolism and loss of muscle mass due to acute GvHD. Proteinuria, albuminuria, and urinary N-acetyl-beta-Dglucosaminidase (NAG) levels were measured as additional renal markers before and after transplantation. Albuminuria and NAG were only significantly increased after allogeneic transplantation, correlating with disease severity between HIP and LIP animals. Histological investigations of the kidneys showed renal infiltration of T-cells and macrophages with endarteriitis, interstitial nephritis, tubulitis, and glomerulitis. T-cells consisted of CD4+, CD8+, and FoxP3+ cells. Renal expression analysis of allogeneic animals showed increases in indoleamine-2,3 dioxygenase (IDO), different cytokines (TNFα, IFN-γ, IL-1α, IL2, IL-6, and IL-10), and adhesion molecules (ICAM-1 and VCAM-1), resembling findings from other tissues in acute GvHD. In summary, our study supports the entity of renal GvHD with histological features suggestive of cell-mediated renal injury. Albuminuria and urinary NAG levels may serve as early markers of renal

  2. Immunomodulation effects of mesenchymal stromal cells on acute graft-versus-host disease after hematopoietic stem cell transplantation.

    PubMed

    Zhao, Ke; Lou, Rui; Huang, Fen; Peng, Yanwen; Jiang, Zujun; Huang, Ke; Wu, Xiuli; Zhang, Yu; Fan, Zhiping; Zhou, Hongsheng; Liu, Can; Xiao, Yang; Sun, Jing; Li, Yangqiu; Xiang, Peng; Liu, Qifa

    2015-01-01

    Refractory acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic stem cell transplantation. This study evaluated the immunomodulation effects of mesenchymal stromal cells (MSCs) from bone marrow of a third-party donor for refractory aGVHD. Forty-seven patients with refractory aGVHD were enrolled: 28 patients receiving MSC and 19 patients without MSC treatment. MSCs were given at a median dose of 1 × 10(6) cells/kg weekly until patients got complete response or received 8 doses of MSCs. After 125 doses of MSCs were administered, with a median of 4 doses (range, 2 to 8) per patient, overall response rate was 75% in the MSC group compared with 42.1% in the non-MSC group (P = .023). The incidence of cytomegalovirus, Epstein-Barr virus infections, and tumor relapse was not different between the 2 groups during aGVHD treatment and follow-up. The incidence and severity of chronic GVHD in the MSC group were lower than those in the non-MSC group (P = .045 and P = .005). The ratio of CD3(+)CD4(+)/CD3(+)CD8(+) T cells, the frequencies of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), and the levels of signal joint T cell-receptor excision DNA circles (sjTRECs) after MSCs treatment were higher than those pretreatment. MSC-treated patients exhibited higher Tregs frequencies and sjTRECs levels than those in the non-MSC group at 8 and 12 weeks after treatment. MSCs derived from bone marrow of a third-party donor are effective to refractory aGVHD. It might reduce the incidence and severity of chronic GVHD in aGVHD patients by improving thymic function and induction of Tregs but not increase the risks of infections and tumor relapse.

  3. Allosuppressor- and allohelper-T cells in acute and chronic graft-vs. -host (GVH) disease. III. Different Lyt subsets of donor T cells induce different pathological syndromes

    SciTech Connect

    Rolink, A.G.; Gleichmann, E.

    1983-08-01

    Previous work from this laboratory has led to the hypothesis that the stimulatory pathological symptoms of chronic graft-vs.-host disease (GVHD) are caused by alloreactive donor T helper (TH) cells, whereas the suppressive pathological symptoms of acute GVHD are caused by alloreactive T suppressor (TS) cells of the donor. We analyzed the Lyt phenotypes of B10 donor T cells required for the induction of either acute or chronic GVHD in H-2-different (B10 X DBA/2)F1 recipients. When nonirradiated F1 mice were used as the recipients, we found unseparated B10 T cells induced only a moderate formation of systemic lupus erythematosus (SLE)-like autoantibodies, but a high percentage of lethal GVHD (LGVHD). In contrast, Lyt-1+2- donor T cells were unable to induce LGVHD in these recipients but were capable of inducing a vigorous formation of SLE-like autoantibodies and severe immune-complex glomerulonephritis. Lyt-1-2+ T cells were incapable of inducing either acute or chronic GVHD. The sensitivity and accuracy of the GVH system were increased by using irradiated F1 mice as recipients and then comparing donor-cell inocula that contained similar numbers of T lymphocytes. Donor-cell inocula were used that had been tested for their allohelper and allosuppressor effects on F1 B cells in vitro. In the irradiated F1 recipients unseparated donor T cells were superior to T cell subsets in inducing LGVHD. In contrast Lyt-1+2- T cells, but neither unseparated T cells nor Lyt-1-2+ T cells, were capable of inducing a vigorous formation of SLE-like auto-antibodies. We conclude that the stimulatory pathological symptoms of chronic GVHD are caused by Lyt-1+2- allohelper T cells. In contrast, the development of the suppressive pathological symptoms of acute GVHD appears to involve alloreactive Lyt-1+2+ T suppressor cells.

  4. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice

    PubMed Central

    Shono, Yusuke; Docampo, Melissa D.; Peled, Jonathan U.; Perobelli, Suelen M.; Velardi, Enrico; Tsai, Jennifer J.; Slingerland, Ann E.; Smith, Odette M.; Young, Lauren F.; Gupta, Jyotsna; Lieberman, Sophia R.; Jay, Hillary V.; Ahr, Katya F.; Rodriguez, Kori A. Porosnicu; Xu, Ke; Calarfiore, Marco; Poeck, Hendrik; Caballero, Silvia; Devlin, Sean M.; Rapaport, Franck; Dudakov, Jarrod A.; Hanash, Alan M.; Gyurkocza, Boglarka; Murphy, George F.; Gomes, Camilla; Liu, Chen; Moss, Eli L.; Falconer, Shannon B.; Bhatt, Ami S.; Taur, Ying; Pamer, Eric G.

    2016-01-01

    After allogeneic hematopoietic stem cell transplantation (allo-HSCT), intestinal bacteria modulate risks of infection and graft-versus-host disease (GVHD). Neutropenic fever is common and treated with a choice of clinically equivalent antibiotics that target obligately anaerobic bacteria (anaerobes) to varying degrees. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam was associated with increased GVHD-related mortality at 5 years (21.5% in imipenem-cilastatin-treated patients vs. 13.1% in untreated patients, p=0.025, and 19.8% in piperacillin-tazobactam-treated patients vs. 11.9% in untreated patients, p=0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (p=0.78 and p=0.98, respectively). Analysis of stool microbiota composition showed that piperacillin-tazobactam administration was associated with increased compositional perturbation. Studies in mouse models demonstrated similar effects of these antibiotics, as well as aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactm compared to aztreonam (p<0.01 and p<0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (p<0.05), but no differences in short-chain fatty acid concentrations or regulatory T cells numbers. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective lining of mucus in the colon (p<0.01) and intestinal barrier function was compromised (p<0.05). Sequencing of mouse stool specimens showed expansion of Akkermansia muciniphila (p<0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation can contribute to murine GVHD. We demonstrate an underappreciated risk for antibiotics with activity against anaerobes to exacerbate colonic GVHD after

  5. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study.

    PubMed

    Curtis, Rochelle E; Metayer, Catherine; Rizzo, J Douglas; Socié, Gérard; Sobocinski, Kathleen A; Flowers, Mary E D; Travis, William D; Travis, Lois B; Horowitz, Mary M; Deeg, H Joachim

    2005-05-15

    Previous studies of recipients of hematopoietic stem-cell transplants suggest that graft-versus-host disease (GVHD) and its therapy may increase the risk for solid cancers, particularly squamous-cell carcinomas (SCCs) of the buccal cavity and skin. However, the importance and magnitude of these associations are not well characterized. We conducted a case-control study of 183 patients with posttransplantation solid cancers (58 SCCs, 125 non-SCCs) and 501 matched control patients within a cohort of 24,011 patients who underwent hematopoietic stem-cell transplantation (HSCT) at 215 centers worldwide. Our results showed that chronic GVHD and its therapy were strongly related to the risk for SCC, whereas no increase in risk was found for non-SCCs. Major risk factors for the development of SCC were long duration of chronic GVHD therapy (P < .001); use of azathioprine, particularly when combined with cyclosporine and steroids (P < .001); and severe chronic GVHD (P = .004). Given that most patients who received prolonged immunosuppressive therapy and those with severe chronic GVHD were also treated with azathioprine, the independent effects of these factors could not be evaluated. Additional analyses determined that prolonged immunosuppressive therapy and azathioprine use were also significant risk factors for SCC of the skin and of the oral mucosa. These data provide further encouragement for strategies to prevent chronic GVHD and for the development of more effective and less carcinogenic treatment regimens for patients with moderate or severe chronic GVHD. Our results also suggest that clinical screening for SCC is appropriate among patients exposed to persistent chronic GVHD, prolonged immunosuppressive therapy, or both.

  6. Child and parent perspectives of the chronic graft-versus-host disease (cGVHD) symptom experience: a concept elicitation study

    PubMed Central

    Baird, Kristin; Crum, Caroline; Powers, Kimberly; Carpenter, Paul; Baker, K. Scott; MacMillan, Margaret L.; Nemecek, Eneida; Lai, Jin-Shei; Mitchell, Sandra A.; Jacobsohn, David A.

    2016-01-01

    Purpose Chronic graft-versus-host disease (cGVHD) is a significant cause of mortality and morbidity after allogeneic hematopoietic cell transplant and is associated with a wide range of distressing symptoms. A pediatric measure of cGVHD-related symptoms is needed to advance clinical research. Our aim was to elicit descriptions of the cGVHD symptom experience directly from children and to compare the specific language used by children to describe their symptoms and the comprehension of symptom concepts across the developmental spectrum. Methods We used qualitative methods to identify the phrases, terms, and constructs that children (ages 5–8 [n =8], 9–12 [n =8], and 13–17 [n =8]) with cGVHD employ when describing their symptoms. The symptom experience of each participant was determined through individual interviews with each participant and parent (5–7 year olds were interviewed together with a parent). Medical practitioners with experience in evaluating cGVHD performed clinical assessments of each participant. Results Pediatric transplant survivors and their parents identified a wide range of bothersome cGVHD symptoms, and common concepts and terminologies to describe these experiences emerged. Overall concordance between patient and parent reports was moderate (70–75 %). No consistent pattern of child under- or over-reporting in comparison to the parent report was observed. Conclusion These study results identify concepts and vocabulary to inform item generation for a new pediatric self-report measure of cGVHD symptoms for use in clinical research. The findings also confirm the prevalence and nature of symptom distress in pediatric patients with cGVHD and support implementation of systematic approaches to symptom assessment and intervention in routine clinical practice. PMID:24077685

  7. A cross-sectional study on vision-related quality of life in patients with ocular GvHD.

    PubMed

    Pezzotta, S; Rossi, G C; Scudeller, L; Antoniazzi, E; Bianchi, P E; Perotti, C; Del Fante, C

    2015-09-01

    Ocular GvHD affects about 40-60% of patients receiving bone marrow transplantation. Ocular complaints worsen quality of life (QoL), which, besides survival time, is a primary end point in a patient's follow-up. The aim of our study was to assess the ocular surface status and vision-related QoL (VRQoL) and explore the potential determinants in VRQoL in patients with chronic GvHD with ocular involvement. In this cross-sectional study, we investigated 40 patients with ocular GvHD after allogeneic hematopoietic stem cell transplantation assessing ocular symptoms and signs, VRQoL and ophthalmologic parameters. The median age was 52.1 years; 32.5% were females. Most of them presented a multiple organ involvement. Ophthalmological parameter examinations were on average abnormal. Corneal staining was severe/very severe in 25%; conjunctival staining in 10% of subjects. The worse QoL scores were on 'general vision', 'ocular pain', 'vision-specific mental health' and 'vision-specific role difficulties'. Both symptoms and sign scores indicate poor VRQoL. A lower VRQoL was related to schooling level, job position, underlying disease and extracorporeal photopheresis. Corneal staining, Schirmer and tear film breakup time were negatively associated to visual function-related subscales. An accurate ophthalmological and VRQoL assessment should be mandatory for a long time to promptly recognize early signs of ocular suffering, and to prevent irreversible ocular complications.

  8. Antigen-Specific Priming is Dispensable in Depletion of Apoptosis-Sensitive T Cells for GvHD Prophylaxis.

    PubMed

    Yarkoni, Shai; Stein, Jerry; Yaniv, Isaac; Askenasy, Nadir

    2014-01-01

    Prophylactic approaches to graft versus host disease (GvHD) have employed both phenotypic reduction of T cells and selective elimination of host-primed donor T cells in vitro and in vivo. An additional approach to GvHD prophylaxis by functional depletion of apoptosis-sensitive donor T cells without host-specific sensitization ex vivo showed remarkable reduction in GHD incidence and severity. We address the role and significance of antigen-specific sensitization of donor T cells and discuss the mechanisms of functional T cell purging by apoptosis for GvHD prevention. Host-specific sensitization is dispensable because migration is antigen-independent and donor T cell sensitization is mediated by multiple and redundant mechanisms of presentation of major and minor histocompatibility complex and tissue antigens by donor and host antigen-presenting cells. Our data suggest that potential murine and human GvH effectors reside within subsets of preactivated T cells susceptible to negative regulation by apoptosis prior to encounter of and sensitization to specific antigens.

  9. Antigen-Specific Priming is Dispensable in Depletion of Apoptosis-Sensitive T Cells for GvHD Prophylaxis

    PubMed Central

    Yarkoni, Shai; Stein, Jerry; Yaniv, Isaac; Askenasy, Nadir

    2014-01-01

    Prophylactic approaches to graft versus host disease (GvHD) have employed both phenotypic reduction of T cells and selective elimination of host-primed donor T cells in vitro and in vivo. An additional approach to GvHD prophylaxis by functional depletion of apoptosis-sensitive donor T cells without host-specific sensitization ex vivo showed remarkable reduction in GHD incidence and severity. We address the role and significance of antigen-specific sensitization of donor T cells and discuss the mechanisms of functional T cell purging by apoptosis for GvHD prevention. Host-specific sensitization is dispensable because migration is antigen-independent and donor T cell sensitization is mediated by multiple and redundant mechanisms of presentation of major and minor histocompatibility complex and tissue antigens by donor and host antigen-presenting cells. Our data suggest that potential murine and human GvH effectors reside within subsets of preactivated T cells susceptible to negative regulation by apoptosis prior to encounter of and sensitization to specific antigens. PMID:24904571

  10. Determinants of functional performance in long-term survivors of allogeneic hematopoietic stem cell transplantation with chronic graft-versus-host disease (cGVHD)

    PubMed Central

    Mitchell, SA; Leidy, N Kline; Mooney, KH; Dudley, WN; Beck, SL; LaStayo, PC; Cowen, EW; Palit, P; Comis, LE; Krumlauf, MC; Avila, DN; Atlam, N; Fowler, DH; Pavletic, SZ

    2009-01-01

    This study examined factors accounting for functional performance limitations in 100 long-term survivors of allogeneic hematopoietic stem cell transplantation with chronic graft-versus-host disease (cGVHD). Functional performance, measured by the SF-36 physical component summary score, was substantially lower (mean = 36.8±10.7) than the US population norm of 50 (P<0.001). The most severe decrements were in physical function (mean = 38.8±10.9) and physical role function (mean = 37.88±11.88); 68% of respondents exceeded the five-point threshold of minimum clinically important difference below the norm on these subscales. Controlling for age and gender, six variables explained 56% of the variance in functional performance: time since cGVHD diagnosis, cGVHD severity, intensity of immunosuppression, comorbidity, functional capacity (distance walked in 2 min, grip strength, and range of motion), and cGVHD symptom bother (F = 11.26; P<0.001). Significant independent predictors of impaired performance were intensive systemic immunosuppression, reduced capacity for ambulation, and greater cGVHD symptom bother (P<0.05). Symptom bother had a direct effect on functional performance, as well as an indirect effect partially mediated by functional capacity (Sobel test, P = 0.004). Results suggest two possible mechanisms underlying impaired functional performance in survivors with cGVHD and underscore the importance of testing interventions to enhance functional capacity and reduce symptom bother. PMID:19784078

  11. Early and Late Extensive Chronic Graft-Versus-Host Disease (cGVHD) In Children Is Characterized By Different Th1/Th2 Cytokine Profiles: Findings Of The Children’s Oncology Group Study (COG), ASCT0031

    PubMed Central

    Rozmus, Jacob; Schultz, Kirk R.; Wynne, Kristin; Kariminia, Amina; Satyanarayana, Preeti; Krailo, Mark; Grupp, Stephan A.; Gilman, Andrew L.; Goldman, Frederick D.

    2011-01-01

    Mechanisms underlying chronic graft-versus-host disease (cGVHD) are numerous, including skewing of Th1/Th2 cytokine expression. cGVHD has biological differences between early and late onset cGVHD. To test whether different Th1/Th2 cytokines are associated with early or late onset cGVHD, peripheral blood was collected from 63 children enrolled on the Children’s Oncology Group phase III trial ASCT0031 evaluating hydroxychloroquine therapy for newly diagnosed extensive cGVHD. mRNA expression of interferon gamma (IFN-γ) and interleukins 2, 4 and 10(IL-2, IL-4 and IL-10) from stimulated peripheral blood mononuclear cells was evaluated by quantitative polymerase chain reaction (Q-PCR). We found that early onset cGVHD (n=33) was characterized by decreased expression of IFN-γ and IL-2 mRNA after non-specific PMA-Ionomycin stimulation. In contrast, late onset cGVHD (n=11) was characterized by decreased expression of IL-4 and IL-2 mRNA after anti-CD3 stimulation of T cells. Receiver Operator Characteristic (ROC) curve analysis revealed that IFN-γ production could determine the absence of early cGVHD (AUC=0.77) and IL-4 (AUC=0.89) and IL-2 (AUC=0.84) the absence of late cGVHD. We did not find any correlation between cytokine expression and a specific immune cell subset. We also showed an increased expression of Foxp3 mRNA in early onset cGVHD and late controls. The different time-dependent cytokine profiles in newly-diagnosed cGVHD suggests that mechanisms underlying cGVHD are temporally regulated. While larger validation studies are needed our data suggests cytokine profiles could potentially be used as biomarkers for the diagnosis of cGVHD. PMID:21669298

  12. Grade Span.

    ERIC Educational Resources Information Center

    Renchler, Ron

    2000-01-01

    This issue reviews grade span, or grade configuration. Catherine Paglin and Jennifer Fager's "Grade Configuration: Who Goes Where?" provides an overview of issues and concerns related to grade spans and supplies profiles of eight Northwest schools with varying grade spans. David F. Wihry, Theodore Coladarci, and Curtis Meadow's…

  13. Initiation of acute graft-versus-host disease by angiogenesis.

    PubMed

    Riesner, Katarina; Shi, Yu; Jacobi, Angela; Kraeter, Martin; Kalupa, Martina; McGearey, Aleixandria; Mertlitz, Sarah; Cordes, Steffen; Schrezenmeier, Jens-Florian; Mengwasser, Jörg; Westphal, Sabine; Perez-Hernandez, Daniel; Schmitt, Clemens; Dittmar, Gunnar; Guck, Jochen; Penack, Olaf

    2017-01-17

    The inhibition of inflammation-associated angiogenesis ameliorates inflammatory diseases by reducing the recruitment of tissue infiltrating leukocytes. However, it is not known if angiogenesis has an active role during the initiation of inflammation or if it is merely a secondary effect occurring in response to stimuli by tissue infiltrating leukocytes. Here we show that angiogenesis precedes leukocyte infiltration in experimental models of inflammatory bowel disease and acute graft-versus-host disease (GVHD). We found that angiogenesis occurred as early as day+2 after allogeneic transplantation mainly in GVHD typical target organs skin, liver and intestines whereas no angiogenic changes appeared due to conditioning or syngeneic transplantation. The initiation phase of angiogenesis was not associated to classical endothelial cell (EC) activation signs, such as Vegfa/VEGFR1+2 upregulation or increased adhesion molecule expression. During early GVHD at day+2, we found significant metabolic and cytoskeleton changes in target organ ECs in gene array- and proteomic analyses. These modifications have significant functional consequences as indicated by profoundly higher deformation in Real-time deformability cytometry. Our results demonstrate that metabolic changes trigger alterations in cell mechanics leading to enhanced migratory and proliferative potential of ECs during the initiation of inflammation. Our study adds evidence to the hypothesis that angiogenesis is involved in the initiation of tissue inflammation during GVHD.

  14. The Role of Purine Metabolites as DAMPs in Acute Graft-versus-Host Disease

    PubMed Central

    Apostolova, Petya; Zeiser, Robert

    2016-01-01

    Acute graft-versus-host disease (GvHD) causes high mortality in patients undergoing allogeneic hematopoietic cell transplantation. An early event in the classical pathogenesis of acute GvHD is tissue damage caused by the conditioning treatment or infection that consecutively leads to translocation of bacterial products [pathogen-associated molecular patterns (PAMPs)] into blood or lymphoid tissue, as well as danger-associated molecular patterns (DAMPs), mostly intracellular components that act as pro-inflammatory agents, once they are released into the extracellular space. A subtype of DAMPs is nucleotides, such as adenosine triphosphate released from dying cells that can activate the innate and adaptive immune system by binding to purinergic receptors. Binding to certain purinergic receptors leads to a pro-inflammatory microenvironment and promotes allogeneic T cell priming. After priming, T cells migrate to the acute GvHD target organs, mainly skin, liver, and the gastrointestinal tract and induce cell damage that further amplifies the release of intracellular components. This review summarizes the role of different purinergic receptors in particular P2X7 and P2Y2 as well as nucleotides in the pathogenesis of GvHD. PMID:27818661

  15. Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL

    PubMed Central

    Hanash, Alan M.; Kappel, Lucy W.; Yim, Nury L.; Nejat, Rebecca A.; Goldberg, Gabrielle L.; Smith, Odette M.; Rao, Uttam K.; Dykstra, Lindsay; Na, Il-Kang; Holland, Amanda M.; Dudakov, Jarrod A.; Liu, Chen; Murphy, George F.; Leonard, Warren J.; Heller, Glenn

    2011-01-01

    IL-21 is a proinflammatory cytokine produced by Th17 cells. Abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL remain incompletely understood. In a murine MHC-mismatched BM transplantation model, we observed that IL-21 receptor knockout (IL-21R KO) donor T cells mediate decreased systemic and gastrointestinal GVHD in recipients of a transplant. This reduction in GVHD was associated with expansion of transplanted donor regulatory T cells and with tissue-specific modulation of Th-cell function. IL-21R KO and wild-type donor T cells showed equivalent alloactivation, but IL-21R KO T cells showed decreased infiltration and inflammatory cytokine production within the mesenteric lymph nodes. However, Th-cell cytokine production was maintained peripherally, and IL-21R KO T cells mediated equivalent immunity against A20 and P815 hematopoietic tumors. In summary, abrogation of IL-21 signaling in donor T cells leads to tissue-specific modulation of immunity, such that gastrointestinal GVHD is reduced, but peripheral T-cell function and GVL capacity are retained. IL-21 is thus an exciting target for therapeutic intervention and improvement of clinical transplantation outcomes. PMID:21596854

  16. Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD).

    PubMed

    Taylor, Patricia A; Ehrhardt, Michael J; Lees, Christopher J; Tolar, Jakub; Weigel, Brenda J; Panoskaltsis-Mortari, Angela; Serody, Jonathan S; Brinkmann, Volker; Blazar, Bruce R

    2007-11-01

    The immunomodulator FTY720 (FTY) has been shown to be beneficial in experimental models of organ transplantation and autoimmunity. We show that FTY significantly inhibited but did not prevent graft-versus-host disease (GVHD) in lethally irradiated or nonirradiated allogeneic recipients. Although most studies implicate prevention of lymphocyte egress from lymphoid organs as the primary mechanism of action, our data indicate that FTY effects on the host are more likely to be responsible for GVHD inhibition. FTY reduced splenic CD11c+ cells by 50%, and similarly reduced CD4+ and CD8+ T-cell responder frequencies in the spleen early after transplantation. Imaging of GFP+ effectors indicated that FTY modified donor effector T-cell migration to secondary lymphoid organs, but did not uniformly trap T cells in lymph nodes or prevent early effector migration to GVHD parenchymal target organs. Administration of FTY only prior to transplantation inhibited GVHD, indicating that the primary function of FTY may be targeted to host cells. FTY was additive with regulatory T cells for GVHD inhibition. FTY slightly impaired but did not abrogate a graft-versus-leukemia (GVL) effect against C1498, a myeloid leukemia. Our data further define the mechanisms of action and provide insight as to the potential clinical uses of FTY in allogeneic bone marrow transplant recipients.

  17. Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation in First Complete Remission Can Abrogate the Poor Outcomes of Children with Acute Myeloid Leukemia Resistant to the First Course of Induction Chemotherapy.

    PubMed

    Mo, Xiao-Dong; Zhang, Xiao-Hui; Xu, Lan-Ping; Wang, Yu; Yan, Chen-Hua; Chen, Huan; Chen, Yu-Hong; Han, Wei; Wang, Feng-Rong; Wang, Jing-Zhi; Liu, Kai-Yan; Huang, Xiao-Jun

    2016-12-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is an important therapy option for children with acute myeloid leukemia (AML) resistant to the first course of induction chemotherapy (IC1st). We aimed to identify the efficacy of unmanipulated haploidentical HSCT (haplo-HSCT) in children with AML in the first complete remission and whether children resistant (IC1st-resistant; n = 38) or sensitive (IC1st-sensitive; n = 59) to the IC1st can achieve comparable outcomes. The cumulative incidence of grades III to IV acute graft-versus-host disease (GVHD) and severe chronic GVHD was .0% versus 20.1% (P = .038) and 21.7% versus 13.2% (P = .238), respectively, for the IC1st-resistant and IC1st-sensitive groups. The 3-year cumulative incidence of relapse and nonrelapse mortality was 22.2% versus 7.6% (P = .061) and 5.3% versus 10.8% (P = .364), respectively, for the IC1st-resistant and IC1st-sensitive groups. The 3-year probability of overall survival and disease-free survival was 76.3% versus 83.0% (P = .657) and 72.5% versus 81.6% (P = .396), respectively, for the IC1st-resistant and IC1st-sensitive groups. Multivariate analysis failed to show significant differences in survival rates between the groups. Thus, our results show that unmanipulated haplo-HSCT may overcome the poor prognostic significance of IC1st-resistance in children with AML, and it is valid as a postremission treatment for children with IC1st-resistant AML lacking an HLA-matched donor.

  18. Extracorporeal photopheresis for graft-versus-host disease: the role of patient, transplant, and classification criteria and hematologic values on outcome—results from a large single-center study

    PubMed Central

    Berger, Massimo; Albiani, Roberto; Sini, Bruno; Fagioli, Franca

    2015-01-01

    Background Extracorporeal photopheresis (ECP) has been shown as active therapy for graft-versus-host disease (GVHD). Study Design and Methods The aim was to ascertain the role of ECP in 71 patients with steroid-refractory or -dependent acute and chronic GVHD (aGVHD and cGVHD) with special focus on hematologic variables and GVHD staging classification. A total of 34 patients were treated for aGVHD and 37 for cGVHD. Results The overall response rate (ORR) for aGVHD was 65% and the complete aGVHD-free survival was 50% (95% confidence interval [CI], 36%-70%). The ORR for cGVHD response was 81% while the complete cGVHD-free survival was 50% (95% CI, 34%-73%). The aGVHD-free survival was associated with aGVHD grading (Grade II 81%, Grade III 33%, and Grade IV 0%, p ≤ 0.00) and the absence of visceral involvement (77% vs. 33%, p = 0.03). The cGVHD-free survival was associated with the female sex (67% vs. 25%, p = 0.01) and with the limited form according to the Seattle classification (67% vs. 20%, p = 0.003). No role for hematologic values or apheresis cell count was found, except for the cGVHD ORR (p = 0.037). Transplant-related mortality and overall survival were associated with ECP response 0% versus 54% (p = 0.0001) and 77% versus 45% (p = 0.03) for aGVHD patients and 7% versus 14% (p = 0.02) and 73% versus 20% (p = 0.0003) for cGVHD patients, respectively. Conclusions While confirming a higher probability of GVHD responses for early GVHD, our study shows no role of hematologic values or apheresis cell count on GVHD response. PMID:25355659

  19. Tacrolimus, Bortezomib, & Thymoglobulin in Preventing Low Toxicity GVHD in Donor Blood Stem Cell Transplant Patients

    ClinicalTrials.gov

    2016-10-21

    Acute Leukemia; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Diffuse Large B-Cell Lymphoma; Follicular Lymphoma; Graft Versus Host Disease; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Myelodysplastic Syndrome; Myelofibrosis; Myeloproliferative Neoplasm; Small Lymphocytic Lymphoma

  20. Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts in Preventing GVHD in Children

    ClinicalTrials.gov

    2016-10-06

    Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Acute Biphenotypic Leukemia; Acute Leukemia of Ambiguous Lineage; Acute Myeloid Leukemia in Remission; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Acute Lymphoblastic Leukemia in Remission; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; RAEB-1; RAEB-2; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

  1. Scurvy: a new problem for patients with chronic GVHD involving mucous membranes; an easy problem to resolve.

    PubMed

    Kletzel, Morris; Powers, Kim; Hayes, Meghan

    2014-08-01

    Vitamin C deficiency in developed countries is typically observed in patients with unique clinical conditions such as cystic fibrosis or anorexia nervosa, or in patients on long-term tube feeds. We report here a clinical observation in six pediatric and adolescent patients (median age 17.5 yr, range 9.8-23.5 yr) with chronic GVHD with mucous membrane involvement found to be vitamin C deficient. These patients' baseline serum vitamin C levels ranged from <0.12 to 0.94 mg/dL (normal value 0.20-1.90 mg/dL), with a mean level 0.56 ± 0.36 mg/dL and a median level 0.6 mg/dL. Among these patients, signs and symptoms of mucositis failed to respond to standard chronic GVHD therapy. After receiving treatment with 2000 mg of ascorbic acid by mouth, daily patients displayed increased serum vitamin C levels. Clinically, this correlated with a remarkable improvement in patients' mucositis and ability to eat.

  2. Impact of Conditioning Regimen on Outcomes for Children with Acute Myeloid Leukemia Undergoing Transplantation in First Complete Remission. An Analysis on Behalf of the Pediatric Disease Working Party of the European Group for Blood and Marrow Transplantation.

    PubMed

    Lucchini, Giovanna; Labopin, Myriam; Beohou, Eric; Dalissier, Arnauld; Dalle, Jean Hughes; Cornish, Jacqueline; Zecca, Marco; Samarasinghe, Sujith; Gibson, Brenda; Locatelli, Franco; Bertrand, Yves; Abdel-Rahman, Fawzi; Socie, Gerald; Sundin, Mikael; Lankester, Arjan; Sedlacek, Peter; Hamladji, Rose Marie; Heilmann, Carsten; Afanasyev, Boris; Hough, Rachel; Peters, Cristina; Bader, Peter; Veys, Paul

    2017-03-01

    Hematopoietic stem cell transplantation (HSCT) represents the cornerstone of treatment in pediatric high-risk and relapsed acute myeloid leukemia (AML). The aim of the present study was to compare outcomes of pediatric patients with AML undergoing HSCT using 3 different conditioning regimens: total body irradiation (TBI) and cyclophosphamide (Cy); busulfan (Bu) and Cy; or Bu, Cy, and melphalan (Mel). In this retrospective study, registry data for patients > 2 and <18 years age undergoing matched allogeneic HSCT for AML in first complete remission (CR1) in 204 European Group for Blood and Marrow Transplantation centers between 2000 and 2010 were analyzed. Data were available for 631 patients; 458 patients received stem cells from a matched sibling donor and 173 from a matched unrelated donor. For 440 patients, bone marrow was used as stem cell source, and 191 patients received peripheral blood stem cells. One hundred nine patients received TBICy, 389 received BuCy, and 133 received BuCyMel as their preparatory regimen. Median follow-up was 55 months. Patients receiving BuCyMel showed a lower incidence of relapse at 5 years (14.7% versus 31.5% in BuCy versus 30% in TBICy, P < .01) and higher overall survival (OS) (76.6% versus 64% versus 64.5%, P = .04) and leukemia-free survival (LFS) (74.5% versus 58% versus 61.9%, P < .01), with a comparable nonrelapse mortality (NRM) (10.8% versus 10.5% versus 8.1%, P = .79). Acute graft-versus-host disease (GVHD) grades III and IV but not chronic GVHD, was higher in patients receiving BuCyMel. Older age at HSCT had an adverse impact on NRM and the use of peripheral blood as stem cell source was associated with increased chronic GVHD and NRM as well as lower LFS and OS. Among pediatric patients receiving HSCT for AML in CR1, the use of BuCyMel conditioning proved superior to TBICy and BuCy in reducing relapse and improving LFS.

  3. Allogeneic stem cell transplantation after reduced-intensity conditioning for acute myeloid leukaemia: impact of chronic graft-versus-host disease.

    PubMed

    Valcárcel, David; Martino, Rodrigo; Piñana, Jose L; Sierra, Jorge

    2009-06-01

    The antineoplastic effect of allogeneic stem cell transplantation after reduced-intensity conditioning (RIC) relies on the graft-versus-tumour (GvT) reaction. GvT is closely linked to the development of graft-versus-host disease (GvHD). The incidence of acute GvHD after RIC seems lower than after myeloablative conditioning (MAC), whereas the incidence of chronic GvHD after RIC seems similar to after MAC. The results of RIC for acute myeloid leukaemia show a non-relapse mortality of approximately 15% at one year, a relapse incidence of approximately 40% after a median of 4-6 months, translating into overall and disease-free survival rates of 40-60%. The factors associated with improved outcome in most studies are the stage of the disease at transplantation, age and the development of chronic GvHD (and thus GvT). In a recent report, chronic GvHD was the most important factor associated with prolonged survival. Future efforts should be directed at aiming to decrease relapse rates. For this purpose, an adequate identification of high-risk patients, close monitoring of minimal residual disease after the procedure, and the use of antineoplastic drugs or immunotherapy may be of help.

  4. The Synthetic Triterpenoid, CDDO, Suppresses Alloreactive T Cell Responses and Reduces Murine Early Acute Graft-versus-Host Disease Mortality

    PubMed Central

    Sun, Kai; Li, Minghui; Konopleva, Marina; Konoplev, Sergej; Stephens, L. Clifton; Kornblau, Steven M.; Frolova, Olga; Wilkins, Danice E. C.; Ma, Weihong; Welniak, Lisbeth A.; Andreeff, Michael; Murphy, William J.

    2015-01-01

    Acute graft-versus-host disease (aGVHD) still remains one of the life-threatening complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Immunomodulation of alloreactive donor T cell responses, as well as cytokine secretion is a potential therapeutic approach for the prevention of aGVHD. The synthetic triterpenoid, CDDO (2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid), exhibits potent antitumor activity and has also been shown to mediate anti-inflammatory and immunomodulatory effects. We therefore wanted to assess the effects of CDDO on early lethal aGVHD. In this study, we found that CDDO significantly inhibited in vitro mixed lymphocyte responses and preferentially promoted the apoptosis of proliferating but not resting alloreactive T cells. Using a full major histocompatibility complex (MHC)-disparate murine aGVHD model, we found that the administration of CDDO immediately after transplantation significantly decreased liver pathology as determined by histologic assessment and prolonged survival in mice. Importantly, administration of CDDO did not adversely impair donor myeloid reconstitution as determined by peripheral blood cell count and the extent of donor chimerism. These findings indicate that CDDO has a significant immunomodulatory effects in vitro and on early lethal aGVHD development, particularly affecting the liver, in a murine allo-HSCT model. PMID:17448911

  5. Minor ABO-mismatches are risk factors for acute graft-versus-host disease in hematopoietic stem cell transplant patients.

    PubMed

    Ludajic, Katarina; Balavarca, Yesilda; Bickeböller, Heike; Rosenmayr, Agathe; Fischer, Gottfried F; Faé, Ingrid; Kalhs, Peter; Pohlreich, David; Kouba, Michal; Dobrovolna, Marie; Greinix, Hildegard T

    2009-11-01

    We investigated the impact of ABO and Rhesus (Rh) blood group matching on the outcome of hematopoietic stem cell transplantation (HSCT) of 154 patients matched at 10/10 HLA loci with unrelated donors. ABO and Rh, as potential risk factors, were modeled with the clinical outcome--acute and chronic graft-versus-host disease (aGVHD, cGVHD), relapse, treatment-related mortality (TRM), and overall survival (OS)--by simple, multiple, and competing risk analyses. We found that minor ABO-mismatches represent a significant risk factor for aGVHD (II-IV) with an estimated risk increase of almost 3-fold (hazard ratio [HR]=2.92, 95% confidence interval [CI]: 1.43-5.95, P=.003), and even 4-fold for aGVHD (III-IV) (HR=4.24, 95% CI: 1.70-10.56, P=.002), but not for other transplant endpoints. No significant association of the Rh matching status with any of the HSCT endpoints was seen. These results suggest that ABO minor mismatches may play a role in aGvHD pathophysiology, possibly by providing the setting for T cell activation and antibody mediated damage. To decrease the risk of aGVHD, ABO matching should be considered in HSCT.

  6. Complete Suppression of the Gut Microbiome Prevents Acute Graft-Versus-Host Disease following Allogeneic Bone Marrow Transplantation

    PubMed Central

    Vossen, Jaak M.; Guiot, Harry F. L.; Lankester, Arjan C.; Vossen, Ann C. T. M.; Bredius, Robbert G. M.; Wolterbeek, Ron; Bakker, Hanny D. J.; Heidt, Peter J.

    2014-01-01

    The hypothesis that elimination of facultative and strict anaerobic microorganisms from the gastro-intestinal tract by antimicrobial drugs in the period of time around allogeneic bone marrow transplantation (BMT) prevents acute graft-versus-host disease (GVHD), was examined in a cohort of 112 children grafted between 1989 and 2002 for hematological malignancies. All patients received T-cell replete marrow from human leukocyte antigens (HLA) matched sibling donors under identical transplantation conditions. To eliminate microorganisms from the gastro-intestinal tract, total gastro-intestinal decontamination (GID) was applied by high doses of non-absorbable antimicrobial drugs while the graft recipient was maintained in strict protective isolation. About half of the children (51%) proved to be successfully decontaminated, and about half (49%) unsuccessfully. One recipient got acute GVHD in the first group and 8 in the second group (p = 0.013). The degree of success of total GID was decisive for the occurrence of acute GVHD, irrespective of the presence of other risk factors such as higher age of recipient and/or donor, female donor for male recipient and carriership or reactivation of herpesviruses. Our results demonstrate that successful total GID of the graft recipient prevents moderate to severe acute GVHD. We suppose that substantial translocation of gastro-intestinal microorganisms or parts of these, functioning as microbial-associated molecular patterns (MAMP's), triggering macrophages/dendritic cells via pattern recognizing receptors (PRR's) is prohibited. As a consequence the initiation and progression of an inflammatory process leading to acute GVHD is inhibited. PMID:25180821

  7. Effect of graft source on unrelated donor hemopoietic stem cell transplantation in adults with acute myeloid leukemia after reduced-intensity or nonmyeloablative conditioning: a study from the Société Francaise de Greffe de Moelle et de Thérapie Cellulaire.

    PubMed

    Malard, Florent; Milpied, Noel; Blaise, Didier; Chevallier, Patrice; Michallet, Mauricette; Lioure, Bruno; Clément, Laurence; Hicheri, Yosr; Cordonnier, Catherine; Huynh, Anne; Yakoub-Agha, Ibrahim; Peffault de Latour, Regis; Mohty, Mohamad

    2015-06-01

    This retrospective report compared the 4-year outcomes of allogeneic stem cell transplantation (allo-SCT) in 651 adult patients with acute myeloid leukemia receiving a reduced-intensity (RIC) or nonmyeloablative conditioning (NMA) regimen according to the type of unrelated donors. These were either umbilical cord blood (UCB, n = 205), a 9/10 mismatched unrelated donor (MisMUD, n = 99), or a 10/10 matched unrelated donor (MUD, n = 347) graft. Neutrophil recovery was slower in UCB (74.5% by day 42) compared with MisMUD (94.8%) and MUD (95.6%) (P < .001). There was no significant difference in nonrelapse mortality between UCB and both MUD (hazard ratio [HR], 1.05; 95% confidence interval [CI], .62 to 1.78; P = .85) and MisMUD (HR, 1.58; 95% CI, .88 to 2.83; P = .13) The relapse/progression was similar between UCB and MisMUD (HR, .62; 95% CI, .37 to 1.03; P = .07), but was significantly lower in MUD compared with UCB (HR, .60; 95% CI, .39 to .92; P = .02). The rate of extensive chronic graft-versus-host disease (GVHD) was similar between UCB and both MUD (HR, 2.15; 95% CI, .93 to 4.97; P = .08) and MisMUD (HR, 1.84; 95% CI, .68 to 4.95; P = .23). The rate of severe grade III and IV acute GVHD was significantly increased in MisMUD compared with UCB (HR, 2.61; 95% CI, 1.30 to 5.23; P = .007). There was no significant difference in overall survival between UCB and both MisMUD (HR, .98; 95% CI, .66 to 1.45; P = .92) and MUD (HR, .74; 95% CI, .52 to 1.03; P = .08). These data suggest that in the setting of RIC/NMA, allo-SCT UCB is a valid alternative graft source, with significantly less chronic GVHD, compared with MisMUD, when there is no MUD available or when urgent transplantation is needed.

  8. Level of Granzyme B-positive T-regulatory cells is a strong predictor biomarker of acute Graft-versus-host disease after day +30 after allo-HSCT.

    PubMed

    Drokov, Mikhail Y; Davydova, Julia O; Kuzmina, Larisa A; Galtseva, Irina V; Kapranov, Nikolay M; Vasilyeva, Vera A; Dubnyak, Darya S; Koroleva, Olga M; Mikhalcova, Ekaterina D; Popova, Natalia N; Parovichnikova, Elena N; Savchenko, Valery G

    2017-03-01

    Acute Graft-versus-host-disease (aGVHD), the major complication and one of the main causes of poor outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nowadays there are no widely accepted cell, plasma or another biomarker that can be used for aGVHD prediction. We hypothesized that a level of Granzyme B-positive T regulatory (GZMB-positive Treg) cells on day+30 after allo-HSCT could be the measure of immune response suppression and could predict aGVHD development after day +30. We applied a widespread and easy-to-perform method of multicolor flow cytometry to measure level of GZMB-positive Treg cells. Levels of GZMB-positive Tregs on day +30 after allo-HSCT were significantly higher in those patients who never developed aGVHD in comparison with the other group of patient with aGVHD after day +30 (p=0.0229). We conclude that the level of GZMB-positive Treg cells is a strong predictor of acute Graft-versus-host disease after day +30 after allo-HSCT.

  9. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multi-center survey

    PubMed Central

    Zeiser, Robert; Burchert, Andreas; Lengerke, Claudia; Verbeek, Mareike; Maas-Bauer, Kristina; Metzelder, Stephan K.; Spoerl, Silvia; Ditschkowski, Markus; Ecsedi, Matyas; Sockel, Katja; Ayuk, Francis; Ajib, Salem; de Fontbrune, Flore Sicre; Na, Il-Kang; Penter, Livius; Holtick, Udo; Wolf, Dominik; Schuler, Esther; Meyer, Everett; Apostolova, Petya; Bertz, Hartmut; Marks, Reinhard; Lübbert, Michael; Wäsch, Ralph; Scheid, Christof; Stölzel, Friedrich; Ordemann, Rainer; Bug, Gesine; Kobbe, Guido; Negrin, Robert; Brune, Mats; Spyridonidis, Alexandros; Schmitt-Gräff, Annette; van der Velden, Walter; Huls, Gerwin; Mielke, Stephan; Grigoleit, Götz Ulrich; Kuball, Jürgen; Flynn, Ryan; Ihorst, Gabriele; Du, Jing; Blazar, Bruce R; Arnold, Renate; Kröger, Nicolaus; Passweg, Jakob; Halter, Jörg; Socié, Gerard; Beelen, Dietrich; Peschel, Christian; Neubauer, Andreas; Finke, Jürgen; Duyster, Justus; von Bubnoff, Nikolas

    2016-01-01

    Despite major improvements in allogeneic hematopoietic cell transplantation over the last decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Pre-clinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grade III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1–7) and SR-cGVHD (1–10). The ORR was 81.5% (44/54) in SR-aGVHD including 25 CRs (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3%–90.7%,95% CI) and 97.4% (92.3%–100%,95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and CMV-reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial. PMID:26228813

  10. Mesenchymal stem cells provide prophylaxis against acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: A meta-analysis of animal models.

    PubMed

    Wang, Li; Zhang, Haiyan; Guan, Lixun; Zhao, Shasha; Gu, Zhenyang; Wei, Huaping; Gao, Zhe; Wang, Feiyan; Yang, Nan; Luo, Lan; Li, Yonghui; Wang, Lili; Liu, Daihong; Gao, Chunji

    2016-09-20

    A meta-analysis of animal models was conducted to evaluate the prophylactic effects of mesenchymal stem cells (MSCs) on acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation. A total of 50 studies involving 1848 animals were included. The pooled results showed that MSCs significantly reduced aGVHD-associated mortality (risk ratio = 0.70, 95% confidence interval 0.62 to 0.79, P = 2.73×10-9) and clinical scores (standardized mean difference = -3.60, 95% confidence interval -4.43 to -2.76, P = 3.61×10-17). In addition, MSCs conferred robust favorable prophylactic effects on aGVHD across recipient species, MSC doses, and administration times, but not MSC sources. Our meta-analysis showed that MSCs significantly prevented mortality and alleviated the clinical manifestations of aGVHD in animal models. These data support further clinical trials aimed at evaluating the efficacy of using MSCs to prevent aGVHD.

  11. Mesenchymal stem cells provide prophylaxis against acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: A meta-analysis of animal models

    PubMed Central

    Guan, Lixun; Zhao, Shasha; Gu, Zhenyang; Wei, Huaping; Gao, Zhe; Wang, Feiyan; Yang, Nan; Luo, Lan; Li, Yonghui; Wang, Lili; Liu, Daihong; Gao, Chunji

    2016-01-01

    A meta-analysis of animal models was conducted to evaluate the prophylactic effects of mesenchymal stem cells (MSCs) on acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation. A total of 50 studies involving 1848 animals were included. The pooled results showed that MSCs significantly reduced aGVHD-associated mortality (risk ratio = 0.70, 95% confidence interval 0.62 to 0.79, P = 2.73×10−9) and clinical scores (standardized mean difference = −3.60, 95% confidence interval −4.43 to −2.76, P = 3.61×10−17). In addition, MSCs conferred robust favorable prophylactic effects on aGVHD across recipient species, MSC doses, and administration times, but not MSC sources. Our meta-analysis showed that MSCs significantly prevented mortality and alleviated the clinical manifestations of aGVHD in animal models. These data support further clinical trials aimed at evaluating the efficacy of using MSCs to prevent aGVHD. PMID:27528221

  12. Early evaluation of immune reconstitution following allogeneic CD3/CD19-depleted grafts from alternative donors in childhood acute leukemia.

    PubMed

    Pérez-Martínez, A; González-Vicent, M; Valentín, J; Aleo, E; Lassaletta, A; Sevilla, J; Vicario, J L; Ramírez, M; Díaz, M A

    2012-11-01

    Graft engineering procedures for hematopoietic SCT (HSCT) may improve the chance of success in matched unrelated donor (MUD) and haploidentical donor transplantations. Successful donor immune reconstitution is important to mediate GVL effects in reduced-intensity conditioning (RIC) HSCT. We prospectively investigated early immune reconstitution and clinical outcome in 30 CD3/CD19-depleted MUD (n=15) or HP (n=15) HSCTs for high-risk childhood leukemia using a fludarabine-based RIC without serotherapy. The graft consisted of a mean of 10.5 × 10(6)/kg CD34+, 77 × 10(3)/kg CD3+ and 39 × 10(6)/kg CD56+ cells. After transplantation, 86% of the patients engrafted. In all, 13% of patients had >grade 3 acute GVHD. Natural killer (NK) cell, DC and T-cell recovery achieved normal values within the first 60 days after transplantation. DC recovery was dominated by the DC2(-) subset. NK-cell phenotype was altered and cytotoxicity was lower compared with their donors. EFS was 50±9% (73±11% for those in CR1 and 26±11% for those with advanced disease). Faster DC2(-) recovery was associated with better outcome, especially in the MUD setting. In summary, CD3/CD19-depleted HSCT with fludarabine-based RIC without serotherapy resulted in favorable patient survival, and rapid NK, DC and T-cell recovery.

  13. Graft-versus-host disease and survival after cord blood transplantation for acute leukemia: a comparison of Japanese versus White populations.

    PubMed

    Kuwatsuka, Yachiyo; Atsuta, Yoshiko; Horowitz, Mary M; Inagaki, Jiro; Kanda, Junya; Kato, Koji; Koh, Katsuyoshi; Zhang, Mei-Jie; Eapen, Mary

    2014-05-01

    An earlier report identified higher risks of acute and chronic graft-versus-host disease (GVHD) in White children compared with the Japanese after HLA-matched sibling transplantations. The current analysis explored whether racial differences are associated with GVHD risks after unrelated umbilical cord blood transplantation. Included are patients of Japanese descent (n = 257) and Whites (n = 260; 168 of 260 received antithymocyte globulin [ATG]). Transplants were performed in the United States or Japan between 2000 and 2009; patients were aged 16 years or younger, had acute leukemia, were in complete remission, and received a myeloablative conditioning regimen. The median ages of the Japanese and Whites who received ATG were younger at 5 years compared with 8 years for Whites who did not receive ATG. In all groups most transplants were mismatched at 1 or 2 HLA loci. Multivariate analysis found no differences in risks of acute GVHD between the Japanese and Whites. However, chronic GVHD was higher in Whites who did not receive ATG compared with the Japanese (hazard ratio, 2.16; P < .001), and treatment-related mortality was higher in Whites who received ATG compared with the Japanese (relative risk, 1.81; P = .01). Nevertheless, there were no significant differences in overall survival between the 3 groups.

  14. CCR7 guides migration of mesenchymal stem cell to secondary lymphoid organs: a novel approach to separate GvHD from GvL effect.

    PubMed

    Li, Hong; Jiang, YanMing; Jiang, XiaoXia; Guo, XiMin; Ning, HongMei; Li, YuHang; Liao, Li; Yao, HuiYu; Wang, XiaoYan; Liu, YuanLin; Zhang, Yi; Chen, Hu; Mao, Ning

    2014-07-01

    Inefficient homing of systemically infused mesenchymal stem cells (MSCs) limits the efficacy of existing MSC-based clinical graft-versus-host disease (GvHD) therapies. Secondary lymphoid organs (SLOs) are the major niches for generating immune responses or tolerance. MSCs home to a wide range of organs, but rarely to SLOs after intravenous infusion. Thus, we hypothesized that targeted migration of MSCs into SLOs may significantly improve their immunomodulatory effect. Here, chemokine receptor 7 (CCR7) gene, encoding a receptor that specifically guides migration of immune cells into SLOs, was engineered into a murine MSC line C3H10T1/2 by retrovirus transfection system (MSCs/CCR7). We found that infusion of MSCs/CCR7 potently prolonged the survival of GvHD mouse model. The infused MSCs/CCR7 migrate to SLOs, relocate in proximity with T lymphocytes, therefore, potently inhibited their proliferation, activation, and cytotoxicity. Natural killer (NK) cells contribute to the early control of leukemia relapse. Although MSCs/CCR7 inhibited NK cell activity in vitro coculture, they did not impact on the proportion and cytotoxic capacities of NK cells in the peripheral blood of GvHD mice. In an EL4 leukemia cell loaded GvHD model, MSCs/CCR7 infusion preserved the graft-versus-leukemia (GvL) effect. In conclusion, this study demonstrates that CCR7 guides migration of MSCs to SLOs and thus highly intensify their in vivo immunomodulatory effect while preserving the GvL activity. This exciting therapeutic strategy may improve the clinical efficacy of MSC based therapy for immune diseases.

  15. Treatment of cutaneous and/or soft tissue manifestations of corticosteroids refractory chronic graft versus host disease (cGVHD) by a total nodal irradiation (TNI).

    PubMed

    Peyraga, Guillaume; Lizee, Thibaut; Gustin, Pierre; Clement-Colmou, Karen; Di Bartolo, Christelle; Supiot, Stephane; Mahe, Marc-Andre; François, Sylvie; Mege, Martine

    2017-02-09

    The management of corticosteroids refractory chronic graft versus host disease (cGVHD) remains controversial. Retrospective analysis of patients treated at the Integrated Center of Oncology by total nodal irradiation (TNI) was performed to evaluate its therapy potency. TNI delivers a dose of 1 Gy in a single session. The delimitation of the fields is clinical (upper limit: external auditory meatus; lower limit: mid-femur). No pre-therapeutic dosimetry scanner was necessary. Evaluation of the efficacy was by clinical measures at 6 months after the treatment. Twelve patients were treated by TNI between January 2010 and December 2013. TNI was used in second-line treatment or beyond. The median time between allograft and TNI was 31.2 months, and the median time between the first manifestations of cGVHD and TNI was about 24.2 months. Of the 12 patients, nine had a clinical response at 6 months (75%), including five complete clinical responses (41.6%). Five patients could benefit from a reduction of corticosteroid doses. Three patients had hematologic toxicity. TNI could be considered as an option for the treatment of a cutaneous and/or soft tissues corticosteroids refractory cGVHD. However, prospective randomized and double-blind trials remain essential to answer the questions about TNI safety and effectiveness.

  16. Tumor Grade

    MedlinePlus

    ... Other Funding Find NCI funding for small business innovation, technology transfer, and contracts Training Cancer Training at ... much of the tumor tissue has normal breast (milk) duct structures Nuclear grade : an evaluation of the ...

  17. Impacts of acute imipramine treatment on plasma and brain amino acid metabolism in mice given graded levels of dietary chicken protein.

    PubMed

    Nagasawa, Mao; Murakami, Tatsuro; Tomonaga, Shozo; Sato, Mikako; Takahata, Yoshihisa; Morimatsu, Fumiki; Furuse, Mitsuhiro

    2012-12-01

    Several studies have shown a relationship between depression and animal protein intake. To evaluate whether the difference of dietary chicken protein levels induces an antidepressant-like effect and potentiates acute antidepressant effects, three levels of dietary chicken protein were used as the representative animal protein with imipramine used as the antidepressant. In addition, the effects of dietary chicken protein on brain metabolism were evaluated. Open field test (OFT) and forced swimming test (FST) were conducted on the 27th and 28th days, respectively. OFT and FST were not influenced by both imipramine and dietary protein levels. However, characteristic effects of imipramine treatment on brain monoamine metabolism were observed in the cerebral cortex and hypothalamus. In addition, dietary protein significantly increased taurine and L-ornithine levels even though these amino acids were not contained in the diets. In conclusion, the metabolism of several amino acids in the plasma and brain were altered by dietary chicken protein.

  18. [Prophylactic effect of CsA, MTX, MMF combined with ATG on GVHD in patients underwent unrelated peripheral blood hematopoietic stem cell transplantation].

    PubMed

    Li, Xiao-Hong; Gao, Chun-Ji; Da, Wan-Ming; Yu, Li; Wu, Xiao-Xiong; Li, Hong-Hua; Ma, Jian; Cao, Yong-Bin

    2010-04-01

    This study was aimed to investigate the prophylactic effect of CsA, MTX and MMF combined with ATG on graft versus host disease (GVHD) after unrelated donor peripheral blood hematopoietic stem cell transplantation (URD-PBHSCT). 33 patients underwent URD-PBHSCT with unrelated donor of HLA matched or 1 locus mismatched. The clinical data of all cases were retrospectively analyzed. URD-PBHSCT recipients received cyclosporin A+short term MTX+mycophenolate mofetil (MMF)+antithymocyte globulin to prevent GVHD (URD-ATG group), while 13 out of 33 patients were given additionally anti-CD25 antibody (URD-ATG+CD25 group). The results showed that engraftment was successfully achieved in 100% of all patients. In URD-ATG+CD25 group and URD-ATG group, the incidence of aGVHD were 23.07% and 45%, the incidence of cGVHD were 0 and 47.4% respectively. The latter was significantly higher than the former (p<0.05). The relapse rate in URD-ATG+CD25 group and URD-ATG group were 53.84% and 15% respectively, the former was significantly higher than the latter (p<0.05). The analysis on disease status of patients before transplantation displayed that the relapse rate of patients in progression status was significantly higher than that of patients in stable status (p<0.01), while the relapse rate of patients in progression status in URD-ATG+CD25 group reached to 100%. The overall survival (OS) at 1 year of patients in URD-ATG+CD25 group and URD-ATG group were 53.8% and 75% respectively, the OS at 5 years of patients in URD-ATG+CD25 group and URD-ATG group were 38.8% and 65% respectively, the OS of patients in URD-ATG group was higher than that of patients in URD-ATG+CD25 group (p<0.05). Simultaneously the OS of patients with progression status before transplantation declined obviously. It is concluded that adopting CsA+MTX+MMF+ATG as the prophylaxis of GVHD for UDR-PBSCT is effective. Reducing the dose of ATG may be good for patient in progression status.

  19. [Bone marrow transplantation in Mexico. Report of the 1st successful case in acute myeloblastic leukemia. Grupo de Trasplante Medular Oseo del INNSZ].

    PubMed

    León, E; Sosa, R

    1992-01-01

    The first case of allogeneic bone marrow transplantation in acute myelogenous leukemia (AML) done in Mexico is reported. The patient was a 26 year old Mexican woman who in October 1987 was diagnosed of having AML of the M2 subtype. After three cycles of the TADOP regimen (6-thioguanine, cytosine-arabinoside, doxorubicin, vincristine & prednisone), the patient entered complete remission. Unfortunately, after a seven month period of remission she suffered a relapse which was refractory to a new chemotherapy cycle. On 9/14/88 an allogeneic BMT from her HLA identical brother was performed. The conditioning regimen consisted of busulfan and cyclophosphamide. Prophylaxis for GVHD consisted of cyclosporine and methylprednisolone. The posttransplantation course was satisfactory, reaching > 500 neutrophils x 10(9)/L on day 14 and > 50,000 platelets x 10(9)/L without support on day 23 posttransplant. The patient developed fever of unknown etiology, which was satisfactorily resolved with ceftazidime, vancomycin and metronidazole. She also presented a grade II oral and esophageal mucositis. As a late complication, on day 90 posttransplant, she developed a bilateral pneumonia which was resolved with sulfamethoxazole-trimethoprim administration. Up to the time of this report (40 months posttransplant) the patient is completely asymptomatic, is under no immunosuppression, and shows no evidence of graft versus host disease or recurrent leukemia.

  20. Fecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut

    PubMed Central

    Fujioka, Yuki; Suda, Wataru; Najima, Yuho; Kuwata, Go; Sasajima, Satoshi; Mimura, Iyo; Morita, Hidetoshi; Sugiyama, Daisuke; Nishikawa, Hiroyoshi; Hattori, Masahira; Hino, Yutaro; Ikegawa, Shuntaro; Yamamoto, Keita; Toya, Takashi; Doki, Noriko; Koizumi, Koichi; Honda, Kenya; Ohashi, Kazuteru

    2016-01-01

    Increasing evidence indicates that the gut microbiota is closely associated with acute graft-versus-host disease (aGVHD) in stem cell transplantation (SCT). Fecal microbiota transplantation (FMT) could represent an alternative treatment option for aGVHD. However, FMT for SCT patients carries a potential risk of infection by infused microbiota because of the severely immunosuppressed status. We therefore conducted a pilot study to evaluate the safety of FMT in SCT. A total of 4 patients with steroid-resistant (n = 3) or steroid-dependent gut aGVHD (n = 1) received FMT. No severe adverse events attributed to FMT were observed. All patients responded to FMT, with 3 complete responses and 1 partial response. Temporal dynamics of microbiota seemed to be linked to the gut condition of patients and peripheral effector regulatory T cells also increased during response to FMT. FMT was safely performed in our patients and might offer a novel therapeutic option for aGVHD. This trial was registered at the University Hospital Medical Information Network (https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000017575) as #UMIN000015115. PMID:27461930

  1. Survival Advantage and Comparable Toxicity in Reduced-Toxicity Treosulfan-Based versus Reduced-Intensity Busulfan-Based Conditioning Regimen in Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation.

    PubMed

    Sakellari, Ioanna; Mallouri, Despina; Gavriilaki, Eleni; Batsis, Ioannis; Kaliou, Maria; Constantinou, Varnavas; Papalexandri, Apostolia; Lalayanni, Chrysavgi; Vadikolia, Chrysanthi; Athanasiadou, Anastasia; Yannaki, Evangelia; Sotiropoulos, Damianos; Smias, Christos; Anagnostopoulos, Achilles

    2017-03-01

    Treosulfan has been incorporated in conditioning regimens for sustained remission without substantial toxicity and treatment-related mortality (TRM). We aimed to analyze the safety and efficacy of a fludarabine 150 mg/m(2) and treosulfan 42 g/m(2) (FluTreo) conditioning regimen in medically infirm patients. Outcomes were compared with those of a similar historical group treated with fludarabine 150 mg/m(2) to 180 mg/m(2), busulfan 6.4 mg/kg, and antithymocyte globulin (ATG) 5 mg/kg to 7.5 mg/kg (FluBuATG). Thirty-one consecutive patients with acute myeloid leukemia (AML; n = 21), myelodysplastic syndrome (MDS; n = 6), or treatment-related AML (n = 4) received FluTreo conditioning. The historical group consisted of 26 consecutive patients treated with FluBuATG. In the FluTreo group, engraftment was prompt in all patients and 74% achieved >99% donor chimerism by day +30. No grades III or IV organ toxicities were noted. One-year cumulative incidences (CI) of acute and chronic graft-versus-host disease (GVHD) were 19.4% and 58.4%. The groups were similar for age, disease risk, lines of treatment, hematopoietic cell transplantation-specific comorbidity index, and acute or chronic GVHD incidence, except that there were more matched unrelated donor recipients in the FluTreo group (P < .001). With 20 (range, 2 to 36) months follow-up for FluTreo and 14 (range, 2 to 136) for FluBuATG, the 1-year cumulative overall survival (OS) probability was 76% versus 57%, respectively (P = .026); 1-year disease-free survival (DFS) was 79% versus 38% (P < .001). In multivariate analysis, the only significantly favorable factor for OS and DFS was FluTreo (P = .010 and P = .012). The CI of relapse mortality was markedly decreased in FluTreo versus FluBuATG (7.4% versus 42.3%, P < .001). In conclusion, the treosulfan-based regimen resulted in favorable OS and DFS with acceptable toxicity and low relapse rates compared with busulfan-based conditioning.

  2. Rapamycin generates anti-apoptotic human Th1/Tc1 cells via autophagy for induction of xenogeneic GVHD.

    PubMed

    Amarnath, Shoba; Flomerfelt, Francis A; Costanzo, Carliann M; Foley, Jason E; Mariotti, Jacopo; Konecki, Daniel M; Gangopadhyay, Anu; Eckhaus, Michael; Wong, Susan; Levine, Bruce L; June, Carl H; Fowler, Daniel H

    2010-05-01

    Murine T cells exposed to rapamycin maintain flexibility towards Th1/Tc1 differentiation, thereby indicating that rapamycin promotion of regulatory T cells (Tregs) is conditional. The degree to which rapamycin might inhibit human Th1/Tc1 differentiation has not been evaluated. In the presence of rapamycin, T cell costimulation and polarization with IL-12 or IFN-α permitted human CD4+ and CD8+ T cell differentiation towards a Th1/Tc1 phenotype; activation of STAT1 and STAT4 pathways essential for Th1/Tc1 polarity was preserved during mTOR blockade but instead abrogated by PI3 kinase inhibition. Such rapamycin-resistant human Th1/Tc1 cells: (1) were generated through autophagy (increased LC3BII expression; phenotype reversion by autophagy inhibition via 3-MA or siRNA for Beclin1); (2) expressed anti-apoptotic bcl-2 family members (reduced Bax, Bak; increased phospho-Bad); (3) maintained mitochondrial membrane potentials; and (4) displayed reduced apoptosis. In vivo, type I polarized and rapamycin-resistant human T cells caused increased xenogeneic graft-versus-host disease (x-GVHD). Murine recipients of rapamycin-resistant human Th1/Tc1 cells had: (1) persistent T cell engraftment; (2) increased T cell cytokine and cytolytic effector function; and (3) T cell infiltration of skin, gut, and liver. Rapamycin therefore does not impair human T cell capacity for type I differentiation. Rather, rapamycin yields an anti-apoptotic Th1/Tc1 effector phenotype by promoting autophagy.

  3. pH-sensitive MRI demarcates graded tissue acidification during acute stroke - pH specificity enhancement with magnetization transfer and relaxation-normalized amide proton transfer (APT) MRI.

    PubMed

    Guo, Yingkun; Zhou, Iris Yuwen; Chan, Suk-Tak; Wang, Yu; Mandeville, Emiri T; Igarashi, Takahiro; Lo, Eng H; Ji, Xunming; Sun, Phillip Zhe

    2016-11-01

    pH-sensitive amide proton transfer (APT) MRI provides a surrogate metabolic biomarker that complements the widely-used perfusion and diffusion imaging. However, the endogenous APT MRI is often calculated using the asymmetry analysis (MTRasym), which is susceptible to an inhomogeneous shift due to concomitant semisolid magnetization transfer (MT) and nuclear overhauser (NOE) effects. Although the intact brain tissue has little pH variation, white and gray matter appears distinct in the MTRasym image. Herein we showed that the heterogeneous MTRasym shift not related to pH highly correlates with MT ratio (MTR) and longitudinal relaxation rate (R1w), which can be reasonably corrected using the multiple regression analysis. Because there are relatively small MT and R1w changes during acute stroke, we postulate that magnetization transfer and relaxation-normalized APT (MRAPT) analysis increases MRI specificity to acidosis over the routine MTRasym image, hence facilitates ischemic lesion segmentation. We found significant differences in perfusion, pH and diffusion lesion volumes (P<0.001, ANOVA). Furthermore, MRAPT MRI depicted graded ischemic acidosis, with the most severe acidosis in the diffusion lesion (-1.05±0.29%/s), moderate acidification within the pH/diffusion mismatch (i.e., metabolic penumbra, -0.67±0.27%/s) and little pH change in the perfusion/pH mismatch (i.e., benign oligemia, -0.04±0.14%/s), providing refined stratification of ischemic tissue injury.

  4. The role of danger signals and ectonucleotidases in acute graft-versus-host disease.

    PubMed

    Apostolova, Petya; Zeiser, Robert

    2016-11-01

    Allogeneic hematopoietic cell transplantation (allo-HCT) represents the only curative treatment approach for many patients with benign or malignant diseases of the hematopoietic system. However, post-transplant morbidity and mortality are significantly increased by the development of acute graft-versus-host disease (GvHD). While alloreactive T cells act as the main cellular mediator of the GvH reaction, recent evidence suggests a critical role of the innate immune system in the early stages of GvHD initiation. Danger-associated molecular patterns released from the intracellular space as well as from the extracellular matrix activate antigen-presenting cells and set pro-inflammatory pathways in motion. This review gives an overview about danger signals representing therapeutic targets with a clinical perspective with a particular focus on extracellular nucleotides and ectonucleotidases.

  5. 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.

  6. Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts From HLA-Matched Related and Unrelated Donors in Preventing GVHD

    ClinicalTrials.gov

    2017-03-29

    Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Acute Biphenotypic Leukemia; Acute Leukemia of Ambiguous Lineage; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Blastic Plasmacytoid Dendritic Cell Neoplasm; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Lymphoblastic Lymphoma; Myelodysplastic Syndrome With Excess Blasts; Myelodysplastic Syndrome With Excess Blasts-1; Myelodysplastic Syndrome With Excess Blasts-2; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive

  7. IL-12/15/18-preactivated NK cells suppress GvHD in a mouse model of mismatched hematopoietic cell transplantation.

    PubMed

    Hüber, Christian M; Doisne, Jean-Marc; Colucci, Francesco

    2015-06-01

    Mismatched hematopoietic cell transplants for treating leukemia are complicated by graft versus host disease (GvHD). Here, we show that adoptively transferred IL-12/15/18-preactivated NK cells suppress GvHD in a mouse model of fully mismatched hematopoietic cell transplantation. These IL-12/15/18-preactivated NK cells maintained Eomesodermin (Eomes) and T-bet expression upon transfer and, while there was no evidence of direct killing of donor T cells or host DCs by the IL-12/15/18-preactivated NK cells, proliferation of donor T cells was inhibited. Strikingly, the graft versus leukemia effect mediated by donor T cells was retained, resulting in improved overall survival of mice that received lymphoma cells, donor allogeneic T cells, and IL-12/15/18-preactivated NK cells. These results suggest that IL-12/15/18-preactivated NK cells may be useful in improving immunotherapy of mismatched hematopoietic cell transplantation. Compared with previously proposed protocols, our findings suggest that in vitro NK-cell preactivation with this cytokine cocktail offers the significant advantage that cytokines do not need to be administered systemically to sustain NK-cell activity, thus avoiding toxicity.

  8. Immunomodulation with dendritic cells and donor lymphocyte infusion converge to induce graft vs neuroblastoma reactions without GVHD after allogeneic bone marrow transplantation

    PubMed Central

    Ash, S; Stein, J; Askenasy, N; Yaniv, I

    2010-01-01

    Background: Mounting evidence points to the efficacy of donor lymphocyte infusion (DLI) and immunisation with tumour-pulsed dendritic cells (DC) in generating graft vs leukaemia reactions after allogeneic bone marrow transplantation (BMT). We assessed the efficacy of DLI and DC in generating potent graft vs neuroblastoma tumour (GVT) reactions following allogeneic BMT. Methods: Mice bearing congenic (H2Ka) Neuro-2a tumours were grafted with allogeneic (H2Kb) T-cell-depleted bone marrow cells. Tumour-pulsed donor DC (DCNeuro2a) were inoculated (on day +7) in conjunction with donor (H2Kb) and haploidentical (H2Ka/b) lymphocytes. Results: Murine Neuro-2a cells elicit immune reactions as efficient as B lymphoma in major histocompatibility complex antigen-disparate mice. Lymphopenia induced by conditioning facilitates GVT, and transition to adaptive immunity is enhanced by simultaneous infusion of and DCNeuro2a and lymphocytes devoid of graft vs host (GVH) activity (H2Ka/b). In variance, the efficacy of DC-mediated immunomodulation was diminished by severe graft vs host disease (GVHD), showing mechanistic dissociation and antagonising potential to GVT. Conclsions: The GVHD is not a prerequisite to induce GVT reactivity after allogeneic BMT, but is rather detrimental to induction of anti-tumour immunity by DC-mediated immunomodulation. Simultaneous inoculation of tumour-pulsed donor DC and DLI synergise in stimulation of potent GVT reactions to the extent of eradication of established NB tumours. PMID:20978501

  9. Acute Kidney Injury in Hematopoietic Stem Cell Transplantation: A Review

    PubMed Central

    Gupta, Mohit; Manu, Gurusidda; Kwatra, Shivani; Owusu, Osei-Tutu

    2016-01-01

    Hematopoietic stem cell transplantation (HSCT) is a highly effective treatment strategy for lymphoproliferative disorders and bone marrow failure states including aplastic anemia and thalassemia. However, its use has been limited by the increased treatment related complications, including acute kidney injury (AKI) with an incidence ranging from 20% to 73%. AKI after HSCT has been associated with an increased risk of mortality. The incidence of AKI reported in recipients of myeloablative allogeneic transplant is considerably higher in comparison to other subclasses mainly due to use of cyclosporine and development of graft-versus-host disease (GVHD) in allogeneic groups. Acute GVHD is by itself a major independent risk factor for the development of AKI in HSCT recipients. The other major risk factors are sepsis, nephrotoxic medications (amphotericin B, acyclovir, aminoglycosides, and cyclosporine), hepatic sinusoidal obstruction syndrome (SOS), thrombotic microangiopathy (TMA), marrow infusion toxicity, and tumor lysis syndrome. The mainstay of management of AKI in these patients is avoidance of risk factors contributing to AKI, including use of reduced intensity-conditioning regimen, close monitoring of nephrotoxic medications, and use of alternative antifungals for prophylaxis against infection. Also, early identification and effective management of sepsis, tumor lysis syndrome, marrow infusion toxicity, and hepatic SOS help in reducing the incidence of AKI in HSCT recipients. PMID:27885340

  10. Cytomegalovirus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation is Associated with a Reduced Risk of Relapse in Patients with Acute Myeloid Leukemia Who Survived to Day 100 after Transplantation: The Japan Society for Hematopoietic Cell Transplantation Transplantation-related Complication Working Group.

    PubMed

    Takenaka, Katsuto; Nishida, Tetsuya; Asano-Mori, Yuki; Oshima, Kumi; Ohashi, Kazuteru; Mori, Takehiko; Kanamori, Heiwa; Miyamura, Koichi; Kato, Chiaki; Kobayashi, Naoki; Uchida, Naoyuki; Nakamae, Hirohisa; Ichinohe, Tatsuo; Morishima, Yasuo; Suzuki, Ritsuro; Yamaguchi, Takuhiro; Fukuda, Takahiro

    2015-11-01

    Cytomegalovirus (CMV) infection is a major infectious complication after allogeneic hematopoietic cell transplantation (allo-HSCT). Recently, it was reported that CMV reactivation is associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). The aim of this study was to evaluate the impact of early CMV reactivation on the incidence of disease relapse after allo-HSCT in a large cohort of patients. The Japan Society for Hematopoietic Cell Transplantation's Transplantation-Related Complication Working Group retrospectively surveyed the database of the Transplant Registry Unified Management Program at the Japan Society for Hematopoietic Cell Transplantation. Patients with AML (n = 1836), acute lymphoblastic leukemia (ALL, n = 911), chronic myeloid leukemia (CML, n = 223), and myelodysplastic syndrome (MDS, n = 569) who underwent their first allo-HSCT from HLA-matched related or unrelated donors between 2000 and 2009 and who survived without disease relapse until day 100 after transplantation were analyzed. Patients who received umbilical cord blood transplantation were not included. Patients underwent surveillance by pp65 antigenemia from the time of engraftment, and the beginning of preemptive therapy was defined as CMV reactivation. Cox proportional hazards models were used to evaluate the risk factors of relapse, nonrelapse, and overall mortality. CMV reactivation and acute/chronic graft-versus-host disease (GVHD) were evaluated as time-dependent covariates. CMV reactivation was associated with a decreased incidence of relapse in patients with AML (20.3% versus 26.4%, P = .027), but not in patients with ALL, CML, or MDS. Among 1836 patients with AML, CMV reactivation occurred in 795 patients (43.3%) at a median of 42 days, and 436 patients (23.7%) relapsed at a median of 221 days after allo-HSCT. Acute GVHD grades II to IV developed in 630 patients (34.3%). By multivariate analysis considering competing risk factors, 3

  11. Increased Foxp3(+)Helios(+) Regulatory T Cells and Decreased Acute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation in Patients Receiving Sirolimus and RGI-2001, an Activator of Invariant Natural Killer T Cells.

    PubMed

    Chen, Yi-Bin; Efebera, Yvonne A; Johnston, Laura; Ball, Edward D; Avigan, David; Lekakis, Lazaros J; Bachier, Carlos R; Martin, Paul; Duramad, Omar; Ishii, Yasuyuki; Han, Semi; Jung, Yu-Jin; Lee, Dana; Kunkel, Lori; Negrin, Robert S; Bui, Jack D

    2017-04-01

    Regulatory T (Treg) cells play a central role in immune tolerance and prevention of aberrant immune responses. Several studies have suggested that the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) can be ameliorated by increasing Tregs. We have developed an approach of in vivo expansion of Tregs with RGI-2001, a novel liposomal formulation of a synthetic derivative of alpha-galactosylceramide, a naturally occurring ligand that binds to CD1 and activates and expands invariant natural killer cells. In preclinical studies, a single intravenous infusion of RGI-2001 expanded Treg and could ameliorate GVHD in a mouse model of allogeneic HCT. To explore the role of RGI-2001 in clinical HCT, we initiated a phase 2A clinical trial (n = 29), testing 2 different doses of RGI-2001 administered as a single infusion on day 0 of allogeneic HCT. RGI-2001 was well tolerated and without infusion reactions or cytokine release syndrome. A subset of patients (8 of 29, 28%) responded to RGI-2001 by inducing a markedly increased number of cells with a Treg phenotype. The Treg had a high Ki-67 index and were almost exclusively Helios(+) and Foxp3(+), indicating that their accumulation was due to expansion of natural Treg. Notably, the incidence of grade 2 to 4 GVHD in the 8 patients who responded to RGI-2001 was 12.5%, compared with 52.4% in the 21 patients who did not respond. No grade 3 or 4 GVHD was observed in the responder group, compared with a 9.5% incidence among nonresponders. Immunosuppression with sirolimus was also associated with a low incidence of GVHD, suggesting that RGI-2001 may have synergized with sirolimus to promote Treg expansion.

  12. Comparison of outcomes after transplantation of G-CSF-stimulated bone marrow grafts versus bone marrow or peripheral blood grafts from HLA-matched sibling donors for patients with severe aplastic anemia.

    PubMed

    Chu, Roland; Brazauskas, Ruta; Kan, Fangyu; Bashey, Asad; Bredeson, Christopher; Camitta, Bruce; Chiang, Kuang-Yueh; Frangoul, Haydar; Gale, Robert Peter; Gee, Adrian; George, Biju; Goldman, Frederick D; Gross, Thomas G; Gupta, Vikas; Hale, Gregory A; Isola, Luis; Ispizua, Alvaro Urbano; Lazarus, Hillard; Marsh, Judith; Russell, James; Sabloff, Mitchell; Waller, Edmund K; Eapen, Mary

    2011-07-01

    We compared outcomes of patients with severe aplastic anemia (SAA) who received granulocyte-colony stimulating factor (G-CSF)-stimulated bone marrow (G-BM) (n = 78), unstimulated bone marrow (BM) (n = 547), or peripheral blood progenitor cells (PBPC) (n = 134) from an HLA-matched sibling. Transplantations occurred in 1997 to 2003. Rates of neutrophil and platelet recovery were not different among the 3 treatment groups. Grade 2-4 acute graft-versus-host disease (aGVHD) (relative risk [RR] = 0.82, P = .539), grade 3-4 aGVHD (RR = 0.74, P = .535), and chronic GVHD (cGVHD) (RR = 1.56, P = .229) were similar after G-BM and BM transplants. Grade 2-4 aGVHD (RR = 2.37, P = .012) but not grade 3-4 aGVHD (RR = 1.66, P = .323) and cGVHD (RR = 5.09, P < .001) were higher after PBPC transplants compared to G-BM. Grade 2-4 (RR = 2.90, P < .001), grade 3-4 (RR = 2.24, P = .009) aGVHD and cGVHD (RR = 3.26, P < .001) were higher after PBPC transplants compared to BM. Mortality risks were lower after transplantation of BM compared to G-BM (RR = 0.63, P = .05). These data suggest no advantage to using G-BM and the observed higher rates of aGVHD and cGVHD in PBPC recipients warrants cautious use of this graft source for SAA. Taken together, BM is the preferred graft for HLA-matched sibling transplants for SAA.

  13. Elevated level of HSPA1L mRNA correlates with graft-versus-host disease.

    PubMed

    Atarod, Sadaf; Turner, Brie; Pearce, Kim Frances; Ahmed, Shaheda S; Norden, Jean; Bogunia-Kubik, Katarzyna; Wang, Xiao-nong; Collin, Matthew; Dickinson, Anne Mary

    2015-06-01

    Graft-versus-host disease (GVHD) can be a fatal complication of allogeneic stem cell transplantation (allo-HSCT). GVHD can be classified as acute (aGVHD: up to 100 days) or chronic (cGVHD: after 100 days) based on the time-point of disease occurrence. At present there are a limited number of biomarkers available for use in the clinic. Thus, the aim of this research was to evaluate the biomarker potential of the extensively studied Heat Shock Protein 70 family members (HSPA1A/HSPA1B and HSPA1L) at the messenger RNA (mRNA) level in acute and cGVHD patient cohorts. In the skin biopsies, HSPA1L mRNA expression was lower in patients with severe aGVHD (grades II-III) when compared to those with none or low grade aGVHD (grades 0-I) and normal controls. In whole blood, HSPA1L mRNA expression level was significantly (p = 0.008) up-regulated at 28 days post-transplant in cGVHD patients with a significant area under the curve (AUC = 0.773). In addition, HSPA1B expression in whole blood was significantly higher at 3 months post-transplant in both the aGVHD grade II-III (p = 0.012) and cGVHD (p = 0.027) patients. Our initial results in this small cohort show that quantifying HSPA1L mRNA expression in the whole blood of allo-HSCT patients at day 28 post-allo-HSCT may be a useful predictive biomarker for cGVHD.

  14. Specific donor Vbeta-associated CD4 T-cell responses correlate with severe acute graft-versus-host disease directed to multiple minor histocompatibility antigens.

    PubMed

    Jones, Stephen C; Friedman, Thea M; Murphy, George F; Korngold, Robert

    2004-02-01

    CXB-2/By (CXB-2) recombinant inbred mice express a subset of the minor histocompatibility antigen (miHA) repertoire expressed by C.B10-H2(b)/LiMcdJ (BALB.B) mice. On lethal irradiation and the transplantation of H2(b)-matched C57BL/6 (B6) T cell-depleted bone marrow cells, along with naive unfractionated T cells, both strains succumb to acute graft-versus-host disease (GVHD). Although alloreactive B6 CD4(+) T cells are a necessary source of T-cell help for the B6 CD8(+) component of the GVHD response in both recipient strains, they are capable of mediating severe GVHD by themselves only in BALB.B mice. Previous CD4(+) T-cell receptor repertoire analysis demonstrated overlapping oligoclonal Vbeta use between the CD4(+) B6 anti-BALB.B and B6 anti-CXB-2 responses, with indications of additional BALB.B unique T-cell responses (Vbeta2 and Vbeta11). We report here that the more severe B6 anti-BALB.B response is not due to a quantitative difference in the responding cells, because the frequency of alloreactive donor CD4(+) T cells over time was equivalent in the spleens of BALB.B versus CXB-2 recipients. The responses were also similar in the number of infiltrating B6 CD4(+) T cells in the lingual epithelium of the 2 recipients. In contrast, a significantly greater degree of infiltration and injury of BALB.B intestinal epithelium correlated with the increased level of clinical GVHD severity. Of most significance, despite the involvement of at least 11 Vbeta-associated CD4(+) T-cell families in the overall B6 anti-BALB.B response, the development of severe GVHD correlated with the presence of Vbeta2- and Vbeta11-positive donor T cells. Transplantation of donor CD4(+) T cells from Vbeta-associated families that were shared between the B6 anti-BALB.B and anti-CXB-2 responses resulted in minimal GVHD potential. These data suggest that severe GVHD across miHA barriers depends on the involvement of a restricted number of potent T-cell specificities and implies that there are

  15. Basiliximab #2: In-Vivo Activated T-Cell Depletion to Prevent Graft-Versus_Host Disease (GVHD) After Nonmyeloablative Allotransplantation for the Treatment of Blood Cancer

    ClinicalTrials.gov

    2016-01-28

    Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Myelodysplasia; Non-Hodgkin's Lymphoma; Hodgkin's Disease; Multiple Myeloma; Myelofibrosis; Anemia, Aplastic; Hemoglobinuria, Paroxysmal

  16. Chronic graft-versus-host disease following umbilical cord blood transplantation: retrospective survey involving 1072 patients in Japan.

    PubMed

    Narimatsu, Hiroto; Miyakoshi, Shigesaburo; Yamaguchi, Takuhiro; Kami, Masahiro; Matsumura, Tomoko; Yuji, Koichiro; Murashige, Naoko; Kusumi, Eiji; Kodama, Yuko; Komatsu, Tsunehiko; Sakamaki, Hisashi; Kouzai, Yasushi; Okada, Masaya; Osugi, Yuko; Kobayashi, Ryoji; Inoue, Masami; Takahashi, Satoshi; Kai, Shunro; Kato, Koji; Inoue-Nagamura, Tokiko; Taniguchi, Shuichi; Kato, Shunichi

    2008-09-15

    We have little information on chronic graft-versus-host disease (GVHD) after cord blood transplantation (CBT). We investigated its clinical features in 1072 Japanese patients with hematologic malignancies who received a transplant through the Japan Cord Blood Bank Network. The primary end point was to investigate the incidence of any chronic GVHD. Median age of the patients was 33 years (range, 0-79 years). The cumulative incidence of chronic GVHD 2 years after transplantation was 28%. Chronic GVHD was fatal in 29 patients. Multivariate analysis demonstrated that development of chronic GVHD was favorably associated with both overall survival and event-free survival. Multivariate analysis identified risk factors of chronic GVHD: higher patient body weight, higher number of mismatched antigens for GVHD direction, myeloablative preparative regimen, use of mycophenolate mofetil in GVHD prophylaxis, and development of grades II to IV acute GVHD. Although chronic GVHD is a significant problem after CBT, it is associated with improved survival, perhaps due to graft-versus-malignancy effects.

  17. Asterisk Grade Study Report.

    ERIC Educational Resources Information Center

    Kokorsky, Eileen A.

    A study was conducted at Passaic County Community College (PCCC) to investigate the operation of a grading system which utilized an asterisk (*) grade to indicate progress in a course until a letter grade was assigned. The study sought to determine the persistence of students receiving the "*" grade, the incidence of cases of students receiving…

  18. Cystitis - acute

    MedlinePlus

    Uncomplicated urinary tract infection; UTI - acute cystitis; Acute bladder infection; Acute bacterial cystitis ... cause. Menopause also increases the risk for a urinary tract infection. The following also increase your chances of having ...

  19. Bone marrow transplantation in the rat. III. Structure of the liver inflammatory lesion in acute graft-versus-host disease

    SciTech Connect

    Leszczynski, D.; Renkonen, R.; Haeyry, P.

    1985-08-01

    The liver is a major parenchymal target organ of acute graft-versus-host disease (aGVHD) after bone marrow transplantation in the rat. The authors have analyzed the nature of cellular infiltrates in the liver using monoclonal antibodies against white cell subsets and investigated the anatomic distribution of the inflammatory cell subsets inside the liver parenchyma. Several types of white cells are present in a normal control liver: In the portal area the T-helper (Th) cells predominate, (surface) immunoglobulin-expressing B cells are present in ample numbers, and most of the phagocytes are Ia-positive. In the central vein area the T-suppressor/killer cells (Tsk) dominate, no B cells are present, and most of the phagocytes are Ia-negative. During aGVHD the number of T cells increases rapidly in the portal area; and after an initial strong increase, the Th/Tsk ratio decreases but remains still above 1. In the central vein area there is also an increase in the number of T cells, compared with that in the syngeneic recipient, but the Th/Tsk ratio rapidly decreases and remains uniformly below 1. During aGVHD the B cells entirely disappear from the portal area, whereas a small but distinct number of mature plasma cells with intracellular immunoglobulin appear in the central vein area. Following irradiation the Ia-positive phagocytic cells entirely disappear from the portal area and decrease distinctly in number in the central vein area. During aGVHD the number of Ia-positive phagocytes increases again in both locations. In the central vein area the positive phagocytes are seen over the background level, and, concomitantly, the Ia-negative phagocytes disappear.

  20. Outcome after HSCT in Philadelphia chromosome positive acute lymphoblastic leukemia in Sweden: a population-based study.

    PubMed

    Hulegårdh, E; Hägglund, H; Ahlberg, L; Karlsson, K; Karbach, H; Markuszewska, A; Persson, I; Åström, M; Hallböök, H

    2014-08-01

    Even in the tyrosine kinase inhibitor era, allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as standard care for adult Philadelphia (Ph) positive acute lymphoblastic leukemia (ALL). In this retrospective national study, we have reviewed the outcome after HSCT in Sweden for adult Ph-positive ALL between 2000 and 2009. In total, 51 patients with median age 42 (range 20-66) years underwent HSCT. Mainly allogeneic HSCT was performed (24 related donor, 24 unrelated donor and one cord blood), and only two patients were treated with an autologous HSCT. The 5-year OS was 51 (37-64) %. The probabilities of morphological relapse and non-relapse mortality (NRM) at 5 years were 36 (23-49) and 18 (9-29) %, respectively. For the allogeneic transplanted, the 5-year OS was for patients <40 years 70 (50-90) % and for patients ≥40 years 34 (16-52) %, p = 0.002. The 5-year probability of NRM was for patients <40 years 10 (2-28) % compared to 25 (11-42) % for patients ≥40 years (p = 0.04). Patients with chronic graft-versus-host disease (GVHD) had a 5-year morphological relapse probability of 20 (6-40) % compared to 59 (35-77) % for patients without chronic GVHD (p = 0.03). Age ≥40 years and the absence of chronic GVHD were confirmed as independent negative prognostic factors for relapse and non-relapse mortality in a multivariate analysis although the impact of chronic GVHD was significant only in the older age cohort.

  1. Grading for Understanding--Standards-Based Grading

    ERIC Educational Resources Information Center

    Zimmerman, Todd

    2017-01-01

    Standards-based grading (SBG), sometimes called learning objectives-based assessment (LOBA), is an assessment model that relies on students demonstrating mastery of learning objectives (sometimes referred to as standards). The goal of this grading system is to focus students on mastering learning objectives rather than on accumulating points. I…

  2. Specific removal of alloreactive T-cells to prevent GvHD in hemopoietic stem cell transplantation: rationale, strategies and perspectives.

    PubMed

    Li Pira, Giuseppina; Di Cecca, Stefano; Montanari, Mauro; Moretta, Lorenzo; Manca, Fabrizio

    2016-07-01

    Hemopoietic stem cell transplantation (HSCT) is a standard procedure for treatment of malignant and non-malignant hematological diseases. HSCT donors include HLA-identical siblings, matched or mismatched unrelated donors and haploidentical related donors. Graft-versus-host disease (GvHD), mediated by donor alloreactive T-cells in the graft, can be triggered by minor histocompatibility antigens in HLA-identical pairs, by alleles at loci not considered for MUD-matching or by the mismatched haplotype in haplo-HSCT. Therefore, removal of donor T-cells, that contain the alloreactive precursors, is required, but T-cell depletion associates with opportunistic infections and with reduced graft-versus-leukemia effect. Selective T-cell depletion strategies have been introduced, like removal of αβ T-lymphocytes and of naive T-cells, two subsets including the alloreactive precursors, but the ultimate goal is specific removal of alloreactive T-cells. Here we review the different approaches to deplete alloreactive T-cells only and discuss pros and cons, specificity, efficiency and efficacy. Combinations of different methods and innovative approaches are also proposed for depleting specific alloreactive T-cells with high efficiency.

  3. How I treat hematologic emergencies in adults with acute leukemia.

    PubMed

    Zuckerman, Tsila; Ganzel, Chezi; Tallman, Martin S; Rowe, Jacob M

    2012-09-06

    Acute myeloid leukemia and acute lymphoblastic leukemia remain devastating diseases. Only approximately 40% of younger and 10% of older adults are long-term survivors. Although curing the leukemia is always the most formidable challenge, complications from the disease itself and its treatment are associated with significant morbidity and mortality. Such complications, discussed herein, include tumor lysis, hyperleukocytosis, cytarabine-induced cellebellar toxicity, acute promyelocytic leukemia differentiation syndrome, thrombohemorrhagic syndrome in acute promyelocytic leukemia, L-asparaginase-associated thrombosis, leukemic meningitis, neutropenic fever, neutropenic enterocolitis, and transfussion-associated GVHD. Whereas clinical trials form the backbone for the management of acute leukemia, emergent clinical situations, predictable or not, are common and do not readily lend themselves to clinical trial evaluation. Furthermore, practice guidelines are often lacking. Not only are prospective trials impractical because of the emergent nature of the issue at hand, but clinicians are often reluctant to randomize such patients. Extensive practical experience is crucial and, even if there is no consensus, management of such emergencies should be guided by an understanding of the underlying pathophysiologic mechanisms.

  4. General Graded Response Model.

    ERIC Educational Resources Information Center

    Samejima, Fumiko

    This paper describes the graded response model. The graded response model represents a family of mathematical models that deal with ordered polytomous categories, such as: (1) letter grading; (2) an attitude survey with "strongly disagree, disagree, agree, and strongly agree" choices; (3) partial credit given in accord with an…

  5. Conversations about Grading

    ERIC Educational Resources Information Center

    Gullen, Kristine; Gullen, James; Erickson-Guy, Nickolas

    2012-01-01

    Grades often are determined by the unspoken values and beliefs of an autonomous teacher, but technology is making grading practices more transparent to parents, students, and educators. The ability to view the grade books of teachers who are teaching the same course in the same district is increasingly raising questions and challenges to what were…

  6. [Grading of prostate cancer].

    PubMed

    Kristiansen, G; Roth, W; Helpap, B

    2016-07-01

    The current grading of prostate cancer is based on the classification system of the International Society of Urological Pathology (ISUP) following a consensus conference in Chicago in 2014. The foundations are based on the frequently modified grading system of Gleason. This article presents a brief description of the development to the current ISUP grading system.

  7. The Meaning of Grades.

    ERIC Educational Resources Information Center

    Teixeira, Serna E.

    1996-01-01

    Asserts that students see grades as an indicator of effort unconnected to the content of the course while teachers regard grades as a measure of achievement within a discipline. Discusses some of the current controversies and approaches concerning grades and how they relate to school reform. (MJP)

  8. Assessment: How Do I "Grade" without Grades?

    ERIC Educational Resources Information Center

    Glazer, Susan Mandel

    1993-01-01

    Examines the A through F system of letter grades used in most schools, suggesting reasons why this framework is inadequate. Proposes a new assessment model which has children demonstrate that they can accomplish a given task on their own. (MDM)

  9. Grading beyond supersymmetry

    SciTech Connect

    Toro, L.A.

    1996-02-01

    Consistent algebraic extensions of the Poincar{acute e} algebra are obtained in which the novel generators can act with commutators or {ital anticommutators} on the Poincar{acute e} generators. {copyright} {ital 1996 American Institute of Physics.}

  10. Effects of a timely therapy with doxycycline on the left ventricular remodeling according to the pre-procedural TIMI flow grade in patients with ST-elevation acute myocardial infarction.

    PubMed

    Cerisano, Giampaolo; Buonamici, Piergiovanni; Valenti, Renato; Moschi, Guia; Taddeucci, Enrico; Giurlani, Letizia; Migliorini, Angela; Vergara, Ruben; Parodi, Guido; Sciagrà, Roberto; Romito, Roberta; Colonna, Paolo; Antoniucci, David

    2014-07-01

    Doxycycline has been demonstrated to reduced left ventricular (LV) remodeling, but its effect in patients with ST-elevation myocardial infarction (STEMI) and a baseline occluded [thrombolysis in myocardial infarction (TIMI) flow grade ≤1] infarct-related artery (IRA) is unknown. According to the baseline TIMI flow grade, 110 patients with a first STEMI were divided into 2 groups. Group 1: 77 patients with TIMI flow ≤1 (40 patients treated with doxycycline and 37 with standard therapy, respectively), and a Group 2: 33 patients with TIMI flow 2-3 (15 patients treated with doxycycline and 18 with standard therapy, respectively). The two randomized groups were well matched in baseline characteristics. A 2D-Echo was performed at baseline and at 6 months, together with a coronary angiography, for the remodeling and IRA patency assessment, respectively. The LV end-diastolic volume index (LVEDVi) decreased in Group 2 [-3 mL/m(2) (IQR: -12 to 4 mL/m(2))], and increased in Group 1 [6 mL/m(2) (IQR: -2 to 14 mL/m(2))], (p = 0.001). In Group 2, LVEDVi reduction was similar regardless of drug therapy, while in Group 1 the LVEDVi was smaller in patients treated with doxycycline as compared to control [3 mL/m(2) (IQR: -3 to 8 mL/m(2)) vs. 10 mL/m(2) (IQR: 1-27 mL/m(2)), p = 0.006]. A similar pattern was observed also for LV end-systolic volume and ejection fraction. In STEMI patients at higher risk, as those with a baseline TIMI flow grade ≤1, doxycycline reduces LV remodeling.

  11. Acute Bronchitis

    MedlinePlus

    ... can also cause acute bronchitis. To diagnose acute bronchitis, your health care provider will ask about your symptoms and listen to your breathing. You may also have other tests. Treatments include rest, fluids, and aspirin (for adults) or ...

  12. A Simple Alternative to Grading

    ERIC Educational Resources Information Center

    Potts, Glenda

    2010-01-01

    In this article, the author investigates whether an alternative grading system (contract grading) would yield the same final grades as traditional grading (letter grading), and whether or not it would be accepted by students. The author states that this study demonstrated that contract grading was widely, and for the most part, enthusiastically…

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

    PubMed

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

    2017-03-01

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

  14. Validation of a grading system for complicated diverticulitis in the prediction of need for operative or percutaneous intervention

    PubMed Central

    Fung, AKY; Ahmeidat, H; McAteer, D

    2015-01-01

    Introduction The current surgical management of acute complicated diverticulitis has seen a major paradigm shift from routine operative intervention to a more conservative approach. This has been made possible by the widespread availability of computed tomography (CT) to enable stratification of the disease severity of acute complicated diverticulitis. The aim of this study was to retrospectively validate a CT grading system for acute complicated diverticulitis in the prediction of the need for operative or percutaneous intervention. Methods Hospital and radiology records were reviewed to identify patients with acute complicated diverticulitis confirmed by CT. A consultant gastrointestinal radiologist, blinded to the clinical outcomes of patients, assigned a score according to the CT grading system. Results Three hundred and sixty-seven patients (34.6%) had CT performed for acute diverticulitis during the study period. Forty-four patients (12.0%) had acute complicated diverticulitis (abscess and/or free intraperitoneal air) confirmed on CT. There were 22 women (50%) and the overall median age was 59 years (range: 19–92 years). According to the CT findings, there was one case with grade 1, eighteen patients with grade 2, four with grade 3 and twenty-one with grade 4 diverticulitis. Three patients with grade 2, three patients with grade 3 and ten patients with grade 4 disease underwent acute radiological or surgical intervention. Conclusions The use of a CT grading system for acute complicated diverticulitis did not predict the need for acute radiological or operative intervention in this small study. Decision making guided by the patient’s clinical condition still retains a primary role in the management of acute complicated diverticulitis. PMID:26263806

  15. Low back pain (acute)

    PubMed Central

    2011-01-01

    Introduction Low back pain affects about 70% of people in resource-rich countries at some point in their lives. Acute low back pain can be self-limiting; however, 1 year after an initial episode, as many as 33% of people still have moderate-intensity pain and 15% have severe pain. Acute low back pain has a high recurrence rate; 75% of those with a first episode have a recurrence. Although acute episodes may resolve completely, they may increase in severity and duration over time. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral drug treatments for acute low back pain? What are the effects of local injections for acute low back pain? What are the effects of non-drug treatments for acute low back pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 49 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, advice to stay active, analgesics (paracetamol, opioids), back exercises, back schools, bed rest, behavioural therapy, electromyographic biofeedback, epidural corticosteroid injections, lumbar supports, massage, multidisciplinary treatment programmes, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), spinal manipulation, temperature treatments (short-wave diathermy, ultrasound, ice, heat), traction, and transcutaneous electrical nerve stimulation

  16. Classroom: Efficient Grading

    ERIC Educational Resources Information Center

    Shaw, David D.; Pease, Leonard F., III.

    2014-01-01

    Grading can be accelerated to make time for more effective instruction. This article presents specific time management strategies selected to decrease administrative time required of faculty and teaching assistants, including a multiple answer multiple choice interface for exams, a three-tier grading system for open ended problem solving, and a…

  17. What Is Fifth Grade?

    ERIC Educational Resources Information Center

    O'Brien, Thomas C.; Wallach, Christine

    2006-01-01

    One of the most consistent regularities observers would see in schools is the grouping of children by grade. The authors' work with schoolchildren causes them to ask, what is a grade beyond a group of children at a particular age? In this article, the authors share a glimpse of an activity involving inference and logical necessity that they…

  18. Controlling Grade Inflation

    ERIC Educational Resources Information Center

    Stanoyevitch, Alexander

    2008-01-01

    In this article concerning grade inflation, the author restricts his attention to the college and university level, although many of the tools and ideas developed here should be useful for high schools as well. The author considers the relationships between grades instructors assign and scores they receive on end-of-the semester student…

  19. Beef grading by ultrasound

    NASA Technical Reports Server (NTRS)

    Gammell, P. M.

    1981-01-01

    Reflections in ultrasonic A-scan signatures of beef carcasses indicate USDA grade. Since reflections from within muscle are determined primarily by fat/muscle interface, richness of signals is direct indication of degree of marbling and quality. Method replaces subjective sight and feel tests by individual graders and is applicable to grade analysis of live cattle.

  20. Middle Grades Ideas.

    ERIC Educational Resources Information Center

    Classroom Computer Learning, 1985

    1985-01-01

    Presents a collection of computer-oriented teaching activities for the middle grades. They focus on Logo activities to sharpen visualization skills, use of spreadsheets, various uses of Apple microcomputer paddles, and writing a program from program output. All activities may be adapted for lower or higher grade levels. (JN)

  1. Growing beyond Grades

    ERIC Educational Resources Information Center

    Perchemlides, Natalia; Coutant, Carolyn

    2004-01-01

    Once students are asked to assess their own writing progress, they will begin to do their best for writing great prose instead of just great grades. Teachers will have to create a grade-free zone, allow students to set their own writing goals, provide a common language such as the Six Traits Model, and provide evaluation and instructional models…

  2. Teaching Middle Grades Science.

    ERIC Educational Resources Information Center

    Georgia State Dept. of Education, Atlanta. Office of Instructional Services.

    Background information and exemplary units for teaching science in Georgia's middle school grades are provided. Discussed in the first section are: (1) the rationale for including science in middle school grades, focusing on science/society/technology, science/social issues, scientific reasoning, and scientific literacy; (2) role of science…

  3. Grain Grading and Handling.

    ERIC Educational Resources Information Center

    Rendleman, Matt; Legacy, James

    This publication provides an introduction to grain grading and handling for adult students in vocational and technical education programs. Organized in five chapters, the booklet provides a brief overview of the jobs performed at a grain elevator and of the techniques used to grade grain. The first chapter introduces the grain industry and…

  4. Making Grades More Meaningful

    ERIC Educational Resources Information Center

    Hochbein, Craig; Pollio, Marty

    2016-01-01

    To expand and improve evidence of grading practices, we seized an opportunity presented by the implementation of standards-based grading practices at 11 high schools in Jefferson County Public Schools in Louisville, Ky. These high-needs schools faced substantial sanctions outlined by recently revised federal and state policies unless they made…

  5. Earth Science, Grade 7.

    ERIC Educational Resources Information Center

    Buffalo Public Schools, NY.

    GRADES OR AGES: Grade 7. SUBJECT MATTER: Earth science. ORGANIZATION AND PHYSICAL APPEARANCE: The introductory material suggests a time schedule for the major units and gives details of the reference materials referred to in the text. The main text is presented in four columns: topical outline, basic understandings, suggested activities and…

  6. Grades out, Badges in

    ERIC Educational Resources Information Center

    Young, Jeffrey R.

    2012-01-01

    Grades are broken. Students grub for them, pick classes where good ones come easily, and otherwise hustle to win the highest scores for the least learning. As a result, college grades are inflated to the point of meaninglessness--especially to employers who want to know which diploma-holder is best qualified for their jobs. An alternative is to…

  7. Third Grade Reading Policies

    ERIC Educational Resources Information Center

    Rose, Stephanie

    2012-01-01

    In 2012, 14 states passed legislation geared toward improving 3rd-grade literacy through identification, intervention, and/or retention initiatives. Today, a total of 32 states and the District of Columbia have policies in statute aimed at improving 3rd-grade reading proficiency. The majority of these states require early assessment and…

  8. Upper Grades Ideas.

    ERIC Educational Resources Information Center

    Classroom Computer Learning, 1985

    1985-01-01

    Describes computer-oriented teaching activities for the upper grades. They focus on the use of databases in history classes, checking taxes, examining aspects of the joystick button on Atari microcomputers, printing control using Logo, and a Logo program that draws whirling squares. All activities can be adapted for lower grades. (JN)

  9. Five Obstacles to Grading Reform

    ERIC Educational Resources Information Center

    Guskey, Thomas R.

    2011-01-01

    Educators seeking to reform grading must combat five long-held traditions that stand as formidable obstacles to change: (1) Grades should provide the basis for differentiating students; (2) grade distributions should resemble a bell-shaped curve; (3) grades should be based on students' standing among classmates; (4) poor grades prompt students to…

  10. 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

  11. View of Highway 120 at Priest Grade. Old Priest Grade ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of Highway 120 at Priest Grade. Old Priest Grade seen at left distance. New Priest Grade at center and right distance. Looking west - Big Oak Flat Road, Between Big Oak Flat Entrance & Merced River, Yosemite Village, Mariposa County, CA

  12. Reduced-intensity stem-cell transplantation for adult acute lymphoblastic leukemia: a retrospective study of 33 patients.

    PubMed

    Hamaki, T; Kami, M; Kanda, Y; Yuji, K; Inamoto, Y; Kishi, Y; Nakai, K; Nakayama, I; Murashige, N; Abe, Y; Ueda, Y; Hino, M; Inoue, T; Ago, H; Hidaka, M; Hayashi, T; Yamane, T; Uoshima, N; Miyakoshi, S; Taniguchi, S

    2005-03-01

    Efficacy of reduced-intensity stem-cell transplantation (RIST) for acute lymphoblastic leukemia (ALL) was investigated in 33 patients (median age, 55 years). RIST sources comprised 20 HLA-identical related donors, five HLA-mismatched related, and eight unrelated donors. Six patients had undergone previous transplantation. Disease status at RIST was first remission (n=13), second remission (n=6), and induction failure or relapse (n=14). All patients tolerated preparatory regimens and achieved neutrophil engraftment (median, day 12.5). Acute and chronic graft-versus-host disease (GVHD) developed in 45 and 64%, respectively. Six patients received donor lymphocyte infusion (DLI), for prophylaxis (n=1) or treatment of recurrent ALL (n=5). Nine patients died of transplant-related mortality, with six deaths due to GVHD. The median follow-up of surviving patients was 11.6 months (range, 3.5-37.3 months). The 1-year relapse-free and overall survival rates were 29.8 and 39.6%, respectively. Of the 14 patients transplanted in relapse, five remained relapse free for longer than 6 months. Cumulative rates of progression and progression-free mortality at 3 years were 50.9 and 30.4%, respectively. These findings suggest the presence of a graft-versus-leukemia effect for ALL. RIST for ALL is worth considering for further evaluation.

  13. Functionally graded boron carbide

    SciTech Connect

    Petrovic, J.J.; McClellan, K.J.; Kise, C.D.; Hoover, R.C.; Scarborough, W.K.

    1998-12-31

    Lightweight body armor is important for the protection of US soldiers in the field. Here, fabrication techniques were developed for producing graded porosity B{sub 4}C, and for producing aluminum-B{sub 4}C and epoxy-B{sub 4}C functionally graded materials. The key fabrication aspect was obtaining the graded porosity B{sub 4}C. The feasibility of producing graded porosity B{sub 4}C using a grading of carbon densification aid produced from a gradient of furfuryl alcohol carbon precursor was demonstrated. This approach is quite promising, but it was not optimized in the present investigation. Graded porosity B{sub 4}C materials were produced by a layering approach using different size distributions of B{sub 4}C powders in the green state, and then densifying the layered assembly by hot pressing at 1,900 C. The hardness of uninfiltrated graded B{sub 4}C, aluminum infiltrated B{sub 4}C, and epoxy infiltrated B{sub 4}C was observed to be similar.

  14. Nebraska Science Standards: Grades K-12

    ERIC Educational Resources Information Center

    Nebraska Department of Education, 2010

    2010-01-01

    This publication presents the Nebraska Science Standards for Grades K-12. The standards are presented according to the following grades: (1) Grades K-2; (2) Grades 3-5; (3) Grades 6-8; and (4) Grades 9-12.

  15. Grading for Understanding - Standards-Based Grading

    NASA Astrophysics Data System (ADS)

    Zimmerman, Todd

    2017-01-01

    Standards-based grading (SBG), sometimes called learning objectives-based assessment (LOBA), is an assessment model that relies on students demonstrating mastery of learning objectives (sometimes referred to as standards). The goal of this grading system is to focus students on mastering learning objectives rather than on accumulating points. I have used SBG in an introductory physics course for the past five years and worked with several physics faculty members to implement SBG in the first and second semester of algebra-based and calculus-based introductory physics courses at a primarily undergraduate comprehensive public university with class sizes of 48 students. In this article I will discuss methods for implementing SBG in a physics class.

  16. Isolated extramedullary cutaneous relapse despite concomitant severe graft-vs.-host disease and tissue chimerism analysis in a patient with acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: A case report

    PubMed Central

    Kantarcioglu, Bulent; Bekoz, Huseyin Saffet; Ogret, Yeliz Duvarci; Cakir, Asli; Kivanc, Demet; Oguz, Fatma Savran; Sargin, Deniz

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with acute lymphoblastic leukemia (ALL). The curative potential of allo-HSCT for ALL is, in part, due to the graft-vs.-leukemia (GVL) effect, in addition to the intensive conditioning chemo-radiotherapy. However, relapse remains the major cause of treatment failure following allo-HSCT for ALL. In the allo-HSCT setting, testing for genetic markers of hematopoietic chimerism has become a part of the routine diagnostic program. Routine chimerism analysis is usually performed in peripheral blood or bone marrow; in fact, little is known about the value of tissue chimerism in patients with extramedullary relapse (EMR) after the allo-HSCT setting. The present study reports on, a case of a patient with ALL who experienced isolated cutaneous EMR despite ongoing graft-vs.-host disease (GVHD), and the results of peripheral blood and skin tissue chimerism studies using multiplex polymerase chain reaction (PCR) of short tandem repeats (STR-PCR). The present case demonstrates that, although complete remission and/or chimerism may be achieved in the bone marrow, chimerism achieved at the tissue level, and the subsequent GVL effect, may be limited, despite concomitant severe GVHD following allo-HSCT. Our tissue chimerism analysis results provide a good example of how skin tissue may be a ‘sanctuary’ site for effector cells of GVL, despite active GVHD and complete hematopoetic chimerism. PMID:28105353

  17. Assigning Grades More Fairly

    ERIC Educational Resources Information Center

    Cheshier, Stephen R.

    1975-01-01

    Describes a simplified method for converting raw scores to standard scores and transforming them to "T-scores" for easy comparison of performance. Obtaining letter grades from T-scores is discussed. A reading list is included. (GH)

  18. Gleason grading system

    MedlinePlus

    ... of Prostatic Neoplasia. In: Wein AJ, Kavoussi LR, Partin AW, Peters CA, eds. Campbell-Walsh Urology . 11th ... nih.gov/pubmed/26956509 . Pierorazio PM, Walsh PC, Partin AW, Epstein JI. Prognostic Gleason grade grouping: data ...

  19. Human umbilical cord blood-derived stromal cells, a new resource in the suppression of acute graft-versus-host disease in haploidentical stem cell transplantation in sublethally irradiated mice.

    PubMed

    Zhang, Cheng; Chen, Xing-Hua; Zhang, Xi; Gao, Lei; Kong, Pei-Yan; Peng, Xian-gui; Liang, Xue; Gao, Li; Gong, Yi; Wang, Qing-Yu

    2011-04-15

    Human umbilical cord blood-derived stromal cells (hUCBDSCs), a novel population isolated from CD34(+) cells by our laboratory, exerted an immunosuppressive effect on xenogenic T cells. This study aimed to investigate whether hUCBDSCs play a critical role in the suppression of acute graft-versus-host disease (aGVHD). The hUCBDSCs were co-cultured with splenocytes (SPCs) of donor C57BL/6 mice. The aGVHD in the recipient (B6×BALB/c) F1 mice was induced by the infusion of bone marrow cells and SPCs from donor mice following sublethal irradiation. The shift in vivo for hUCBDSCs was detected. The proliferation and cell cycle of SPCs were tested by cell counting kit-8 and flow cytometry, respectively. The expression of CD49b natural killer (NK) cells and CD3 T cells was detected by flow cytometry in co-culture and post-transplantation. IL-4, and IFN-γ were detected by ELISA in the serum of co-culture and post-transplantation. The survival time, body weight, clinical score, and histopathological score were recorded for mice post-transplantation. The hUCBDSCs promoted the proliferation of SPCs and significantly increased the ratio of the S and G(2)/M phase (p < 0.05). The hUCBDSCs significantly increased the expression of CD49b NK cells and IL-4 protein and decreased the expression of CD3 T cells and IFN-γ protein both in vitro and in vivo. The survival time of mice with co-transplantation of hUCBDSCs was significantly prolonged, and decreased clinical and histopathological scores were also observed. The hUCBDSCs were continually detected in the target organs of GVHD. These results suggest that hUCBDSCs possess the capability of suppressing aGVHD, possibly via their influence on CD3 T cells, NK cells, and cytokines.

  20. Effect of donor CTLA-4 alleles and haplotypes on graft-versus-host disease occurrence in Tunisian patients receiving a human leukocyte antigen-identical sibling hematopoietic stem cell transplant.

    PubMed

    Sellami, Mohamed Hichem; Bani, Meriem; Torjemane, Lamia; Kaabi, Houda; Ladeb, Saloua; Ben Othmane, Tarek; Hmida, Slama

    2011-02-01

    The CTLA-4 genetic variation, such as single nucleotide polymorphisms (SNPs) may be critical and can affect the functional activity of cells that initiate the graft-versus-host disease (GVHD) effects. The aim of this study is to examine the effect of donor CTLA-4 alleles and haplotypes for the -318C>T and the 49A>G polymorphisms on the occurrence of GVHD in Tunisians recipients of HSCs. A total of 112 patients and their 112 respective sibling donors of HSCs were enrolled in this study. All patients had either grades 0-I or grades II-IV acute GVHD, or chronic GVHD. The SNPs genotyping assay was performed using sets of sequence specific primers (SSP-PCR). The single marker association analysis showed that the 49G allele, in a genetic recessive model, may be a potential risk factor only for the chronic GVHD (p = 0.032, odds ratio [OR] = 2.58, 95% confidence interval = 1.05-6.32). The haplotypes analyses showed that the CTLA-4 -318C49G nucleotide combination is significantly associated with the incidence of chronic GVHD (p = 0.043, χ² = 3.27). Donor CTLA-4 -318C49G haplotype may be a significant risk factor for developing chronic GVHD after allo-stem cell transplantation. We suppose that donor T cells expressing this haplotype in a homozygous state have higher proliferation than those expressing other haplotypes, especially after recognition of the recipient's minor histocompatibility antigens.

  1. Measuring grade inflation: a clinical grade discrepancy score.

    PubMed

    Paskausky, Anna L; Simonelli, M Colleen

    2014-08-01

    Grade inflation presents pedagogical and safety concerns for nursing educators and is defined as a "greater percentage of excellent scores than student performances warrant" (Speer et al., 2000, p. 112). This descriptive correlational study evaluated the relationship of licensure exam-style final written exams and faculty assigned clinical grades from undergraduate students (N = 281) for evidence of grade inflation at a private undergraduate nursing program in the Northeast of the United States and developed a new measurement of grade inflation, the clinical grade discrepancy score. This measurement can be used in programs where clinical competency is graded on a numeric scale. Evidence suggested grade inflation was present and the clinical grade discrepancy score was an indicator of the severity of grade inflation. The correlation between licensure-style final written exams and faculty assigned clinical grades was moderate to low at 0.357. The clinical grade discrepancy scores were 98% positive indicating likely grade inflation. Some 70% of clinical grade discrepancy scores indicated a difference of student licensure-style final written exams and faculty assigned clinical grades of at least one full letter grade (10 points out of 100). Use of this new measure as a tool in exploring the prevalence of grade inflation and implications for patient safety are discussed.

  2. How Consistent Are Course Grades? An Examination of Differential Grading

    ERIC Educational Resources Information Center

    Rauschenberg, Samuel

    2014-01-01

    Differential grading occurs when students in courses with the same content and curriculum receive inconsistent grades across teachers, schools, or districts. It may be due to many factors, including differences in teacher grading standards, district grading policies, student behavior, teacher stereotypes, teacher quality, and curriculum adherence.…

  3. The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial.

    PubMed

    Armand, Philippe; Kim, Haesook T; Sainvil, Marie-Michele; Lange, Paulina B; Giardino, Angela A; Bachanova, Veronika; Devine, Steven M; Waller, Edmund K; Jagirdar, Neera; Herrera, Alex F; Cutler, Corey; Ho, Vincent T; Koreth, John; Alyea, Edwin P; McAfee, Steven L; Soiffer, Robert J; Chen, Yi-Bin; Antin, Joseph H

    2016-04-01

    Inhibition of the mechanistic target of rapamycin (mTOR) pathway has clinical activity in lymphoma. The mTOR inhibitor sirolimus has been used in the prevention and treatment of graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (HSCT). A retrospective study suggested that patients with lymphoma undergoing reduced intensity conditioning (RIC) HSCT who received sirolimus as part of their GVHD prophylaxis regimen had a lower rate of relapse. We therefore performed a multicentre randomized trial comparing tacrolimus, sirolimus and methotrexate to standard regimens in adult patients undergoing RIC HSCT for lymphoma in order to assess the possible benefit of sirolimus on HSCT outcome. 139 patients were randomized. There was no difference overall in 2-year overall survival, progression-free survival, relapse, non-relapse mortality or chronic GVHD. However, the sirolimus-containing arm had a significantly lower incidence of grade II-IV acute GVHD (9% vs. 25%, P = 0·015), which was more marked for unrelated donor grafts. In conclusion, the addition of sirolimus for GVHD prophylaxis in RIC HSCT is associated with no increased overall toxicity and a lower risk of acute GVHD, although it does not improve survival; this regimen is an acceptable option for GVHD prevention in RIC HSCT. This trial is registered at clinicaltrials.gov (NCT00928018).

  4. Vorinostat and Decitabine in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-08-26

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Secondary Acute Myeloid Leukemia; Splenic Marginal Zone Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma

  5. Acute Pancreatitis and Pregnancy

    MedlinePlus

    ... Pancreatitis Acute Pancreatitis and Pregnancy Acute Pancreatitis and Pregnancy Timothy Gardner, MD Acute pancreatitis is defined as ... pancreatitis in pregnancy. Reasons for Acute Pancreatitis and Pregnancy While acute pancreatitis is responsible for almost 1 ...

  6. Eight Steps to Meaningful Grading

    ERIC Educational Resources Information Center

    Deddeh, Heather; Main, Erin; Fulkerson, Sharon Ratzlaff

    2010-01-01

    A group of teachers at Clifford Smart Middle School in Michigan's Walled Lake Consolidated School District have broken free from traditional grading in order to embrace a more meaningful grading practice. Using standards-based grading practices, they believe their grading now accurately communicates to students and parents the student's mastery…

  7. Teachers' Experiences of Unfair Grading

    ERIC Educational Resources Information Center

    Alm, Fredrik; Colnerud, Gunnel

    2015-01-01

    Grading is often perceived as one of a teacher's most difficult tasks. Despite most teachers endeavoring to grade their students as objectively as possible, many students feel that they are subject to unfair grading. The aim of this study is to describe what it is about a teacher's grading that contributes to the perception of unfairness. This…

  8. Arizona Academic Standards: Grade 7

    ERIC Educational Resources Information Center

    Arizona Department of Education, 2009

    2009-01-01

    This document contains the Arizona academic standards for Grade 7. The following 11 standards are reviewed: (1) The Arts Standard 2006 --Grade 7; (2) Comprehensive Health Education/Physical Activity Standards 1997--Essentials (Grades 4-8); (3) Foreign and Native Language Standards 1997--Essentials (Grades 4-8); (4) Reading Standard Articulated by…

  9. Arizona Academic Standards, Grade 4

    ERIC Educational Resources Information Center

    Arizona Department of Education, 2007

    2007-01-01

    This publication contains Arizona public schools' academic standards for grade 4. The contents of this document include the following: (1) The Arts Standard 2006--Grade 4; (2) Comprehensive Health Education/Physical Activity Standards 1997--Essentials (Grades 4-8); (3) Foreign and Native Language Standards 1997--Essentials (Grades 4-8); (4)…

  10. Arizona Academic Standards, Grade 8

    ERIC Educational Resources Information Center

    Arizona Department of Education, 2009

    2009-01-01

    This publication contains the updated academic standards of Arizona for Grade 8. The contents of this document include the following: (1) The Arts Standard 2006--Grade 8; (2) Comprehensive Health Education/Physical Activity Standards 1997--Essentials (Grades 4-8); (3) Foreign and Native Language Standards 1997--Essentials (Grades 4-8); (4) Reading…

  11. Arizona Academic Standards: Grade 4

    ERIC Educational Resources Information Center

    Arizona Department of Education, 2009

    2009-01-01

    This publication contains Arizona public schools' academic standards for grade 4. The contents of this document include the following: (1) The Arts Standard 2006--Grade 4; (2) Comprehensive Health Education/Physical Activity Standards 1997--Essentials (Grades 4-8); (3) Foreign and Native Language Standards 1997--Essentials (Grades 4-8); (4)…

  12. Arizona Academic Standards, Grade 2

    ERIC Educational Resources Information Center

    Arizona Department of Education, 2009

    2009-01-01

    This publication contains Arizona public schools' academic standards for grade 2. The contents of this document include the following: (1) The Arts Standard 2006--Grade 2; (2) Comprehensive Health Education/Physical Activity Standards 1997--Foundations (Grades 1-3); (3) Foreign and Native Language Standards 1997--Foundations (Grades 1-3); (4)…

  13. Arizona Academic Standards, Grade 3

    ERIC Educational Resources Information Center

    Arizona Department of Education, 2009

    2009-01-01

    This publication contains Arizona public schools' academic standards for grade 3. The contents of this document include the following: (1) The Arts Standard 2006--Grade 3; (2) Comprehensive Health Education/Physical Activity Standards 1997--Foundations (Grades 1-3); (3) Foreign and Native Language Standards 1997--Foundations (Grades 1-3); (4)…

  14. Arizona Academic Standards, Grade 1

    ERIC Educational Resources Information Center

    Arizona Department of Education, 2009

    2009-01-01

    This publication contains Arizona public schools' academic standards for Grade 1. The contents of this document include the following: (1) The Arts Standard 2006--Grade 1; (2) Comprehensive Health Education/Physical Activity Standards 1997--Foundations (Grades 1-3); (3) Foreign and Native Language Standards 1997--Foundations (Grades 1-3); (4)…

  15. Serving Grades Over the Internet.

    ERIC Educational Resources Information Center

    Harris, James K.

    This paper demonstrates a grade server that allows college students to access their grades over the Internet from the instructor's home page. Using a CGI (common gateway interface) program written in Visual Basic, the grades are read directly from an Excel spreadsheet and presented to the requester after he/she enters a password. The grade for…

  16. Graded-index magnonics

    NASA Astrophysics Data System (ADS)

    Davies, C. S.; Kruglyak, V. V.

    2015-10-01

    The wave solutions of the Landau-Lifshitz equation (spin waves) are characterized by some of the most complex and peculiar dispersion relations among all waves. For example, the spin-wave ("magnonic") dispersion can range from the parabolic law (typical for a quantum-mechanical electron) at short wavelengths to the nonanalytical linear type (typical for light and acoustic phonons) at long wavelengths. Moreover, the long-wavelength magnonic dispersion has a gap and is inherently anisotropic, being naturally negative for a range of relative orientations between the effective field and the spin-wave wave vector. Nonuniformities in the effective field and magnetization configurations enable the guiding and steering of spin waves in a deliberate manner and therefore represent landscapes of graded refractive index (graded magnonic index). By analogy to the fields of graded-index photonics and transformation optics, the studies of spin waves in graded magnonic landscapes can be united under the umbrella of the graded-index magnonics theme and are reviewed here with focus on the challenges and opportunities ahead of this exciting research direction.

  17. [Acute pancreatitis].

    PubMed

    Hecker, M; Mayer, K; Askevold, I; Collet, P; Weigand, M A; Krombach, G A; Padberg, W; Hecker, A

    2014-03-01

    Acute pancreatitis is a potentially fatal disease with individually differing expression of systemic involvement. For this reason early diagnosis with subsequent risk stratification is essential in the clinical management of this frequent gastroenterological disorder. Severe forms of acute pancreatitis occur in approximately 20 % of cases often requiring intensive care monitoring and interdisciplinary therapeutic approaches. In the acute phase adequate fluid replacement and sufficient analgesic therapy is of major therapeutic importance. Concerning the administration of antibiotics and the nutritional support of patients with acute pancreatitis a change in paradigms could be observed in recent years. Furthermore, endoscopic, radiological or surgical interventions can be necessary depending on the severity of the disease and potential complications.

  18. Bronchitis - acute

    MedlinePlus

    ... to breathe. Other symptoms of bronchitis are a cough and coughing up mucus. Acute means the symptoms ... diagnosed with chronic bronchitis, you must have a cough with mucus on most days for at least ...

  19. Acute Bronchitis

    MedlinePlus

    ... bronchitis? Acute bronchitis is inflammation of your bronchial tree. The bronchial tree consists of tubes that carry air into your ... weeks or months. This happens because the bronchial tree takes a while to heal. A lasting cough ...

  20. Diarrhoea in adults (acute)

    PubMed Central

    2011-01-01

    Introduction An estimated 4.6 billion cases of diarrhoea occurred worldwide in 2004, resulting in 2.2 million deaths. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute diarrhoea in adults living in resource-rich countries? What are the effects of treatments for acute mild-to-moderate diarrhoea in adults from resource-rich countries travelling to resource-poor countries? What are the effects of treatments for acute mild-to-moderate diarrhoea in adults living in resource-poor countries? What are the effects of treatments for acute severe diarrhoea in adults living in resource-poor countries? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 72 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics, antimotility agents, antisecretory agents, bismuth subsalicylate, diet, intravenous rehydration, nasogastric tube rehydration, oral rehydration solutions (amino acid oral rehydration solution, bicarbonate oral rehydration solution, reduced osmolarity oral rehydration solution, rice-based oral rehydration solution, standard oral rehydration solution), vitamin A supplementation, and zinc supplementation. PMID:21718555

  1. Atrial fibrillation (acute onset)

    PubMed Central

    2014-01-01

    Introduction Acute atrial fibrillation is rapid, irregular, and chaotic atrial activity of recent onset. Various definitions of acute atrial fibrillation have been used in the literature, but for the purposes of this review we have included studies where atrial fibrillation may have occurred up to 7 days previously. Risk factors for acute atrial fibrillation include increasing age, cardiovascular disease, alcohol, diabetes, and lung disease. Acute atrial fibrillation increases the risk of stroke and heart failure. The condition resolves spontaneously within 24 to 48 hours in more than 50% of people; however, many people will require interventions to control heart rate or restore sinus rhythm. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent embolism, for conversion to sinus rhythm, and to control heart rate in people with recent-onset atrial fibrillation (within 7 days) who are haemodynamically stable? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 26 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amiodarone, antithrombotic treatment before cardioversion, atenolol, bisoprolol, carvedilol, digoxin, diltiazem, direct current cardioversion, flecainide, metoprolol, nebivolol, propafenone, sotalol, timolol, and verapamil. PMID:25430048

  2. Assessment of acute foot and ankle sprains.

    PubMed

    Lynam, Louise

    2006-07-01

    Acute ankle and foot trauma is a regular emergency presentation and prompt strategic assessment skills are required to enable nurses to categorise and prioritise these injuries appropriately. This article provides background information on the anatomy and physiology of the lower limb to help nurses to identify various grades of ankle sprain as well as injuries that are limb threatening

  3. Social Studies: Grade 8.

    ERIC Educational Resources Information Center

    Manitoba Dept. of Education, Winnipeg.

    This Manitoba (Canada) curriculum guide for eighth grade social studies students contains suggested teaching strategies and learning activities in four units covering: (1) life during prehistoric and early historic times; (2) ancient civilizations; (3) life in early modern Europe; and (4) life in the modern world. Each unit includes an overview,…

  4. American Independence. Fifth Grade.

    ERIC Educational Resources Information Center

    Crosby, Annette

    This fifth grade teaching unit covers early conflicts between the American colonies and Britain, battles of the American Revolutionary War, and the Declaration of Independence. Knowledge goals address the pre-revolutionary acts enforced by the British, the concepts of conflict and independence, and the major events and significant people from the…

  5. Purpose-Driven Grading

    ERIC Educational Resources Information Center

    Carlson, Jane A. K.; Kimpton, Ann

    2010-01-01

    Allowing students to improve their grade by revising their written work may help students learn to revise, but it gives them no incentive to turn in quality work from the start. This article proposes a way to invert the process, thereby teaching students how to revise, while enforcing a more disciplined approach to good writing. (Contains 3…

  6. Cutting Class Harms Grades

    ERIC Educational Resources Information Center

    Taylor, Lewis A., III

    2012-01-01

    An accessible business school population of undergraduate students was investigated in three independent, but related studies to determine effects on grades due to cutting class and failing to take advantage of optional reviews and study quizzes. It was hypothesized that cutting classes harms exam scores, attending preexam reviews helps exam…

  7. Career Education, Grade 6.

    ERIC Educational Resources Information Center

    Syracuse City School District, NY.

    Part of the Syracuse (New York) city school district's guided occupational orientation program, the student workbook consists of information and question sheets suitable for grade 6 career education studies on topics in the labor field, including labor laws, wages, and unions; job applications and interviews; on-the-job training; and social…

  8. First Grade Baseline Evaluation

    ERIC Educational Resources Information Center

    Center for Innovation in Assessment (NJ1), 2013

    2013-01-01

    The First Grade Baseline Evaluation is an optional tool that can be used at the beginning of the school year to help teachers get to know the reading and language skills of each student. The evaluation is composed of seven screenings. Teachers may use the entire evaluation or choose to use those individual screenings that they find most beneficial…

  9. Early Grades Ideas.

    ERIC Educational Resources Information Center

    Classroom Computer Learning, 1985

    1985-01-01

    Presents a collection of computer-oriented teaching activities for the early grades. They include creating musical tones using Atari PILOT, a simulation of traffic lights, teacher-friendly password protection, drawing the alphabet using Logo, and using the Commodore 64's special character graphics. (JN)

  10. Elementary Science: Grade 2.

    ERIC Educational Resources Information Center

    Carroll County Public Schools, Westminster, MD.

    This grade 2 science curriculum guide contains three activity units: (1) insects; (2) measuring; and (3) sink or float. Each unit contains a rationale, teacher background material, lesson plans, and lists of resources including books, audiovisual materials, resource persons, and science activity modules. The lesson plans list the science processes…

  11. Career Awareness: Grade 5.

    ERIC Educational Resources Information Center

    Boise City Independent School District, ID.

    A broad educational background is necessary to meet ever changing occupational fields, and career education is an approach incorporating career information within regular school curriculum. For the elementary level, career awareness is the main thrust in this program to integrate students and community. The format for grade five, performance…

  12. Health, Grade 3.

    ERIC Educational Resources Information Center

    Bui Van Bao; And Others

    This is the third in a series of health primers for elementary education in Vietnam. It is written for Vietnamese children at the third grade level. The fifty-three lessons are integrated into one story. Each lesson is illustrated and briefly summarized. The eight chapters are: (1) Hygiene, at home, in school and in public places; (2) Food and…

  13. Reader. Grade 4.

    ERIC Educational Resources Information Center

    Center for Applied Linguistics, Arlington, VA.

    This textbook is the fourth in the official reading series developed by the Ministry of Education in Saigon and used in all public schools in Vietnam. The books in this series have been reprinted in their entirety from the original editions for use in elementary schools in the United States which have Vietnamese students. This grade 4 reader…

  14. EIGHTH GRADE ENGLISH CURRICULUM.

    ERIC Educational Resources Information Center

    University City School District, MO.

    A CURRICULUM GUIDE FOR TEACHING EIGHTH-GRADE ENGLISH WAS DEVELOPED IN 1965 AT UNIVERSITY CITY, MISSOURI. FOUR UNITS ARE PRESENTED IN DETAILED OUTLINE FORM--"PAST THROUGH PROLOGUE,""GROWING UP,""WHAT IS HUMOR," AND "HEROES, REAL AND UNREAL." THREE OTHER UNITS ARE SUGGESTED BUT NOT OUTLINED--"VALUE AND…

  15. Graded SPSS Exercises.

    ERIC Educational Resources Information Center

    Allen, Mary J.

    The attached materials have been developed for use on the CSU CYBER Computer's Statistical Package for the Social Sciences (SPSSONL). The assignments are graded in difficulty and gradually introduce new commands and require the practice of previously learned commands. The handouts begin with basic instructions for logging on; then XEDIT is taught…

  16. Early Grades Ideas.

    ERIC Educational Resources Information Center

    Classroom Computer Learning, 1984

    1984-01-01

    Presents computer-oriented teaching suggestions suitable for early grades. They include creating houses and stained glass ornaments using Logo, recording class activities with a database management program, making mazes with graphics programs, making drawings with a KoalaPad, and using a program to introduce computers to non-English speaking…

  17. Career Awareness: Grade 6.

    ERIC Educational Resources Information Center

    Boise City Independent School District, ID.

    A broad educational background is necessary to meet ever changing occupational fields, and career education is an approach incorporating career information within the regular school curriculum. For the elementary level, career awareness is the main thrust in this program to integrate students and community. The format for grade six, performance…

  18. Multiple Option Grade Contracts.

    ERIC Educational Resources Information Center

    Partin, Ronald L.

    1979-01-01

    A flexible, point contract system is described which maximizes the advantages of a criterion-referenced contract system while eliminating some of the disadvantages of standard grade contracts. This model has been used by the author in a variety of high school and college courses. (Author/SJL)

  19. Health, Grade 5.

    ERIC Educational Resources Information Center

    Bui Van Bao; And Others

    This is the fifth and last of the Vietnamese series of elementary health textbooks. This one was designed for fifth grade students in Vietnam. The thirty-five lessons are presented in the form of short stories with illustrations and a short summary. The four chapters cover the ordinary symptoms of illness, elementary notions of microbes and…

  20. Elementary Science: Grade 5.

    ERIC Educational Resources Information Center

    Carroll County Public Schools, Westminster, MD.

    This grade 5 science curriculum guide contains four activity units: (1) mineral identification; (2) earth science; (3) soil analysis; and (4) small friends community. Each unit contains a letter to the parents to introduce the unit, lesson plans, and word searches. The lesson plans list the science processes involved, content objectives,…

  1. Endangered Animals. Second Grade.

    ERIC Educational Resources Information Center

    Popp, Marcia

    This second grade teaching unit centers on endangered animal species around the world. Questions addressed are: What is an endangered species? Why do animals become extinct? How do I feel about the problem? and What can I do? Students study the definition of endangered species and investigate whether it is a natural process. They explore topics…

  2. Middle Grades Ideas.

    ERIC Educational Resources Information Center

    Classroom Computer Learning, 1984

    1984-01-01

    Presents five activities suitable for middle grades. These include listings for a car race (BASIC) and poetry (Pilot) programs, and activities on graphics without programing, new meanings (related to computers) of old words, and developing a list of historical events. (JN)

  3. Compromised recovery of natural interferon-alpha/beta-producing cells after allogeneic hematopoietic stem cell transplantation complicated by acute graft-versus-host disease and glucocorticoid administration.

    PubMed

    Kitawaki, T; Kadowaki, N; Ishikawa, T; Ichinohe, T; Uchiyama, T

    2003-07-01

    Delayed recovery of the immune system is a major cause of post-transplant infection. Natural interferon (IFN)-alpha/beta-producing cells (IPC) appear to play a critical role in inducing effective immune responses to a variety of microbial pathogens by producing an enormous amount of IFN-alpha/beta and thereafter by differentiating into dendritic cells. Here, we examined the recovery of IPC as well as other immune cells in 28 patients after allogeneic hematopoietic stem cell transplantation (HSCT) in order to investigate the role of IPC in post-transplant immune reconstitution. In uncomplicated cases, IPC frequency recovered to the lower range of normal values within 30 days after transplantation, resembling the prompt recovery of other cell types in innate immunity. In contrast, the recovery of IPC was profoundly suppressed in the cases with acute graft-versus-host disease (GVHD) and glucocorticoid administration. The patients with lower numbers of IPC were significantly more susceptible to viral infection. The prompt recovery of IPC in uncomplicated cases may contribute to establishing a first line of host defense at the early stage after allogeneic HSCT, whereas the marked suppression of IPC recovery accompanying acute GVHD and glucocorticoid administration may increase the risk of opportunistic infections.

  4. Hepatic injury following reduced intensity unrelated cord blood transplantation for adult patients with hematological diseases.

    PubMed

    Kusumi, Eiji; Kami, Masahiro; Kanda, Yoshinobu; Murashige, Naoko; Seki, Kunihiko; Fujiwara, Masayo; Koyama, Rikako; Komatsu, Tsunehiko; Hori, Akiko; Tanaka, Yuji; Yuji, Koichiro; Matsumura, Tomoko; Masuoka, Kazuhiro; Wake, Atsushi; Miyakoshi, Shigesaburo; Taniguchi, Shuichi

    2006-12-01

    Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant

  5. Does Grade Inflation Decrease the Reliability of Grades?

    ERIC Educational Resources Information Center

    Singleton, Royce, Jr.; Smith, Eliot R.

    1978-01-01

    The effect of grade inflation on the reliability of undergraduate grade point averages at a university was examined. It was shown that there has been some decline in reliability, but this is ameliorated by the use of plus and minus attachments to grades. (JKS)

  6. B-Cell-Based and Soluble Biomarkers in Body Liquids for Predicting Acute/Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Juric, Mateja Kralj; Shevtsov, Maxim; Mozes, Petra; Ogonek, Justyna; Crossland, Rachel E.; Dickinson, Anne M.; Greinix, Hildegard T.; Holler, Ernst; Weissinger, Eva M.; Multhoff, Gabriele

    2017-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main curative therapy for hematological malignancy such as leukemias, lymphomas, or multiple myelomas and some other hematological disorders. In this therapy, cure of hematological diseases relies on graft-versus-malignancy effects by allogenic immune cells. However, severe posttransplant treatment-associated complications such as acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD) limit this approach. Most research into GvHD has concentrated on the aGvHD, while the more complex and multifaceted chronic form has been largely poorly investigated. cGvHD is a multi-organ autoimmune disorder and is the major cause of non-relapse morbidity and mortality following allo-HSCT, occurring in about 50% of patients, or 13,000–15,000 patients per year worldwide. Therefore, there is a high medical need for an early prediction of these therapy-associated toxicities. Biomarkers have gained importance over the last decade in diagnosis, in prognosis, and in prediction of pending diseases or side effects. Biomarkers can be cells, factors isolated from target tissues, or soluble factors that can be detected in body fluids. In this review, we aim to summarize some of the recent developments of biomarkers in the field of allo-HSCT. We will focus on cell-based biomarkers (B-cell subsets) for cGvHD and soluble factors including microRNA (miRNA), which are excreted into serum/plasma and urine. We also discuss the potential role of cytosolic and extracellular 70 kDa heat shock proteins (HSP70) as potential biomarkers for aGvHD and their role in preclinical models. Proteomic biomarkers in the blood have been used as predictors of treatment responses in patients with aGvHD for many years. More recently, miRNAs have been found to serve as a biomarker to diagnose aGvHD in the plasma. Another development relates to urine-based biomarkers that are usually detected by capillary

  7. 7 CFR 51.304 - Combination grades.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Standards for Grades of Apples Grades § 51.304 Combination grades. (a) Combinations of the above grades may... permitted in connection with the U.S. apple grades. When Combination grades are packed, at least 50 percent of the apples in any lot shall meet the requirements of the higher grade in the combination....

  8. 7 CFR 51.304 - Combination grades.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Standards for Grades of Apples Grades § 51.304 Combination grades. (a) Combinations of the above grades may... permitted in connection with the U.S. apple grades. When Combination grades are packed, at least 50 percent of the apples in any lot shall meet the requirements of the higher grade in the combination....

  9. 7 CFR 51.304 - Combination grades.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Standards for Grades of Apples Grades § 51.304 Combination grades. (a) Combinations of the above grades may... permitted in connection with the U.S. apple grades. When Combination grades are packed, at least 50 percent of the apples in any lot shall meet the requirements of the higher grade in the combination....

  10. Grade Inflation: Metaphor and Reality

    ERIC Educational Resources Information Center

    Kamber, Richard; Biggs, Mary

    2003-01-01

    Grade inflation has become a general term for teachers and administrators in recent times and is an ambiguous denomination which needs to be identified. The allegory and reality of grade inflation is discussed.

  11. Determinants for grading Malaysian rice

    NASA Astrophysics Data System (ADS)

    ChePa, Noraziah; Yusoff, Nooraini; Ahmad, Norhayati

    2016-08-01

    Due to un-uniformity of rice grading practices in Malaysia, zones which actively producing rice in Malaysia are using their own way of grading rice. Rice grading is important in determining rice quality and its subsequent price in the market. It is an important process applied in the rice production industry with the purpose of ensuring that the rice produced for the market meets the quality requirements of consumer. Two important aspects that need to be considered in determining rice grades are grading technique and determinants to be used for grading (usually referred as rice attributes). This article proposes the list of determinants to be used in grading Malaysian rice. Determinants were explored through combination of extensive literature review and series of interview with the domain experts and practitioners. The proposed determinants are believed to be beneficial to BERNAS in improving the current Malaysian rice grading process.

  12. Graft-versus-host disease management.

    PubMed

    Mistrik, M; Bojtarova, E; Sopko, L; Masakova, L; Roziakova, L; Martinka, J; Batorova, A

    Graft-versus-host disease (GVHD) remains a major problem of allogeneic hematopoietic-stem cell transplantation (HSCT) and an obstacle for successful outcome. Clinically significant acute GVHD (grade II or higher) developed in 20 to 65 percent of the patients. Death due to this complication accounts for approximately 50 percent of the deaths that are not due to a relapse of the neoplasm. Up to 70 % of patients who survive beyond day 100 develop chronic GVHD and it is the leading cause of nonrelapse mortality more than 2 years after allogeneic HSCT. In addition, chronic GVHD is associated with decreased quality of life, impaired functional status, and ongoing need for immunosuppressive medications. The incidence of chronic GVHD is increasing because of expansion of the donor population beyond HLA-identical siblings, older recipient age, use of peripheral blood cells as the graft source, and infusion of donor lymphocytes for treatment of recurrent malignancy after HSCT. With the current rush in new findings related to GVHD, we see a significant advancement in its management. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of GVHD, as access to the most sophisticated advances may vary depending on local circumstances (Tab. 4, Fig. 1, Ref. 51).

  13. Autologous stem cell transplantation versus alternative allogeneic donor transplants in adult acute leukemias.

    PubMed

    Claude Gorin, Norbert

    2016-04-01

    The availability of alternative sources of stem cells including most recently T-replete haploidentical marrow or peripheral blood, and the increasing use of reduced-intensity conditioning (RIC), renders feasible an allogeneic transplant to almost all patients with acute leukemia up to 70 years of age. Autologous stem cell transplantation (ASCT) for consolidation of complete remission (CR), however, offers in some circumstances an alternative option. Although associated with a higher relapse rate, autologous transplant benefits from a lower non-relapse mortality, the absence of graft-versus-host disease (GVHD), and a better quality of life for long-term survivors. The recent use of intravenous busulfan (IVBU) with high-dose melphalan, better monitoring of minimal residual disease (MRD), and maintenance therapy post autografting bring new interest. Few retrospective studies compared the outcome following alternative donor versus autologous transplants for remission consolidation. Genoidentical and phenoidentical allogeneic stem cell transplantations are undisputed gold standards, but there are no data showing the superiority of alternative allogeneic donor over autologous transplantation, at the time of undetectable MRD, in patients with good- and intermediate-1 risk acute myelocytic leukemia (AML) in first complete remission (CR1), acute promyelocytic leukemia in second complete remission (CR2), and Philadelphia chromosome-positive (Ph(+)) acute lymphocytic leukemia (ALL).

  14. 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

  15. Graded Causation and Defaults

    DTIC Science & Technology

    2012-08-01

    in philosophy and the law in part because of its connection with issues of moral and legal responsibility (see for example, Moore [2009] for a...viewpoints in the flower-watering example described in the introduction: (a) Beebee [2004] and Moore [2009], for example, argue against the existence...relevant sense) of his death. Moore [2009] uses this type of case to argue that our ordinary notion of actual causation is graded, rather than all-or

  16. The Unbearable Importance of Grading

    ERIC Educational Resources Information Center

    Parini, Jay

    2008-01-01

    Grading is one of the primary venues of teaching. In this article, the author shares his experience of grading papers. He alleges that the hardest papers to grade are those where nothing is really "wrong" with the prose or the argument, where everything is "sort of" correct but nothing is vivid, nothing quite original. Students must learn in time…

  17. Taking the Grading Conversation Public

    ERIC Educational Resources Information Center

    Reeves, Douglas B.

    2011-01-01

    To manage effective grading reform, education leaders must engage teachers, parents, communities, and policymakers in a rational discussion about grading. Doug Reeves suggests that leaders start the conversation with a discussion of the principles on which all stakeholders can agree; make clear what will not change under the new grading policy; be…

  18. Arizona Academic Standards, Grade 6

    ERIC Educational Resources Information Center

    Arizona Department of Education, 2009

    2009-01-01

    This publication contains an updated academic standards of Arizona public schools for grade 6. The contents of this document include the following: (1) The Arts Standard 2006--Grade 6; (2) Comprehensive Health Education/Physical Activity Standards 1997--Essentials (Grades 4-8); (3) Foreign and Native Language Standards 1997--Essentials (Grades…

  19. Arizona Academic Standards, Grade 5

    ERIC Educational Resources Information Center

    Arizona Department of Education, 2009

    2009-01-01

    This publication contains an updated academic standards of Arizona public schools for grade 5. The contents of this document include the following: (1) The Arts Standard 2006--Grade 5; (2) Comprehensive Health Education/Physical Activity Standards 1997--Essentials (Grades 4-8); (3) Foreign and Native Language Standards 1997--Foundations (Grades…

  20. Field grading in capacitor margins

    NASA Astrophysics Data System (ADS)

    Springer, T. E.; Sarjeant, W. J.; Nunnally, W. C.

    1981-06-01

    Some of the results of modeling electric fields in the margin of a bogey plastic film liquid impregnant capacitor are presented where effects of foil edge shape, different impregnants, and grading wires are examined. It is concluded that placement tolerance and connection problems make grading wires impractical and that folded foil edges are still the best solution to field grading.

  1. Acute Pancreatitis

    PubMed Central

    Geokas, Michael C.

    1972-01-01

    For many decades two types of acute pancreatitis have been recognized: the edematous or interstitial and the hemorrhagic or necrotic. In most cases acute pancreatitis is associated with alcoholism or biliary tract disease. Elevated serum or urinary α-amylase is the most important finding in diagnosis. The presence of methemalbumin in serum and in peritoneal or pleural fluid supports the diagnosis of the hemorrhagic form of the disease in patients with a history and enzyme studies suggestive of pancreatitis. There is no characteristic clinical picture in acute pancreatitis, and its complications are legion. Pancreatic pseudocyst is probably the most common and pancreatic abscess is the most serious complication. The pathogenetic principle is autodigestion, but the precise sequence of biochemical events is unclear, especially the mode of trypsinogen activation and the role of lysosomal hydrolases. A host of metabolic derangements have been identified in acute pancreatitis, involving lipid, glucose, calcium and magnesium metabolism and changes of the blood clotting mechanism, to name but a few. Medical treatment includes intestinal decompression, analgesics, correction of hypovolemia and other supportive and protective measures. Surgical exploration is advisable in selected cases, when the diagnosis is in doubt, and is considered imperative in the presence of certain complications, especially pancreatic abscess. PMID:4559467

  2. Comparison of outcomes after donor lymphocyte infusion with or without prior chemotherapy for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Mo, Xiao-Dong; Zhang, Xiao-Hui; Xu, Lan-Ping; Wang, Yu; Yan, Chen-Hua; Chen, Huan; Chen, Yu-Hong; Han, Wei; Wang, Feng-Rong; Wang, Jing-Zhi; Liu, Kai-Yan; Huang, Xiao-Jun

    2017-03-11

    The efficacy of donor lymphocyte infusion (DLI) without chemotherapy was investigated and compared with that of chemotherapy prior to DLI (Chemo-DLI) in patients who were minimal residual disease (MRD)-positive after allogeneic hematopoietic stem cell transplantation (HSCT). We enrolled 115 consecutive patients who received either DLI (n = 20) or Chemo-DLI (n = 95) during the same period. For each DLI recipient, three recipients matched for age at the HSCT, underlying diseases, and the year of the HSCT were randomly selected from the Chemo-DLI cohort (n = 60). The 2-year cumulative incidence of severe acute graft-versus-host disease (GVHD) and chronic GVHD was comparable between the groups. Fifteen (75.0%) and 47 (78.3%) patients in the DLI and Chemo-DLI groups turned MRD-negative, respectively. The 2-year cumulative incidences of relapse and non-relapse mortality after intervention were 30.7 versus 39.6% (P = 0.582) and 10.3 versus 6.0% (P = 0.508) in the DLI and Chemo-DLI groups, respectively. The 2-year probabilities of disease-free, overall, and GVHD-free/relapse-free survival after preemptive intervention were 58.9 versus 54.3% (P = 0.862), 69.3 versus 78.1% (P = 0.361), and 44.4 versus 35.1% (P = 0.489) in the DLI and Chemo-DLI groups, respectively. In multivariate analysis, the intervention method did not significantly influence the clinical outcomes. In summary, preemptive DLI alone may be effective for patients who are MRD-positive and may be a potential alternative for patients who refuse or are unable to receive Chemo-DLI after HSCT.

  3. 7 CFR 810.1404 - Grades and grade requirements for sorghum.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 7 2012-01-01 2012-01-01 false Grades and grade requirements for sorghum. 810.1404... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Sorghum Grades and Grade Requirements § 810.1404 Grades and grade requirements for sorghum. Grading factors Grades U.S. Nos. 1 1 2 3...

  4. 7 CFR 810.1404 - Grades and grade requirements for sorghum.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 7 2013-01-01 2013-01-01 false Grades and grade requirements for sorghum. 810.1404... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Sorghum Grades and Grade Requirements § 810.1404 Grades and grade requirements for sorghum. Grading factors Grades U.S. Nos. 1 1 2 3...

  5. Grade-dependent Proteomics Characterization of Kidney Cancer*S⃞

    PubMed Central

    Perroud, Bertrand; Ishimaru, Tatz; Borowsky, Alexander D.; Weiss, Robert H.

    2009-01-01

    Kidney cancer is frequently metastatic on presentation at which point the disease is associated with a 95% mortality. Assessment of tumor grade on pathological examination is the most powerful means for prognostication as well as for stratification of patients into those who might respond to conventional or targeted therapy. Although there exist several grading systems in common use, all suffer from significant disparity among observers. In an attempt to objectify this process as well as to acquire grade-specific mechanistic information, we performed LC-MS/MS-based proteomics analysis on 50 clear cell kidney cancers equally distributed among normal tissues and Fuhrman grades 1–4. Initial experiments confirmed the utility of using archived formalin-fixed paraffin-embedded samples for LC-MS/MS-based proteomics analysis, and the LC-MS/MS findings were validated by extensive immunoblotting. We now show that changes among many biochemical processes and pathways are strongly grade-dependent with the glycolytic and amino acid synthetic pathways highly represented. In addition, proteins relating to acute phase and xenobiotic metabolism signaling are highly represented. Self-organized mapping of proteins with similar patterns of expression led to the creation of a heat map that will be useful in grade characterization as well as in future research relating to oncogenic mechanisms and targeted therapies for kidney cancer. PMID:19164279

  6. Acute Hemorrhagic Edema of Infancy.

    PubMed

    Serra E Moura Garcia, C; Sokolova, A; Torre, M L; Amaro, C

    2016-01-01

    Acute Hemorrhagic Edema of Infancy is a small vessel leucocytoclastic vasculitis affecting young infants. It is characterized by large, target-like, macular to purpuric plaques predominantly affecting the face, ear lobes and extremities. Non-pitting edema of the distal extremities and low-grade fever may also be present. Extra-cutaneous involvement is very rare. Although the lesions have a dramatic onset in a twenty-four to forty-eight hour period, usually the child has a non-toxic appearance. In most cases there are no changes in laboratory parameters. The cutaneous biopsy reveals an inflammatory perivascular infiltrate. It is a benign and auto-limited disease, with complete resolution within two to three weeks leaving no sequelae in the majority of cases. No recurrences are described. We report a case of a 42-day old girl admitted at our hospital with Acute Hemorrhagic Edema of Infancy.

  7. Grade inflation: a problem in nursing?

    PubMed

    King-Jones, Malena; Mitchell, Abigail

    2012-01-01

    This article examines grade inflation in higher education and in nursing education. The factors related to grade inflation and consequences of grade inflation are explored. Actions that address grade inflation and recommendations for future research in nursing education are provided.

  8. Grading the teacher

    NASA Astrophysics Data System (ADS)

    Swartz, Clifford E.

    2000-04-01

    Several fads ago there was a movement to grade teachers in terms of their competency — competency-based testing. Everyone knows that there are good teachers and there are bad teachers. The trouble is, it's hard to define the categories. It's like the Supreme Court justice who couldn't define pornography, but knew it when he saw it. In New York State, prospective teachers must take tests in both pedagogy and subject material. That seems reasonable. There ought to be some minimum standards, so I thought that I would try my hand at setting up such requirements.

  9. Acute Vestibulopathy

    PubMed Central

    Cha, Yoon-Hee

    2011-01-01

    The presentation of acute vertigo may represent both a common benign disorder or a life threatening but rare one. Familiarity with the common peripheral vestibular disorders will allow the clinician to rapidly “rule-in” a benign disorder and recognize when further testing is required. Key features of vertigo required to make an accurate diagnosis are duration, chronicity, associated symptoms, and triggers. Bedside tests that are critical to the diagnosis of acute vertigo include the Dix-Hallpike maneuver and canalith repositioning manuever, occlusive ophthalmoscopy, and the head impulse test. The goal of this review is to provide the clinician with the clinical and pathophysiologic background of the most common disorders that present with vertigo to develop a logical differential diagnosis and management plan. PMID:23983835

  10. Acute Blindness.

    PubMed

    Meekins, Jessica M

    2015-09-01

    Sudden loss of vision is an ophthalmic emergency with numerous possible causes. Abnormalities may occur at any point within the complex vision pathway, from retina to optic nerve to the visual center in the occipital lobe. This article reviews specific prechiasm (retina and optic nerve) and cerebral cortical diseases that lead to acute blindness. Information regarding specific etiologies, pathophysiology, diagnosis, treatment, and prognosis for vision is discussed.

  11. Comparison of Non-myeloablative Conditioning Regimens for Lymphoproliferative Disorders

    PubMed Central

    Hong, Sanghee; Le-Rademacher, Jennifer; Artz, Andrew; McCarthy, Philip L.; Logan, Brent R.; Pasquini, Marcelo C.

    2014-01-01

    Hematopoietic cell transplantation (HCT) with non-myeloablative conditioning (NMA) for lymphoproliferative diseases (LD) includes fludarabine with and without low-dose total body irradiation (TBI). Transplant outcomes were compared among patients ≥40 years with LD who received a HCT with TBI (N=382) and no-TBI (N=515) NMA from 2001 to 2011. The groups were comparable except for donor, graft, prophylaxis for graft-versus-host disease (GVHD), disease status and year of HCT. Cumulative incidences of grades II–IV GVHD at 100 days, were 29% and 20% (p=0.001), and chronic GVHD at 1 year were 54% and 44% (p=0.004) for TBI and no-TBI, respectively. Multivariate analysis of progression/relapse, treatment failure and mortality showed no outcome differences by conditioning. Full donor chimerism at day 100 was observed in 82% vs. 64% in the TBI and no-TBI groups, respectively (p=0.006). Subset of four most common conditioning/ GVHD prophylaxis combinations demonstrated higher rates of grades II–IV acute (p<0.001) and chronic GVHD (p<0.001) among recipients of TBI-mycophenolate mofetil (MMF) compared to other combinations. TBI-based NMA conditioning induces faster full donor chimerism but overall survival outcomes are comparable to no-TBI regimens. Combination of TBI and MMF are associated with higher rates of GVHD without impact on survival outcomes in patients with LD. PMID:25437248

  12. Generation of memory T cells for adoptive transfer using clinical-grade anti-CD62L magnetic beads.

    PubMed

    Verfuerth, S; Sousa, P S E; Beloki, L; Murray, M; Peters, M D; O'Neill, A T; Mackinnon, S; Lowdell, M W; Chakraverty, R; Samuel, E R

    2015-10-01

    Pre-clinical studies of allogeneic stem cell transplantation suggest that depletion of naive T cells from donor lymphocytes will reduce the risk of GvHD but preserve immunity to infectious pathogens. In this study, we have established a clinical-grade protocol under good manufacturing practice conditions for purging CD62L(+) naive T cells from steady-state leukapheresis products using the CliniMACS system. The efficacy of immunomagnetic CD62L depletion was assessed by analysis of cell composition and functional immune responses. A median 2.9 log CD62L depletion was achieved with no evidence of CD62L shedding during the procedure and a mean T-cell yield of 47%. CD62L(-) cells comprised an equal mix of CD4(+) and CD8(+) T cells, with elimination of B cells but maintenance of regulatory T cells and natural killer cell populations. CD62L-depleted T cells were predominantly CD45RA(-) and CD45RA(+) effector memory (>90%) and contained the bulk of pentamer-staining antivirus-specific T cells. Functional assessment of CD62L(-) cells revealed the maintenance of antiviral T-cell reactivity and a reduction in the alloreactive immune response compared with unmanipulated cells. Clinical-grade depletion of naive T cells using immunomagnetic CD62L beads from steady-state leukapheresis products is highly efficient and generates cells suitable for adoptive transfer in the context of clinical trials.

  13. Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Sociéte Française de Greffe de Moelle et de Thérapie Cellulaire.

    PubMed

    Mohty, M; Labopin, M; Balère, M L; Socié, G; Milpied, N; Tabrizi, R; Ifrah, N; Hicheri, Y; Dhedin, N; Michallet, M; Buzyn, A; Cahn, J-Y; Bourhis, J-H; Blaise, D; Raffoux, C; Espérou, H; Yakoub-Agha, I

    2010-11-01

    This retrospective report assessed the impact of rabbit antithymocyte globulins (ATG), incorporated within a standard myeloablative conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT) using human leukocyte antigen-matched unrelated donors (HLA-MUD), on the incidence of acute and chronic graft-vs-host disease (GVHD). In this series of leukemia patients, 120 patients (70%) did not receive ATG ('no-ATG' group), whereas 51 patients received ATG ('ATG' group). With a median follow-up of 30.3 months, the cumulative incidence of grade 3-4 acute GVHD was 36% in the no-ATG group and 20% in the ATG group (P = 0.11). The cumulative incidence of extensive chronic GVHD was significantly lower in the ATG group as compared to the no-ATG group (4 vs 32%, respectively; P = 0.0017). In multivariate analysis, the absence of use of ATG was the strongest parameter associated with an increased risk of extensive chronic GVHD (relative risk) = 7.14, 95% CI: 1.7-33.3, P = 0.008). At 2 years, the probability of nonrelapse mortality, relapse, overall and leukemia-free survivals was not significantly different between the no-ATG and ATG groups. We conclude that the addition of ATG to GVHD prophylaxis resulted in decreased incidence of extensive chronic GVHD without an increase in relapse or nonrelapse mortality, and without compromising survival after myeloablative allo-SCT from HLA-MUD.

  14. The evolving Gleason grading system.

    PubMed

    Chen, Ni; Zhou, Qiao

    2016-02-01

    The Gleason grading system for prostate adenocarcinoma has evolved from its original scheme established in the 1960s-1970s, to a significantly modified system after two major consensus meetings conducted by the International Society of Urologic Pathology (ISUP) in 2005 and 2014, respectively. The Gleason grading system has been incorporated into the WHO classification of prostate cancer, the AJCC/UICC staging system, and the NCCN guidelines as one of the key factors in treatment decision. Both pathologists and clinicians need to fully understand the principles and practice of this grading system. We here briefly review the historical aspects of the original scheme and the recent developments of Gleason grading system, focusing on major changes over the years that resulted in the modern Gleason grading system, which has led to a new "Grade Group" system proposed by the 2014 ISUP consensus, and adopted by the 2016 WHO classification of tumours of the prostate.

  15. Haploidentical peripheral blood stem cell transplantation without irradiation or busulfan after reduced-intensity conditioning for KMT2A(MLL)-rearranged infant B-cell precursor acute lymphoblastic leukemia: Report of two cases.

    PubMed

    Yoshimi, Ai; Kato, Keisuke; Hosaka, Sho; Suzuki, Ryoko; Fukushima, Hiroko; Nakao, Tomohei; Kobayashi, Chie; Fukushima, Takashi; Koike, Kazutoshi; Sumazaki, Ryo; Tsuchida, Masahiro

    2017-03-22

    We present two infants with KMT2A(MLL)-gene-R-associated BCP-ALL, who received HLA haploidentical PBSCT after RIC. The patients developed ALL at age 6 months and 3 months, respectively. Case 1 underwent PBSCT at the second CR with detectable KMT2A-AFF1(MLL-AF4) fusion gene transcript at 11 months of age, and Case 2 at the first CR without KMT2A-MLLT1(MLL-ENL) fusion gene transcript at 8 months of age. Both patients received G-CSF-mobilized unmanipulated peripheral blood mononuclear cells from their HLA haploidentical mothers after administration of FLU, MEL, and ATG. Tacrolimus, methotrexate, and mPSL were administered as prophylaxis against GVHD. Engraftment was rapidly obtained with complete chimerism in both patients. Acute adverse events included acute GVHD in Case 1 and bacterial sepsis in Case 2. At last clinical check at age 5 years and 4 years, respectively, both patients were recurrence-free and attained normal growth and development. We conclude that PBSCT from an HLA haploidentical mother with non-TBI and non-BU regimen seems feasible and efficacious, offering favorable life quality for infants.

  16. Mechanics of Graded Wrinkles

    NASA Astrophysics Data System (ADS)

    Raayai-Ardakani, Shabnam; Boyce, Mary

    2013-03-01

    Shark skin is known for its anti-fouling and self-cleaning properties. In attempts to mimic this pattern for getting similar properties, different surface patterns such as Sharklet and wrinkles have been previously introduced. Wrinkled patterns have gained importance in applications such as microfluidics, wetting and adhesion. Through buckling of a thin film of stiff material on a substrate of softer material, and maintaining symmetric geometries, ordered wrinkled patterns can be created. However, it can be shown that using the same principle, by changing the geometry of the surface, the dimensions of the wrinkles can be altered. This alteration turns ordered wrinkles into graded wrinkles which have more resemblance to shark skin than the ordered wrinkles, maintaining the same wave length while each wave having different amplitude. Here using finite element models, experiments and analytical solutions, the relations between different geometries and the resulting patterns were investigated.

  17. Prediction of Grade of Dropout from 3rd Grade Data.

    ERIC Educational Resources Information Center

    Lloyd, Dee Norman; Bleach, Gail

    Measures of background characteristics, school performance, and test achievement were analyzed for four race-by-sex samples of third graders who were known to have later become high school dropouts. In each sample, age in the third grade, course marks, and standardized achievement scores were found to be significantly related to the grade in which…

  18. Grade 10 to Grade 12 Mathematics Resources: Annotated Bibliography.

    ERIC Educational Resources Information Center

    Western Canadian Protocol for Collaboration in Basic Education, Edmonton (Alberta).

    This annotated bibliography identifies English language resources endorsed by all Western Canadian Protocol (WCP) jurisdictions implementing The Common Curriculum Framework for K-12 Mathematics Grade 10 to Grade 12. Resources in this annotated bibliography were selected through a collaborative review process based on their high level of fidelity…

  19. Anti-CD19 chimeric antigen receptor T-cell therapy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia

    PubMed Central

    Zhu, Yang-min; Wu, Zhao; Tan, You-ping; Du, Yuan-yuan; Liu, Zhi; Ou, Rui-ming; Liu, Shuang; Pu, Cheng-fei; Jiang, Jing; Wang, Jin-ping; Xiao, Lei; Zhang, Qing

    2016-01-01

    Abstract Rationale: The presence of the Philadelphia chromosome (Ph) in acute lymphoblastic leukemia (ALL) has been associated with a high risk of disease relapse and a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for adults with Ph-positive ALL, but relapse remains the primary cause of treatment failure, and is associated with an extremely poor prognosis. The emergence of resistance to tyrosine kinase inhibitors (TKIs) poses a challenge for patients with disease relapses after initial treatment with TKI-containing regimens. Patient concerns: Two patients with TKI-resistant recurrent Ph-positive ALL. Diagnoses: Ph-positive ALL. Interventions: Anti-CD19 CAR T-cell infusion. Outcomes: One patient's bone marrow blasts decreased significantly, and the other reached negative minimal residual disease (MRD). However, we first recorded the development of new-onset acute graft-versus-host disease (aGVHD) after anti-CD19 CAR T-cell infusion in a patient who received allogeneic HSCT. Our 2 case reports also demonstrate the efficacy of anti-CD19 CAR T-cell therapy in the treatment of TKI-resistant Ph-positive ALL. Lessons: Our report suggests that anti-CD19 CAR T-cell therapy may be a promising option for the treatment of relapsed Ph-positive ALL after conventional chemotherapy or allogeneic HSCT. However, caution is due given the possibility of the adverse effects of cytokine release syndrome (CRS)-induced aGVHD for patients receiving allogeneic HSCT. PMID:28002337

  20. The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplant for Patients with Acute Leukemia

    PubMed Central

    Holter-Chakrabarty, Jennifer L.; Pierson, Namali; Zhang, Mei-Jie; Zhu, Xiaochun; Akpek, Görgün; Aljurf, Mahmoud D.; Artz, Andrew S.; Baron, Frédéric; Bredeson, Christopher N.; Dvorak, Christopher C.; Epstein, Robert B.; Lazarus, Hillard M.; Olsson, Richard F.; Selby, George B.; Williams, Kirsten M.; Cooke, Kenneth R.; Pasquini, Marcelo C.; McCarthy, Philip L.

    2015-01-01

    Limited clinical data are available to assess whether the sequencing of cyclophosphamide (Cy) and total body irradiation (TBI) changes outcomes. We evaluated the sequence in 1769 (CyTBI N=948, TBICy N=821) recipients of related or unrelated hematopoietic cell transplantation (HCT) who received TBI (1200-1500cGY) for acute leukemia from 2003 to 2010. The two cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Ph+ ALL, HLA matched siblings, stem cell source, anti-thymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect TRM (24% vs. 23% at 3y, p=0.67; relative risk [RR] 1.01, p=0.91), leukemia relapse (27% vs. 29% at 3y, p=0.34; RR 0.89, p=0.18), leukemia-free survival (49% vs. 48% at3y, p=0.27; RR 0.93, p=0.29), chronic GVHD (45% vs. 47% at 1y, p=0.39; RR 0.9, p=0.11) or overall survival (53% vs. 52% at 3y, p=0.62; RR 0.96, p=0.57) for CyTBI and TBICy respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (p=0.08). This study demonstrates that the sequence of Cy and TBI does not impact transplant outcomes and complications in patients with acute leukemia undergoing HCT with myeloablative conditioning. PMID:25840335

  1. Umbilical Cord Blood Transplantation Outcomes in Acute Myelogenous Leukemia/Myelodysplastic Syndrome Patients Aged ≥70 Years.

    PubMed

    Sandhu, Karamjeet S; Brunstein, Claudio; DeFor, Todd; Bejanyan, Nelli; Arora, Mukta; Warlick, Erica; Weisdorf, Daniel; Ustun, Celalettin

    2016-02-01

    The maximum age of patients receiving allogeneic hematopoietic stem cell transplantation (alloHCT) has been moving up over time. However, the availability of a suitable HLA-matched sibling donor may limit access of this patient population to alloHCT. We retrospectively investigated the outcomes of umbilical cord blood transplantation (UCBT) after reduced-intensity conditioning regimens in patients aged ≥70 years with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) between 2010 and 2014. During this period 70 patients with AML/MDS were referred to our center for alloHCT consideration. Twenty-two patients (33%) received alloHCT: 10 UCBT, 9 HLA full-matched sibling donor transplantation, 2 haploidentical alloHCT, and 1 unrelated donor alloHCT. In UCBT, cumulative incidences of nonrelapse mortality and relapse were 20% and 30% at 2 years, respectively. The cumulative incidence of acute graft-versus-host disease (GVHD) at day +100 and chronic GVHD at 2 years was 10%. Seven patients had viral reactivation/infections. Rates of overall survival and disease-free survival were 60% and 50% at 2 years, respectively. Moreover, these outcomes seemed to be similar to that of patients aged 60 to 69 years receiving UCBT (n = 60) and patients aged ≥70 years receiving HLA full-matched sibling donor transplantation (n = 9). These results suggest that UCBT is feasible in selected AML/MDS patients aged ≥70 years. In fact, UCBT shortens the required time for an unrelated donor search and thus increases the chance of proceeding with alloHCT, which might contribute to higher rates of alloHCT in the referral group. Outcomes of UCBT are promising; however, larger studies with a longer follow-up are needed.

  2. Practicing Good Habits, Grade 4.

    ERIC Educational Resources Information Center

    Van Cong Lau; And Others

    This illustrated textbook was designed for teaching civics and values to fourth grade students in Vietnam. It is divided into six chapters: (1) At School (recapitulation of the grade three program, friendship, respect for the teacher, team work, discipline, honor); (2) In the Street: Traffic Regulations; (3) At Home (the extended family spirit,…

  3. Learning-Centered Grading Practices

    ERIC Educational Resources Information Center

    Campbell, Conni

    2012-01-01

    The research on grading practice over two decades is clear: grading practices are firmly held beliefs that are near and dear to the teaching professional. At a time when government, business and industry, and the general public are calling for an accountability of student knowledge and abilities, classroom assessment practices could be…

  4. Grading Exceptional and Struggling Learners

    ERIC Educational Resources Information Center

    Jung, Lee Ann; Guskey, Thomas R.

    2011-01-01

    How can you ensure that you are grading your exceptional students fairly? Teachers receive very little guidance for grading students with disabilities, English learners, and those receiving services through a response-to-intervention (RTI) process. This practitioner-friendly book provides teachers and administrators with an effective framework for…

  5. Science: Grade 3. Interim Guide.

    ERIC Educational Resources Information Center

    Manitoba Dept. of Education and Training, Winnipeg.

    This guide is one of a set of 10 science guides, each covering a separate grade in Manitoba, together covering kindergarten through grade 9. The guides have been designed to provide a framework for building scientific concepts and developing the learning of process skills. They replace an earlier set of guides dated 1979. Each guide is essentially…

  6. Teaching Literacy in Fourth Grade

    ERIC Educational Resources Information Center

    Johnson, Denise

    2008-01-01

    Fourth grade is an important year for literacy learning. Having left the primary grades behind, students must grapple with more demanding texts and content material. Effective, motivating instruction can help them succeed. This book helps teachers create an energized and organized learning environment in which all students can improve their…

  7. Health Curriculum Guide. Fifth Grade.

    ERIC Educational Resources Information Center

    Syosset Central School District 2, NY.

    GRADES OR AGES: Grade five. SUBJECT MATTER: Health education. ORGANIZATION AND PHYSICAL APPEARANCE: This guide is illustrated with drawings and bound in a spiral binder. It is divided into five "strands" or topics and a bibliography. The five strands are as follows: Physical Health; Sociological Health Problems; Mental Health; Environmental and…

  8. Science: Grade 7. Interim Guide.

    ERIC Educational Resources Information Center

    Manitoba Dept. of Education and Training, Winnipeg.

    This guide is one of a set of 10 science guides, each covering a separate grade in Manitoba, together covering kindergarten through grade 9. The guides have been designed to provide a framework for building scientific concepts and developing the learning of process skills. They replace an earlier set of guides dated 1979. Each guide is essentially…

  9. Science: Grade 8. Interim Guide.

    ERIC Educational Resources Information Center

    Manitoba Dept. of Education and Training, Winnipeg.

    This guide is one of a set of 10 science guides, each covering a separate grade in Manitoba, together covering kindergarten through grade 9. The guides have been designed to provide a framework for building scientific concepts and developing the learning of process skills. They replace an earlier set of guides dated 1979. Each guide is essentially…

  10. Science: Grade 5. Interim Guide.

    ERIC Educational Resources Information Center

    Manitoba Dept. of Education and Training, Winnipeg.

    This guide is one of a set of 10 science guides, each covering a separate grade in Manitoba, together covering kindergarten through grade 9. The guides have been designed to provide a framework for building scientific concepts and developing the learning of process skills. They replace an earlier set of guides dated 1979. Each guide is essentially…

  11. Science: Grade 6. Interim Guide.

    ERIC Educational Resources Information Center

    Manitoba Dept. of Education and Training, Winnipeg.

    This guide is one of a set of 10 science guides, each covering a separate grade in Manitoba, together covering kindergarten through grade 9. The guides have been designed to provide a framework for building scientific concepts and developing the learning of process skills. They replace an earlier set of guides dated 1979. Each guide is essentially…

  12. Science Grade 7, Long Form.

    ERIC Educational Resources Information Center

    New York City Board of Education, Brooklyn, NY. Bureau of Curriculum Development.

    The Grade 7 Science course of study was prepared in two parallel forms. A short form designed for students who had achieved a high measure of success in previous science courses; the long form for those who have not been able to maintain the pace. Both forms contain similar content. The Grade 7 guide is the first in a three-year sequence for…

  13. Science: Grade 9. Interim Guide.

    ERIC Educational Resources Information Center

    Manitoba Dept. of Education and Training, Winnipeg.

    This guide is one of a set of 10 science guides, each covering a separate grade in Manitoba, together covering kindergarten through grade 9. The guides have been designed to provide a framework for building scientific concepts and developing the learning of process skills. They replace an earlier set of guides dated 1979. Each guide is essentially…

  14. Graded geometry and Poisson reduction

    SciTech Connect

    Cattaneo, A. S.; Zambon, M.

    2009-02-02

    The main result extends the Marsden-Ratiu reduction theorem in Poisson geometry, and is proven by means of graded geometry. In this note we provide the background material about graded geometry necessary for the proof. Further, we provide an alternative algebraic proof for the main result.

  15. Starting the Conversation about Grading

    ERIC Educational Resources Information Center

    Brookhart, Susan M.

    2011-01-01

    As they attempt to make the transition to standards-based grading, many schools go off track or get swamped by side issues, writes Brookhart. They waste energy having hard discussions about grading practice details that, by themselves, cannot accomplish real reform. Instead, schools should focus discussion on major questions: What meaning do we…

  16. Group Grades Miss the Mark.

    ERIC Educational Resources Information Center

    Kagan, Spencer

    1995-01-01

    Some teachers justify group grading for cooperative projects using specious arguments that invoke real-world comparison, employment skills, motivation, teacher workload, and credit for teamwork. This article argues that group grades are blatantly unfair, invalidate report cards, undermine motivation, convey the wrong message, violate individual…

  17. Coastal Studies for Primary Grades.

    ERIC Educational Resources Information Center

    Butler, Venetia R.; Roach, Ellen M.

    1986-01-01

    Describes a set of field trips for participants of the Coastal Environmental Education for Primary Grades program in Georgia. Includes a sample of the activities used by first- and second-grade students. Discusses follow-up activities and the need for more educational programs dealing with sand dunes and saltwater marshes. (TW)

  18. Elementary Science Curriculum, Grade 2.

    ERIC Educational Resources Information Center

    Stoneham Public Schools, MA.

    This is one of a set of curriculum guides for the Stoneham Elementary School Science Program (see SE 012 153 - SE 012 158). Each guide contains a chart illustrating the scope and sequence of the physical, life, and earth sciences introduced at each grade level. For each of the topics introduced at this grade level, an overview of the topic, a list…

  19. Elementary Science Curriculum, Grade 4.

    ERIC Educational Resources Information Center

    Stoneham Public Schools, MA.

    This is one of a set of curriculum guides for the Stoneham Elementary School Science Program (see SE 012 153 - SE 012 158). Each guide contains a chart illustrating the scope and sequence of the physical, life, and earth sciences introduced at each grade level. For each of the topics introduced at this grade level an overview of the topic, a list…

  20. Elementary Science Curriculum, Grade 6.

    ERIC Educational Resources Information Center

    Stoneham Public Schools, MA.

    This is one of a set of curriculum guides for the Stoneham Elementary School Science Program (see SE 012 153 - SE 012 158). Each guide contains a chart illustrating the scope and sequence of the physical, life, and earth sciences introduced at each grade level. For each of the topics introduced at this grade level an overview of the topic, a list…

  1. Science: Grade 2. Interim Guide.

    ERIC Educational Resources Information Center

    Manitoba Dept. of Education and Training, Winnipeg.

    This guide is one of a set of 10 science guides, each covering a separate grade in Manitoba, together covering kindergarten through grade 9. The guides have been designed to provide a framework for building scientific concepts and developing the learning of process skills. They replace an earlier set of guides dated 1979. Each guide is essentially…

  2. Elementary Science Curriculum, Grade 5.

    ERIC Educational Resources Information Center

    Stoneham Public Schools, MA.

    This is one of a set of curriculum guides for the Stoneham Elementary School Science Program (see SE 012 153 - SE 012 158). Each guide contains a chart illustrating the scope and sequence of the physical, life, and earth sciences introduced at each grade level. For each of the topics introduced at this grade level an overview of the topic, a list…

  3. Grading System and Student Effort

    ERIC Educational Resources Information Center

    Paredes, Valentina

    2017-01-01

    Several papers have proposed that the grading system affects students' incentives to exert effort. In particular, the previous literature has compared student effort under relative and absolute grading systems, but the results are mixed and the implications of the models have not been empirically tested. In this paper, I build a model where…

  4. Elementary Science Curriculum, Grade 3.

    ERIC Educational Resources Information Center

    Stoneham Public Schools, MA.

    This is one of a set of curriculum guides for the Stoneham Elementary School Science Program (see SE 012 153 - SE 012 158). Each guide contains a chart illustrating the scope and sequence of the physical, life, and earth sciences introduced at each grade level. For each of the topics introduced at this grade level, an overview of the topic, a list…

  5. Grading Practices: The Third Rail

    ERIC Educational Resources Information Center

    Erickson, Jeffrey A.

    2010-01-01

    Although Social Security funds are in decline and no solution is evident, few politicians have the temerity to try to change the system. Why? Because Social Security is the third rail in politics: if one touches it, he or she will die. The field of education has an issue that is equally as lethal: grading. Grading is one of the most private…

  6. Alternatives to Grading Student Writing.

    ERIC Educational Resources Information Center

    Tchudi, Stephen, Ed.

    The result of an investigation into the grading writing by the National Council of Teachers of English Committee on Alternatives to Grading Student Writing, this collection of essays offers the writing teacher several innovative and interesting options. Following an introduction by the editor (chair of the Committee), in which he delineates the…

  7. First Grade Pre-Screening

    ERIC Educational Resources Information Center

    Center for Innovation in Assessment (NJ1), 2013

    2013-01-01

    The First Grade Pre-Screening is designed to be used at the start of the first grade school year so that teachers can obtain information about their incoming students. This information is intended to give teachers insight about what math and reading skills a student may or may not have at the beginning of the year. The information can aid teachers…

  8. Science: Grade 1. Interim Guide.

    ERIC Educational Resources Information Center

    Manitoba Dept. of Education and Training, Winnipeg.

    This guide is one of a set of 10 science guides, each covering a separate grade in Manitoba, together covering kindergarten through grade 9. The guides have been designed to provide a framework for building scientific concepts and developing the learning of process skills. They replace an earlier set of guides dated 1979. Each guide is essentially…

  9. Incidence and outcome of invasive fungal diseases after allogeneic stem cell transplantation: a prospective study of the Gruppo Italiano Trapianto Midollo Osseo (GITMO).

    PubMed

    Girmenia, Corrado; Raiola, Anna Maria; Piciocchi, Alfonso; Algarotti, Alessandra; Stanzani, Marta; Cudillo, Laura; Pecoraro, Clara; Guidi, Stefano; Iori, Anna Paola; Montante, Barbara; Chiusolo, Patrizia; Lanino, Edoardo; Carella, Angelo Michele; Zucchetti, Elisa; Bruno, Benedetto; Irrera, Giuseppe; Patriarca, Francesca; Baronciani, Donatella; Musso, Maurizio; Prete, Arcangelo; Risitano, Antonio Maria; Russo, Domenico; Mordini, Nicola; Pastore, Domenico; Vacca, Adriana; Onida, Francesco; Falcioni, Sadia; Pisapia, Giovanni; Milone, Giuseppe; Vallisa, Daniele; Olivieri, Attilio; Bonini, Alessandro; Castagnola, Elio; Sica, Simona; Majolino, Ignazio; Bosi, Alberto; Busca, Alessandro; Arcese, William; Bandini, Giuseppe; Bacigalupo, Andrea; Rambaldi, Alessandro; Locasciulli, Anna

    2014-06-01

    Epidemiologic investigation of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be useful to identify subpopulations who might benefit from targeted treatment strategies. The Gruppo Italiano Trapianto Midollo Osseo (GITMO) prospectively registered data on 1858 consecutive patients undergoing allo-HSCT between 2008 and 2010. Logistic regression analysis was performed to identify risk factors for proven/probable IFD (PP-IFD) during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT and to evaluate the impact of PP-IFDs on 1-year overall survival. The cumulative incidence of PP-IFDs was 5.1% at 40 days, 6.7% at 100 days, and 8.8% at 12 months post-transplantation. Multivariate analysis identified the following variables as associated with PP-IFDs: transplant from an unrelated volunteer donor or cord blood, active acute leukemia at the time of transplantation, and an IFD before transplantation in the early phase; transplant from an unrelated volunteer donor or cord blood and grade II-IV acute graft-versus-host disease (GVHD) in the late phase; and grade II-IV acute GVHD and extensive chronic GVHD in the very late phase. The risk for PP-IFD was significantly higher when acute GVHD was followed by chronic GVHD and when acute GVHD occurred in patients undergoing transplantation with grafts from other than matched related donors. The presence of PP-IFD was an independent factor in long-term survival (hazard ratio, 2.90; 95% confidence interval, 2.32 to 3.62; P < .0001). Our findings indicate that tailored prevention strategies may be useful in subpopulations at differing levels of risk for PP-IFDs.

  10. Acute laminitis.

    PubMed

    Baxter, G M

    1994-12-01

    Laminitis is an inflammation of the sensitive laminae along the dorsal aspect of the digit and is considered to be a secondary complication of several predisposing or primary factors. Affected horses are usually very lame, have increased digital pulses, are painful to hoof testers along the toe of the foot, and have evidence of downward rotation or distal displacement of the distal phalanx present on radiographs. Treatments for acute laminitis include anti-inflammatory drugs, anti-endotoxin therapy, vasodilators, antithrombotic therapy, corrective trimming and shoeing, and surgical procedures. Treatment regimens are very controversial and the true efficacy of these treatments is unknown. The quality of laminae damage that occurs with laminitis, however, probably has greater influence on the success of treatment and outcome of the horse than the treatment regimen itself.

  11. Treosulfan-Based Conditioning and Hematopoietic Cell Transplantation for Nonmalignant Diseases: A Prospective Multi-Center Trial

    PubMed Central

    Burroughs, Lauri M.; Nemecek, Eneida R.; Torgerson, Troy R.; Storer, Barry E.; Talano, Julie-An; Domm, Jennifer; Giller, Roger H.; Shimamura, Akiko; Delaney, Colleen; Skoda-Smith, Suzanne; Thakar, Monica S.; Baker, K. Scott; Rawlings, David J.; Englund, Janet A.; Flowers, Mary E. D.; Deeg, H. Joachim; Storb, Rainer; Woolfrey, Ann E.

    2015-01-01

    Hematopoietic cell transplantation (HCT) is effective in the treatment of patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM) particularly in patients with co-morbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n=4) or unrelated (n=27) grafts following conditioning with treosulfan (total dose: 42 g/m2), fludarabine (total dose: 150 mg/m2), ± thymoglobulin (6 mg/kg; n=22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II–IV and III–IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10% and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grade III-IV acute GVHD (0% versus 33%; P = 0.005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases, and support the need for future disease-specific clinical trials. PMID:25196857

  12. 7 CFR 51.304 - Combination grades.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., CERTIFICATION, AND STANDARDS) United States Standards for Grades of Apples Grades § 51.304 Combination grades...) Combinations other than these are not permitted in connection with the U.S. apple grades. When Combination grades are packed, at least 50 percent of the apples in any lot shall meet the requirements of the...

  13. 7 CFR 51.304 - Combination grades.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., CERTIFICATION, AND STANDARDS) United States Standards for Grades of Apples Grades § 51.304 Combination grades...) Combinations other than these are not permitted in connection with the U.S. apple grades. When Combination grades are packed, at least 50 percent of the apples in any lot shall meet the requirements of the...

  14. Grading a Large Organic Laboratory Course.

    ERIC Educational Resources Information Center

    Kandel, Marjorie

    1988-01-01

    Discusses the problems of grading an organic laboratory course. Proposes that the grade should be based as: products--30 percent of the grade; notebooks--30 percent of the grade; exams and final report--40 percent of the grade. Gives an exception policy for special considerations. (MVL)

  15. 7 CFR 52.772 - Grades.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... United States Standards for Grades of Canned Red Tart Pitted Cherries 1 Identity and Grades § 52.772 Grades. (a) “U.S. Grade A” (or “U.S. Fancy”) is the quality of canned red tart pitted cherries that have.... Canned red tart pitted cherries of this grade may contain not more than eight cherries per sample...

  16. [GRADE: Methodology for formulating and grading recommendations in clinical practice].

    PubMed

    Sanabria, Andrea Juliana; Rigau, David; Rotaeche, Rafael; Selva, Anna; Marzo-Castillejo, Mercè; Alonso-Coello, Pablo

    2015-01-01

    Clinical practice guidelines (CPG) provide recommendations on the benefits and harms of different healthcare interventions. Proper CPG development and implementation can potentially reduce variability in clinical practice while improving its quality and safety. The GRADE system is used to assess the quality of evidence and to grade the strength of recommendations in the context of the development of CPGs, systematic reviews or health technology assessments. The aim of this article is to describe the main characteristics of the GRADE system through relevant examples in the context of primary care.

  17. Antibiotics for acute otitis media in children.

    PubMed

    Nitsche, María Pía; Carreño, Monica

    2015-10-29

    Acute otitis media is one of the most common infectious diseases diagnosed in children. Antibiotic treatment use remains controversial. This summary aims to evaluate the effectiveness and safety of antibiotics in children with acute otitis media. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 18 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded antibiotics reduce pain at 48-72 hours and reduce the risk of tympanic perforations in children with acute otitis media, but they do not reduce late recurrences and increase the risk of side effects (rash, vomiting and diarrhea).

  18. Unmanipulated haploidentical bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update.

    PubMed

    Bacigalupo, A; Dominietto, A; Ghiso, A; Di Grazia, C; Lamparelli, T; Gualandi, F; Bregante, S; Van Lint, M T; Geroldi, S; Luchetti, S; Grasso, R; Pozzi, S; Colombo, N; Tedone, E; Varaldo, R; Raiola, A M

    2015-06-01

    This is a report of 148 patients with hematologic malignancies who received an unmanipulated haploidentical bone marrow transplant (BMT), followed by post-transplant high-dose cyclophosphamide (PT-CY). All patients received a myeloablative conditioning consisting of thiotepa, busulfan, fludarabine (n=92) or TBI, fludarabine (n=56). The median age was 47 years (17-74); 47 patients were in first remission (CR1), 37 in second remission (CR2) and 64 had an active disease; all patients were first grafts. The diagnosis was acute leukemia (n=75), myelodisplastic syndrome (n=24), myelofibrosis (n=16), high-grade lymphoma (n=15) and others (n=18). GVHD prophylaxis consisted in PT-CY on days +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median day for neutrophil engraftment was day +18 (13-32). The cumulative incidence of grades II-IV acute GVHD was 24%, and of grades III-IV GVHD 10%. The incidence of moderate-severe chronic GVHD was 12%. With a median follow-up for the surviving patients of 313 days (100-1162), the cumulative incidence of transplant-related mortality (TRM) is 13%, and the relapse-related death is 23%. The actuarial 22 months overall survival is 77% for CR1 patients, 49% for CR2 patients and 38% for patients grafted in relapse (P<0.001). Major causes of death were relapse (22%), GVHD (2%) and infections (6%). We confirm our initial results, suggesting that a myeloablative conditioning regimen followed by unmanipulated haploidentical BMT with PT-CY, results in a low risk of acute and chronic GVHD and encouraging rates of TRM and overall survival, also for patients with active disease at the time of transplant.

  19. Acute dengue in a neonate secondary to perinatal transmission.

    PubMed

    Chin, P S; Khoo, A P C; Asmah Hani, A W; Chem, Y K; Norizah, I; Chua, K B

    2008-08-01

    We report a newborn baby girl with acute dengue due to vertical transmission. A 31 year old factory worker of 38+ week gestation, gravida 5 para 3+1, developed acute dengue fever two days prior to delivery. She delivered a normal term baby girl by spontaneous vaginal delivery and recovered uneventfully without peripartum haemorrhage despite the presence of thrombocytopenia. The baby girl developed low grade fever on day four of post-natal life and except for the transient thrombocytopenia, also recovered uneventfully following three days of mild illness. The clinical diagnosis of acute dengue virus infection was confirmed by laboratory tests.

  20. 7 CFR 810.1604 - Grades and grade requirements for soybeans.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 7 2013-01-01 2013-01-01 false Grades and grade requirements for soybeans. 810.1604... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Soybeans Principles Governing the Application of Standards § 810.1604 Grades and grade requirements for soybeans. Grading factors Grades...

  1. 7 CFR 810.1604 - Grades and grade requirements for soybeans.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 7 2014-01-01 2014-01-01 false Grades and grade requirements for soybeans. 810.1604... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Soybeans Principles Governing the Application of Standards § 810.1604 Grades and grade requirements for soybeans. Grading factors Grades...

  2. 7 CFR 810.1604 - Grades and grade requirements for soybeans.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 7 2012-01-01 2012-01-01 false Grades and grade requirements for soybeans. 810.1604... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Soybeans Principles Governing the Application of Standards § 810.1604 Grades and grade requirements for soybeans. Grading factors Grades...

  3. 7 CFR 810.1604 - Grades and grade requirements for soybeans.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 7 2010-01-01 2010-01-01 false Grades and grade requirements for soybeans. 810.1604... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Soybeans Principles Governing the Application of Standards § 810.1604 Grades and grade requirements for soybeans. Grading factors Grades...

  4. 7 CFR 810.1604 - Grades and grade requirements for soybeans.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 7 2011-01-01 2011-01-01 false Grades and grade requirements for soybeans. 810.1604... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Soybeans Principles Governing the Application of Standards § 810.1604 Grades and grade requirements for soybeans. Grading factors Grades...

  5. Grade 6 Science Curriculum Specifications.

    ERIC Educational Resources Information Center

    Alberta Dept. of Education, Edmonton. Curriculum Branch.

    This material describes curriculum specifications for grade 6 science in Alberta. Emphases recommended are: (1) process skills (50%); (2) psychomotor skills (10%); (3) attitudes (10%); and (4) subject matter (30%). Priorities within each category are identified. (YP)

  6. Salivary proteomic analysis and acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Chiusolo, Patrizia; Giammarco, Sabrina; Fanali, Chiara; Bellesi, Silvia; Metafuni, Elisabetta; Sica, Simona; Iavarone, Federica; Cabras, Tiziana; Messana, Irene; Leone, Giuseppe; Castagnola, Massimo

    2013-06-01

    Graft-versus-host disease (GVHD) is the major life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), developing in 35%-70% of all allo-HSCT recipients despite immunosuppressive prophylaxis. The recent application of proteomic tools that allow screening for differentially expressed or excreted proteins in body fluids could possibly identify specific biomarkers for GVHD. Whole saliva is highly attractive for noninvasive specimen collection. In the present study, we collected saliva specimens from 40 consecutives patients who underwent allo-HSCT between December 2008 and March 2011 at our institution. The specimens were analyzed by HPLC coupled to electrospray-ionization mass spectrometry. Variable expression of S100 protein family members (S100A8, S100A9, and S100A7) was detected. Fourteen of 23 patients with GVHD demonstrated the presence of S100A8, compared with only 2 patients without GVHD and 0 patients in the control group (P = .001). S100A7 was detectable in 11 of the 23 patients with GVHD but was absent in the other 2 groups (P = .0001). S100A9-short was detected in 20 patients with GVHD, in 9 patients without GVHD, and in 8 healthy volunteers (P = .01) Further studies are needed to clarify the role of these proteins as a marker of GVHD or as an index of mucosal inflammation.

  7. A patient with seminal vesiculitis prior to acute chlamydial epididymitis.

    PubMed

    Furuya, Ryoji; Takahashi, Satoshi; Furuya, Seiji; Takeyama, Koh; Tsukamoto, Taiji

    2005-10-01

    This is the first report of a case of seminal vesiculitis prior to acute chlamydial epididymitis. At the first visit to the clinic, the patient wished to check whether he had Chlamydia trachomatis in his genital tract, because his wife had been diagnosed as having chlamydial cervicitis. He had no specific symptoms at that time; however, transrectal ultrasonograpy (TRUS) revealed swelling of seminal vesicles, which suggested the presence of seminal vesiculitis. Two days after the first visit, he had high-grade fever and was diagnosed as having acute epididymitis caused by C. trachomatis. We had previously reported that seminal vesiculitis was always complicated with acute epididymitis, so this case could provide important evidence that seminal vesiculitis might precede acute epididymitis. It suggested that acute epididymitis could be affected by seminal vesiculitis via the retrograde transmission route.

  8. Anaphylaxis: acute treatment and management.

    PubMed

    Ring, Johannes; Grosber, Martine; Möhrenschlager, Matthias; Brockow, Knut

    2010-01-01

    Anaphylaxis is the maximal variant of an acute life-threatening immediate-type allergy. Due to its often dramatic onset and clinical course, practical knowledge in the management of these reactions is mandatory both for physicians and patients. It has to be distinguished between acute treatment modalities and general recommendations for management of patients who have suffered from an anaphylactic reaction. Acute treatment comprises general procedures like positioning, applying an intravenous catheter, call for help, comfort of the patient as well as the application of medication. The acute treatment modalities are selected depending upon the intensity of the clinical symptomatology as they are categorized in 'severity grades'. First of all it is important to diagnose anaphylaxis early and consider several differential diagnoses. This diagnosis is purely clinical and laboratory tests are of no help in the acute situation. Epinephrine is the essential antianaphylactic drug in the pharmacologic treatment. It should be first applied intramuscularly, only in very severe cases or under conditions of surgical interventions intravenous application can be tried. Furthermore, glucocorticosteroids are given in order to prevent protracted or biphasic courses of anaphylaxis; they are of little help in the acute treatment. Epinephrine autoinjectors can be used by the patient him/herself. Histamine H(1)-antagonists are valuable in mild anaphylactic reactions; they should be given intravenously if possible. The replacement of volume is crucial in antianaphylactic treatment. Crystalloids can be used in the beginning, in severe shock colloid volume substitutes have to be applied. Patients suffering from an anaphylactic episode should be observed over a period of 4-10 h according to the severity of the symptomatology. It is crucial to be aware or recognize risk patients as for example patients with severe uncontrolled asthma, or under beta-adrenergic blockade. When bronchial

  9. Antileukemic and long-term effects of two regimens with or without TBI in allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia.

    PubMed

    Dai, Q Y; Souillet, G; Bertrand, Y; Galambrun, C; Bleyzac, N; Manel, A M; Bruno, B; Souillet, A L; Homole, E; Pages, M P; Berlier, P; David, M; Berthier, J C; Massenavette, B; Contamin, B; Philippe, N

    2004-10-01

    Between September 1986 and June 1997, 24 children with high-risk ALL in CR1 were allografted after TAM (fractionated TBI, high-dose Ara-C, and melphalan; n = 10) or BAM protocol (busulfan, high-dose Ara-C, and melphalan; n = 14). The EFS for transplants from sibling donors was 33% with TAM and 62% with BAM (P = 0.148). The probability of acute GvHD was 70% with TAM and 15% with BAM (P = 0.003). Four of 17 evaluable patients relapsed: one after TAM and three after BAM. In all, 46 other children transplanted in CR beyond CR1 were studied for sequelae. Long-term side effects were more frequent in TAM vs BAM. In children with ALL, busulfan may be a good alternative to TBI to improve the quality of life.

  10. Less graft-versus-host disease after rabbit antithymocyte globulin conditioning in unrelated bone marrow transplantation for leukemia and myelodysplasia: comparison with matched related bone marrow transplantation.

    PubMed

    Atta, Elias Hallack; de Oliveira, Danielli Cristina Muniz; Bouzas, Luis Fernando; Nucci, Márcio; Abdelhay, Eliana

    2014-01-01

    One of the major drawbacks for unrelated donor (UD) bone marrow transplantation (BMT) is graft-versus-host disease (GVHD). Despite results from randomized trials, antithymocyte globulin (ATG) is not routinely included for GVHD prophylaxis in UD BMT by many centers. One of ways to demonstrate the usefulness of rabbit ATG in UD BMT is to evaluate how its results approximate to those observed in matched related (MRD) BMT. Therefore, we compared the outcomes between UD BMT with rabbit ATG (Thymoglobulin) for GVHD prophylaxis (n = 25) and MRD BMT (n = 91) for leukemia and myelodysplasia. All but one patient received a myeloablative conditioning regimen. Grades II-IV acute GVHD were similar (39.5% vs. 36%, p = 0.83); however, MRD BMT recipients developed more moderate-severe chronic GVHD (36.5% vs. 8.6%, p = 0.01) and GVHD-related deaths (32.5% vs. 5.6%, p = 0.04). UD BMT independently protected against chronic GVHD (hazard ratio 0.23, p = 0.04). The 6-month transplant-related mortality, 1-year relapse incidence, and 5-year survival rates were similar between patients with non-advanced disease in the MRD and UD BMT groups, 13.8% vs. 16.6% (p = 0.50), 20.8% vs. 16.6% (p = 0.37), and 57% vs. 50% (p = 0.67), respectively. Stable full donor chimerism was equally achieved (71.3% vs. 71.4%, p = 1). Incorporation of rabbit ATG in UD BMT promotes less GVHD, without jeopardizing chimerism evolution, and may attain similar survival outcomes as MRD BMT for leukemia and myelodysplasia especially in patients without advanced disease.

  11. Pentoxifylline Treatment in Acute Pancreatitis (AP)

    ClinicalTrials.gov

    2016-09-14

    Acute Pancreatitis (AP); Gallstone Pancreatitis; Alcoholic Pancreatitis; Post-ERCP/Post-procedural Pancreatitis; Trauma Acute Pancreatitis; Hypertriglyceridemia Acute Pancreatitis; Idiopathic (Unknown) Acute Pancreatitis; Medication Induced Acute Pancreatitis; Cancer Acute Pancreatitis; Miscellaneous (i.e. Acute on Chronic Pancreatitis)

  12. 10 CFR 830.7 - Graded approach.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Graded approach. 830.7 Section 830.7 Energy DEPARTMENT OF ENERGY NUCLEAR SAFETY MANAGEMENT § 830.7 Graded approach. Where appropriate, a contractor must use a graded approach to implement the requirements of this part, document the basis of the graded...

  13. School Organization: Grade Span. Trends and Issues.

    ERIC Educational Resources Information Center

    Renchler, Ron

    This paper examines grade spans (grade configurations) and their importance in community school systems. Research has shown that geographic location often dictates the kind of grade configuration districts use. Furthermore, every grade configuration has strengths and weaknesses, and school officials must focus on developing the positive potential…

  14. Does Competition among Schools Encourage Grade Inflation?

    ERIC Educational Resources Information Center

    Walsh, Patrick

    2010-01-01

    This paper considers whether high schools in competitive environments use grade inflation to attract and retain families, perhaps in addition to more constructive responses. Two measures of grade inflation are used: the cutoffs used by each school to assign a letter grade to a percent score and high school grade point average after controlling for…

  15. 10 CFR 830.7 - Graded approach.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 4 2014-01-01 2014-01-01 false Graded approach. 830.7 Section 830.7 Energy DEPARTMENT OF ENERGY NUCLEAR SAFETY MANAGEMENT § 830.7 Graded approach. Where appropriate, a contractor must use a graded approach to implement the requirements of this part, document the basis of the graded...

  16. 10 CFR 830.7 - Graded approach.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 4 2013-01-01 2013-01-01 false Graded approach. 830.7 Section 830.7 Energy DEPARTMENT OF ENERGY NUCLEAR SAFETY MANAGEMENT § 830.7 Graded approach. Where appropriate, a contractor must use a graded approach to implement the requirements of this part, document the basis of the graded...

  17. 10 CFR 830.7 - Graded approach.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Graded approach. 830.7 Section 830.7 Energy DEPARTMENT OF ENERGY NUCLEAR SAFETY MANAGEMENT § 830.7 Graded approach. Where appropriate, a contractor must use a graded approach to implement the requirements of this part, document the basis of the graded...

  18. 10 CFR 830.7 - Graded approach.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 4 2012-01-01 2012-01-01 false Graded approach. 830.7 Section 830.7 Energy DEPARTMENT OF ENERGY NUCLEAR SAFETY MANAGEMENT § 830.7 Graded approach. Where appropriate, a contractor must use a graded approach to implement the requirements of this part, document the basis of the graded...

  19. Grading: Why You Should Trust Your Judgment

    ERIC Educational Resources Information Center

    Guskey, Thomas R.; Jung, Lee Ann

    2016-01-01

    Many educators consider grades calculated from statistical algorithms more accurate, objective, and reliable than grades they calculate themselves. But in this research, the authors first asked teachers to use their professional judgment to choose a summary grade for hypothetical students. When the researchers compared the teachers' grade with the…

  20. 7 CFR 52.772 - Grades.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Cherries 1 Identity and Grades § 52.772 Grades. (a) “U.S. Grade A” (or “U.S. Fancy”) is the quality of canned red tart pitted cherries that have at least the following attributes: (1) At least a reasonably... system outlined in this subpart. Canned red tart pitted cherries of this grade may contain not more...

  1. Strategies for Computerized Adaptive Grading Testing.

    ERIC Educational Resources Information Center

    Xiao, Beiling

    1999-01-01

    Evaluated three strategies for assigning examinees to grading categories in computerized adaptive testing. The expected a posteriori-based method had more correct classifications in the middle range of grade levels and more errors for the extremes than the golden section search grading test and the Z-score grading test. (SLD)

  2. Haploidentical transplantation with post-infusion cyclophosphamide in advanced Hodgkin lymphoma.

    PubMed

    Castagna, L; Bramanti, S; Devillier, R; Sarina, B; Crocchiolo, R; Furst, S; El-Cheikh, J; Granata, A; Faucher, C; Harbi, S; Morabito, L; Mariotti, J; Puvinathan, S; Weiller, P J; Chabannon, C; Mokart, D; Carlo-Stella, C; Bouabdallah, R; Santoro, A; Blaise, D

    2017-01-16

    We investigated the use of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of advanced Hodgkin lymphoma (HL). Sixty-two consecutive HL patients underwent haplo-HSCT. Unmanipulated stem cells and post-transplant cyclophosphamide were given to all patients as GVHD prophylaxis. At 100 days, the cumulative incidence of grades 2-3 and grades 3-4 acute GVHD was 23% and 4%, respectively. The chronic GVHD (cGVHD) cumulative incidence was 16%, with one patient experiencing severe cGVHD. The 3-year OS, PFS, relapse rates and 1-year non-relapse mortality (NRM) were 63%, 59%, 21% and 20%, respectively. Uncontrolled disease status and high hematopoietic cell transplantation comorbidity index (HCT-CI) were associated with lower OS, whereas PBSC was an independent protective factor. Uncontrolled disease and HCT-CI >2 was predictive for NRM. Finally, disease status other than CR was predictive of relapse. In conclusion, haplo-HSCT is a valid treatment in advanced HL, offering excellent rates of survival and acceptable toxicities.Bone Marrow Transplantation advance online publication, 16 January 2017; doi:10.1038/bmt.2016.348.

  3. Acute bacterial parotitis following acute stroke.

    PubMed

    Lee, V K; Kimbrough, D J; Jarquin-Valdivia, A A

    2009-06-01

    Acute bacterial parotitis (ABP) is a relatively uncommon condition that tends to occur in debilitated older patients. We report a case of an older woman that presented with an acute intracerebral hemorrhage who developed ABP. This morbidity led to endotracheal intubation, mechanical ventilation, tracheostomy and gastrostomy, all of which were not initially needed. We discuss the proposed physiopathology and etiopathogenesis of ABP in adults.

  4. Acute Lymphocytic Leukemia

    MedlinePlus

    ... hard for blood to do its work. In acute lymphocytic leukemia (ALL), also called acute lymphoblastic leukemia, there are too ... of white blood cells called lymphocytes or lymphoblasts. ALL is the most common type of cancer in ...

  5. Acute arterial occlusion - kidney

    MedlinePlus

    Acute renal arterial thrombosis; Renal artery embolism; Acute renal artery occlusion; Embolism - renal artery ... kidneys need a good blood supply. The main artery to the kidney is called the renal artery. ...

  6. Acute kidney failure

    MedlinePlus

    Kidney failure; Renal failure; Renal failure - acute; ARF; Kidney injury - acute ... There are many possible causes of kidney damage. They include: ... cholesterol (cholesterol emboli) Decreased blood flow due to very ...

  7. Acute phosphate nephropathy.

    PubMed

    Monfared, Ali; Habibzadeh, Seyed Mahmoud; Mesbah, Seyed Alireza

    2014-05-01

    We present acute phosphate nephropathy in a 28-year-old man, which was developed after a car accident due to rhabdomyolysis. Treatment of acute kidney injury was done with administration of sodium bicarbonate.

  8. Acute Pancreatitis and Pregnancy

    MedlinePlus

    ... and Pregnancy Acute Pancreatitis and Pregnancy Timothy Gardner, MD Acute pancreatitis is defined as the sudden inflammation ... the incidence of recurrent attacks minimized. Timothy Gardner, MD is Director of Pancreatic Disorders at Dartmouth-Hitchcock ...

  9. Birth order and transplantation outcome in HLA-identical sibling stem cell transplantation: an analysis on behalf of the Center for International Blood and Marrow Transplantation.

    PubMed

    Dobbelstein, Christiane; Ahn, Kwang Woo; Haagenson, Michael; Hale, Gregory A; van Rood, Jon J; Miklos, David; Waller, Edmund K; Spellman, Stephen R; Fernandez-Vina, Marcelo; Ganser, Arnold; Aljurf, Mahmoud; Bornhaeuser, Martin; Gupta, Vikas; Marino, Susan R; Pollack, Marilyn S; Reddy, Vijay; Eder, Matthias; Lee, Stephanie J

    2013-05-01

    Allogeneic stem cell transplantation (SCT) is the most effective treatment option for many hematologic malignancies, but graft-versus-host disease (GVHD) remains a major cause of treatment failure. Along with well-established risk factors for transplantation outcomes, recent single-center studies have identified a birth order effect in HLA-identical sibling SCT, with lower rates of acute and chronic GVHD and improved overall survival when the donor is younger than the recipient. One hypothesized mechanism for this effect is microchimerism due to fetomaternal and transmaternal sibling cell trafficking during pregnancy as the donor is exposed to recipient antigens in utero. The aim of the present study was to validate previously reported single-center data in a large, multicenter cohort provided by the Center for International Blood and Marrow Transplantation. All adult and pediatric patients (n = 11,365) with a hematologic malignancy who underwent allogeneic SCT with a graft from an HLA-identical sibling donor between 1990 and 2007 were included. When donors were younger than recipients, there was a significantly lower rate of acute GVHD grade II-IV and chronic GVHD in children, as well as a lower rate of chronic GVHD in adolescents. However, the hypothesized overall positive effect of lower relapse and better survival when donors are younger than recipients was not observed. Our data suggest that if otherwise equally matched, a graft from a younger sibling may be superior to a graft from an older sibling for children and adolescents undergoing SCT.

  10. A phase II study of sirolimus, tacrolimus, and rabbit anti-thymocyte globulin as graft-versus-host prophylaxis after unrelated-donor peripheral blood stem cell transplant

    PubMed Central

    Khaled, Samer K.; Palmer, Joycelynne; StillerMS, Tracey; Senitzer, David; Maegawa, Rodrigo; Rodriguez, Roberto; Parker, Pablo M.; Nademanee, Auayporn; Cai, Ji-Lian; Snyder, David S.; Karanes, Chatchada; Osorio, Edna; Thomas, Sandra H.; Forman, Stephen J.; Nakamura, Ryotaro

    2012-01-01

    We report on a prospective phase II trial of 32 patients who underwent unrelated donor hematopoietic cell transplantation, with a tacrolimus, sirolimus and rabbit anti-thymoctye globulin GVHD prophylactic regimen. The primary study endpoint was incidence of grades II-IV acute GVHD, with 80% power to detect a 30% decrease compared to institutional historical controls. Median age at transplant was 60 (19-71). Twenty-three patients (72%) received reduced-intensity conditioning, while the remainder received full-intensity regimens. Median follow up for surviving patients was 35 months (range: 21 - 49). The cumulative incidence of acute GVHD was 37.3% and the 2-year cumulative incidence of cGVHD was 63%. We observed TMA in seven patients (21.8%), one of whom also developed sinusoidal obstructive syndrome (SOS). Four patients of 32 (12.5%) failed to engraft, and three of these four died. As a result, enrollment to this trial was closed before the targeted accrual of 60 patients. Two-year overall survival was 65.5% and event-free survival was 61.3%. Two-year cumulative incidence of relapse was 12.5% and non-relapse mortality (NRM) was 15.6%. NRM and aGVHD rates were lower than historical rates; however, the unexpectedly high incidence of graft failure requires caution in the design of future studies with this regimen. PMID:23000644

  11. Health Education Curriculum Guide. Grade 9 Through Grade 12.

    ERIC Educational Resources Information Center

    Dependents Schools (DOD), Washington, DC.

    This guide has been prepared to assist teachers of grades nine through twelve students in the implementation of health education into the curriculum. The book contains student objectives, suggested activities, and pertinent questions which will provide the basic tools to meet program goals. The ten major areas of instruction are: 1) consumer…

  12. Health Education Curriculum Guide. Grade 5 Through Grade 8.

    ERIC Educational Resources Information Center

    Dependents Schools (DOD), Washington, DC.

    This guide has been prepared to assist the teacher of grades five through eight students in the implementation of health education into the curriculum. The booklet contains student objectives, suggested activities, and pertinent questions which will provide the basic tools to meet program goals. The ten major areas of instruction are: 1) consumer…

  13. Family LIfe Education Curriculum: Grade 7 through Grade 9 Level.

    ERIC Educational Resources Information Center

    Cumberland County Schools, Fayetteville, NC.

    This document presents a curriculum unit in family life education for students in grades 7 through 9 that encompasses learning about human sexuality, interpersonal relationships, and roles within the family. The unit is designed to attain the following goals: (1) to help students gain a detailed knowledge of the anatomy, physiology, and uniqueness…

  14. 7 CFR 810.404 - Grades and grade requirements for corn.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 7 2014-01-01 2014-01-01 false Grades and grade requirements for corn. 810.404... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Corn Principles Governing the Application of Standards § 810.404 Grades and grade requirements for corn. Grade Minimum test weight...

  15. 7 CFR 810.404 - Grades and grade requirements for corn.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 7 2010-01-01 2010-01-01 false Grades and grade requirements for corn. 810.404... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Corn Principles Governing the Application of Standards § 810.404 Grades and grade requirements for corn. Grade Minimum test weight...

  16. 7 CFR 810.404 - Grades and grade requirements for corn.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 7 2013-01-01 2013-01-01 false Grades and grade requirements for corn. 810.404... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Corn Principles Governing the Application of Standards § 810.404 Grades and grade requirements for corn. Grade Minimum test weight...

  17. 7 CFR 810.404 - Grades and grade requirements for corn.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 7 2012-01-01 2012-01-01 false Grades and grade requirements for corn. 810.404... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Corn Principles Governing the Application of Standards § 810.404 Grades and grade requirements for corn. Grade Minimum test weight...

  18. 7 CFR 810.404 - Grades and grade requirements for corn.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 7 2011-01-01 2011-01-01 false Grades and grade requirements for corn. 810.404... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Corn Principles Governing the Application of Standards § 810.404 Grades and grade requirements for corn. Grade Minimum test weight...

  19. Ohio Proficiency Tests for Grade 12. Fact Sheets. Twelfth-Grade Mathematics.

    ERIC Educational Resources Information Center

    Ohio State Dept. of Education, Columbus.

    Beginning in February 1994, twelfth-grade students who have passed the Ohio Ninth-grade Proficiency Tests in all areas will take the Twelfth-grade Proficiency Tests in writing, reading, mathematics, and citizenship. This fact sheet describes the Twelfth-grade Proficiency Test in mathematics, which is designed to measure a twelfth-grade level of…

  20. 7 CFR 810.206 - Grades and grade requirements for barley.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 7 2012-01-01 2012-01-01 false Grades and grade requirements for barley. 810.206... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Barley Principles Governing the Application of Standards § 810.206 Grades and grade requirements for barley. Grade Minimum limits of—...

  1. 7 CFR 810.206 - Grades and grade requirements for barley.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 7 2013-01-01 2013-01-01 false Grades and grade requirements for barley. 810.206... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Barley Principles Governing the Application of Standards § 810.206 Grades and grade requirements for barley. Grade Minimum limits of—...

  2. 7 CFR 810.206 - Grades and grade requirements for barley.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 7 2010-01-01 2010-01-01 false Grades and grade requirements for barley. 810.206... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Barley Principles Governing the Application of Standards § 810.206 Grades and grade requirements for barley. Grade Minimum limits of—...

  3. 7 CFR 810.206 - Grades and grade requirements for barley.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 7 2014-01-01 2014-01-01 false Grades and grade requirements for barley. 810.206... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Barley Principles Governing the Application of Standards § 810.206 Grades and grade requirements for barley. Grade Minimum limits of—...

  4. 7 CFR 810.206 - Grades and grade requirements for barley.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 7 2011-01-01 2011-01-01 false Grades and grade requirements for barley. 810.206... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Barley Principles Governing the Application of Standards § 810.206 Grades and grade requirements for barley. Grade Minimum limits of—...

  5. Instructional and Grading Practices That Change Grading Fidelity: An Action Research Study

    ERIC Educational Resources Information Center

    Smith, Michael A.

    2014-01-01

    Historically, final course grades of sixth- through eighth-grade language arts, mathematics, and eighth grade science students at the primary research site, Site A (pseudonym), suggest a high degree of grade inflation or disassociation when grade point averages (GPA) were compared to actual student performance levels as measured by annual state…

  6. 7 CFR 810.1004 - Grades and grade requirements for oats.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 7 2012-01-01 2012-01-01 false Grades and grade requirements for oats. 810.1004... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Oats Principles Governing the Application of Standards § 810.1004 Grades and grade requirements for oats. Grade Minimum limits— Test...

  7. 7 CFR 810.1004 - Grades and grade requirements for oats.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 7 2013-01-01 2013-01-01 false Grades and grade requirements for oats. 810.1004... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Oats Principles Governing the Application of Standards § 810.1004 Grades and grade requirements for oats. Grade Minimum limits— Test...

  8. Anomalies and graded coisotropic branes

    NASA Astrophysics Data System (ADS)

    Li, Yi

    2006-03-01

    We compute the anomaly of the axial U(1) current in the A-model on a Calabi-Yau manifold, in the presence of coisotropic branes discovered by Kapustin and Orlov. Our results relate the anomaly-free condition to a recently proposed definition of graded coisotropic branes in Calabi-Yau manifolds. More specifically, we find that a coisotropic brane is anomaly-free if and only if it is gradable. We also comment on a different grading for coisotropic submanifolds introduced recently by Oh.

  9. Acute Appendicitis in Patients with Acute Leukemia

    PubMed Central

    Kim, Ki Up; Kim, Jin Kyeung; Won, Jong Ho; Hong, Dae Sik; Park, Hee Sook; Park, Kyeung Kyu

    1993-01-01

    The decision to operate for abdominal pain in patients with leukopenia can be exceedingly difficult. Surgical exploration may be the only effective way to differentiate acute appendicitis from other causes, but it involves considerable risk of infectious complications due to immunesuppression. Leukemic patients, who presented significant RLQ pain, had been indicated for operation, despite having advanced disease or having had received chemotherapy or steroids. Four adult leukemia patients, complicated by acute appendictis, were reviewed. Two patients were in induction chemotherapy, one receiving salvage chemotheapy due to relapse and the other was in conservative treatment. Two patients were acute myelocytic leukemia (AML), one had acute lymphocytic leukemia (ALL), and the other had aleukemic leukemia. All patients underwent appendectomy and recovered without complication. Our experience supports the theory that the surgical management of appendicitis in acute leukemia is the most effective way, in spite of leukopenia. PMID:8268146

  10. Sepsis and Acute Kidney Injury.

    PubMed

    Bilgili, Beliz; Haliloğlu, Murat; Cinel, İsmail

    2014-12-01

    Acute kindney injury (AKI) is a clinical syndrome which is generally defined as an abrupt decline in glomerular filtration rate, causing accumulation of nitrogenous products and rapid development of fluid, electrolyte and acid base disorders. In intensive care unit sepsis and septic shock are leading causes of AKI. Sepsis-induced AKI literally acts as a biologic indicator of clinical deterioration. AKI triggers variety of immune, inflammatory, metabolic and humoral patways; ultimately leading distant organ dysfunction and increases morbidity and mortality. Serial mesurements of creatinine and urine volume do not make it possible to diagnose AKI at early stages. Serum creatinine influenced by age, weight, hydration status and become apparent only when the kidneys have lost 50% of their function. For that reason we need new markers, and many biomarkers in the diagnosis of early AKI activity is assessed. Historically "Risk-Injury-Failure-Loss-Endstage" (RIFLE), "Acute Kidney Injury Netwok" (AKIN) and "The Kidney Disease/ Improving Global Outcomes" (KDIGO) classification systems are used for diagnosing easily in clinical practice and research and grading disease. Classifications including diagnostic criteria are formed for the identification of AKI. Neutrophil gelatinase associated lipocalin (NGAL), cystatin-C (Cys-C), kidney injury molecule-1 (KIM-1) and also "cell cycle arrest" molecules has been concerned for clinical use. In this review the pathophysiology of AKI, with the relationship of sepsis and the importance of early diagnosis of AKI is evaluated.

  11. Sepsis and Acute Kidney Injury

    PubMed Central

    Bilgili, Beliz; Haliloğlu, Murat; Cinel, İsmail

    2014-01-01

    Acute kindney injury (AKI) is a clinical syndrome which is generally defined as an abrupt decline in glomerular filtration rate, causing accumulation of nitrogenous products and rapid development of fluid, electrolyte and acid base disorders. In intensive care unit sepsis and septic shock are leading causes of AKI. Sepsis-induced AKI literally acts as a biologic indicator of clinical deterioration. AKI triggers variety of immune, inflammatory, metabolic and humoral patways; ultimately leading distant organ dysfunction and increases morbidity and mortality. Serial mesurements of creatinine and urine volume do not make it possible to diagnose AKI at early stages. Serum creatinine influenced by age, weight, hydration status and become apparent only when the kidneys have lost 50% of their function. For that reason we need new markers, and many biomarkers in the diagnosis of early AKI activity is assessed. Historically “Risk-Injury-Failure-Loss-Endstage” (RIFLE), “Acute Kidney Injury Netwok” (AKIN) and “The Kidney Disease/ Improving Global Outcomes” (KDIGO) classification systems are used for diagnosing easily in clinical practice and research and grading disease. Classifications including diagnostic criteria are formed for the identification of AKI. Neutrophil gelatinase associated lipocalin (NGAL), cystatin-C (Cys-C), kidney injury molecule-1 (KIM-1) and also “cell cycle arrest” molecules has been concerned for clinical use. In this review the pathophysiology of AKI, with the relationship of sepsis and the importance of early diagnosis of AKI is evaluated. PMID:27366441

  12. Modeling First Grade Reading Development

    ERIC Educational Resources Information Center

    Mesmer, Heidi Anne E.; Williams, Thomas O.

    2014-01-01

    This study tested a hypothesized model examining reading proficiency across first grade. It addressed how alphabetics at the beginning of the year were mediated by applied and automated skills at the middle of the year to explain actualized reading at the end of the year. The alphabetic skills of 102 first graders were measured in October and the…

  13. The Hoosier Connection: Grade 8.

    ERIC Educational Resources Information Center

    Harris, Ira; And Others

    This eighth grade teacher's guide with student activities is designed to create greater awareness of Indiana, its geography, history, government, and future and is designed to be used as a supplement to the study of the U.S. Constitution and the Indiana Constitution. In the first section, entitled "Geography of Indiana," the lessons…

  14. Grade Two, Environmental Education Guide.

    ERIC Educational Resources Information Center

    Project I-C-E, Green Bay, WI.

    This second grade environmental education guide is one of a series of guides, K-12, which were developed by teachers to help introduce environmental education into the total curriculum. The guides are supplementary in design; it is the teacher's decision when the concepts, objectives, activities, and resources may best be integrated into the…

  15. Let's Eliminate the Eighth Grade!

    ERIC Educational Resources Information Center

    Ogden, William R.

    2008-01-01

    With tongue tentatively hovering in the direction of the distal side of the tooth line and the lining of the inner cheek, the author suggests terminating the elementary school years with the seventh grade and requiring completion of nine to twelve months of paid work experience before the resumption of high school. Maintaining that a practical…

  16. Teacher's Guide, Ecology, Grade 7.

    ERIC Educational Resources Information Center

    Yadkin Valley Economic Development District, Inc., Walnut Cove, NC.

    This teacher's guide has been constructed to assist in developing and implementing a life science course with an environment/ecological unit for Grade 7. Designed primarily for use with other science units, it offers numerous multidisciplinary activities which emphasize involvement in problem-solving through open-ended investigation rather than…

  17. Grade Four, Environmental Education Guide.

    ERIC Educational Resources Information Center

    Project I-C-E, Green Bay, WI.

    This fourth grade environmental education guide is one of a series of guides, K-12, which were developed by teachers to help introduce environmental education into the total curriculum. The guides are supplementary in design; it is the teacher's decision when the concepts, objectives, activities, and resources may best be integrated into the…

  18. Grading Philosophy Survey, Fall 1989.

    ERIC Educational Resources Information Center

    Catonsville Community Coll., MD. Office of Institutional Research.

    In 1989, a survey was conducted at Catonsville Community College to establish a consensus about the underlying philosophy governing the college's grading policy. The survey respondents included 167 full-time or adjunct faculty members, 15 student personnel professionals, 8 administrators, and 6 library, media, or telecommunications professionals.…

  19. Teaching Music, Grades 5, 6.

    ERIC Educational Resources Information Center

    New York City Board of Education, Brooklyn, NY. Div. of Curriculum and Instruction.

    This curriculum guide has been prepared for use by both the music specialist and the classroom teacher in New York City. It outlines areas of musical subject matter appropriate for students in grades five and six. The materials are presented in six sections. "Rhythmic Experiences" introduces students to a variety of meters and rhythms…

  20. Social Studies Curriculum: Grade Six.

    ERIC Educational Resources Information Center

    Pease, Arthur

    This document outlines the content of the grade 6 social studies curriculum of the Lebanon School District, Lebanon, New Hampshire. The program is essentially a chronological review of western civilization, which includes pre-historic man, early civilization, classical civilizations of Greece and Rome, Medieval period, and the Age of Expansion.…

  1. Grade Three, Environmental Education Guide.

    ERIC Educational Resources Information Center

    Project I-C-E, Green Bay, WI.

    This third grade environmental education guide is one of a series of guides, K-12, that were developed by teachers to help introduce environmental education into the total curriculum. The guides are supplementary in design; it is the teacher's decision when the concepts, objectives, activities, and resources may best be integrated into the…

  2. Storybook Writing in First Grade

    ERIC Educational Resources Information Center

    Hertz-Lazarowitze, Rachel

    2004-01-01

    Research literature on writing storybooks overlooks first graders. This is puzzling as children enter first grade having emergent literacy, in reading, writing, and story composition. It may reflect the belief that at this age children should learn to read and write (conventionally) as the curriculum demands, while elaborate writing is assumed to…

  3. The Humanistic Method of Grading.

    ERIC Educational Resources Information Center

    Nichols, Otis Clovis

    1981-01-01

    Sets forth a guideline for incorporating humanism into grading with built-in adjustments that accommodate some human weaknesses. Built-in adjustments cancel or neutralize some of the blunders that are inherent in the teaching, learning, and testing processes that reflect student assessment. (Author)

  4. Contract grading in clinical evaluation.

    PubMed

    Schoolcraft, V; Delaney, C

    1982-01-01

    The use of contracts in grading clinical performance has provided faculty with a solution to two important problems. One has been how to ensure that students are graded consistently among the various faculty who are grading the same clinical component of a course. The second has been to increase the opportunity for individualized attention to student learning needs. We have been pleased to see all the faculty members increase their input and involvement in the continuing modifications of the contract. Although we have taken the major responsibility for the semi-annual revisions of the contract, other faculty members have been increasingly more explicit in their evaluations and suggestions as their experience with the contract has expanded. Their confidence in this method of clinical evaluation has increased with each semester of use. We plan to continue in the refinement of the instrument and will develop materials for the use of other faculty groups who are interested in developing similar contracts. We are also designing a survey to attempt to discover how widespread is the use of contract grading in clinical areas.

  5. Learning by Sharing Graded Papers.

    ERIC Educational Resources Information Center

    Reisin, Gail

    1990-01-01

    Discusses using students' graded papers as a "text" to be read and commented upon by other students. Notes that sharing students' papers (and the teacher's comments) (1) reassures the students that they are not the only ones making errors; (2) deepens their understanding of literature; and (3) increases their awareness of writing styles and…

  6. Grading Rubrics: Hoopla or Help?

    ERIC Educational Resources Information Center

    Howell, Rebecca J.

    2014-01-01

    The purpose of the study was to offer some quantitative, multivariate evidence concerning the impact of grading rubric use on academic outcome among American higher education students. Using a pre-post, quasi-experimental research design, cross-sectional data were derived from undergraduates enrolled in an elective during spring and fall 2009 at…

  7. Caney's Third Grade Rocket Program.

    ERIC Educational Resources Information Center

    Warnock, Joe; Hudiburg, George E.

    1984-01-01

    This narrative description of a special program for third-grade students to raise funds for and to construct, launch, and fly their own rockets illustrates benefits of heightened confidence and self-perception among participants, hands-on experience in a highly technical area, and increased community support and involvement. (MM)

  8. Teacher's Guide, Ecology, Grade 10.

    ERIC Educational Resources Information Center

    Yadkin Valley Economic Development District, Inc., Walnut Cove, NC.

    This teacher's guide has been constructed to assist in developing and implementing a life science course with an environment/ecological unit for Grade 10. Designed primarily for use with other science units, it offers numerous multidisciplinary activities which emphasize involvement in problem-solving through open-ended investigation rather than…

  9. Metric Activities, Grades K-6.

    ERIC Educational Resources Information Center

    Draper, Bob, Comp.

    This pamphlet presents worksheets for use in fifteen activities or groups of activities designed for teaching the metric system to children in grades K through 6. The approach taken in several of the activities is one of conversion between metric and English units. The majority of the activities concern length, area, volume, and capacity. A…

  10. The Reliability of College Grades

    ERIC Educational Resources Information Center

    Beatty, Adam S.; Walmsley, Philip T.; Sackett, Paul R.; Kuncel, Nathan R.; Koch, Amanda J.

    2015-01-01

    Little is known about the reliability of college grades relative to how prominently they are used in educational research, and the results to date tend to be based on small sample studies or are decades old. This study uses two large databases (N > 800,000) from over 200 educational institutions spanning 13 years and finds that both first-year…

  11. Practicing Good Habits, Grade 2.

    ERIC Educational Resources Information Center

    Nguyen Van Quan; And Others

    This illustrated primer, designed for second grade students in Vietnam, consists of stories depicting rural family life in Vietnam. The book is divided into the following six chapters: (1) Practicing Good Habits (health, play, helpfulness); (2) Duties at Home (grandparents, father and mother, servants, the extended family; (3) Duties in School…

  12. Teacher's Guide, Health. Grade 1.

    ERIC Educational Resources Information Center

    Bui huy Bao; And Others

    This is the teaching guide accompanying the elementary health instructional program designed for children at the first grade level in Vietnam. The goal is to integrate the school program with the realities of the health conditions in the community. The teaching method outlined in the guide is based on three principals: (1) preparation at home, (2)…

  13. 8th Grade Canadian Trip.

    ERIC Educational Resources Information Center

    Jelinek, Gilbert; Schoenike, Paul

    Ideas are offered for helping eighth-grade students incorporate an at-home field trip to Canada into a social studies unit. The teachers who developed the unit state that students can complete the 21-day imaginary trip in five hours of classroom time when appropriate materials are available and the classroom environment is conducive to working on…

  14. Marine Science Activities, Grade Six.

    ERIC Educational Resources Information Center

    Kolb, James A.

    This unit, one of a series designed to develop and foster an understanding of the marine environment, presents marine science activities for grade 6 students. The unit is divided into the following sections: (1) Pagoo (story of a hermit crab); (2) introduction to marine environments; (3) salt water environment; (4) sea water investigations; (5)…

  15. Linguistics in the Elementary Grades.

    ERIC Educational Resources Information Center

    Dawkins, John

    1965-01-01

    When the science of linguistics is treated as a variety of ways for searching for truth and theory, rather than as a body of established theories, it can be taught successfully in the early grades. Some of the generalizations in linguistics (e.g., the articulatory description of differences between significant sounds, of the classification of…

  16. Research Supporting Middle Grades Practice

    ERIC Educational Resources Information Center

    Hough, David L., Ed.

    2010-01-01

    Exemplary Middle Grades Research: Evidence-Based Studies Linking Theory to Practice features research published throughout 2009 in MGRJ that has been identified by the Information Age Publishing's review board as the most useful in terms of assisting educators with making practical applications from evidence-based studies to classroom and school…

  17. School Grading and Institutional Contexts

    ERIC Educational Resources Information Center

    Dardanoni, Valentino; Modica, Salvatore; Pennisi, Aline

    2011-01-01

    We study how the relationship between students' cognitive ability and their school grades depends on institutional contexts. In a simple abstract model, we show that unless competence standards are set at above-school level or the variation of competence across schools is low, students' competence valuation will be heterogeneous, with weaker…

  18. Elementary School Dance. Grade Two.

    ERIC Educational Resources Information Center

    Wotherspoon, Bill

    Outlines are presented for 30 creative dance lessons for second grade children. Each lesson description includes: (1) a statement of the lesson objective; (2) an overview of how the lesson illuminates a general concept of dancing; (3) musical equipment needed; (4) introductory activities; (5) tasks for skill development; (6) suggestions for the…

  19. Elementary School Dance. Grade One.

    ERIC Educational Resources Information Center

    Wotherspoon, Bill

    Outlines are presented for 30 creative dance lessons for first grade children. Each lesson description includes: (1) a statement of the lesson objective; (2) an overview of how the lesson illuminates a general concept of dancing; (3) musical equipment needed; (4) introductory activities; (5) tasks for skill development; (6) suggestions for the…

  20. Elementary School Dance. Grade Six.

    ERIC Educational Resources Information Center

    Wotherspoon, Bill

    Outlines are presented for 30 creative dance lessons for sixth grade children. Each lesson description includes: (1) a statement of the lesson objective; (2) an overview of how the lesson illuminates a general concept of dancing; (3) musical equipment needed; (4) introductory activities; (5) tasks for skill development; (6) suggestions for the…

  1. Elementary School Dance. Grade Three.

    ERIC Educational Resources Information Center

    Wotherspoon, Bill

    Outlines are presented for 30 creative dance lessons for third grade children. Each lesson description includes: (1) a statement of the lesson objective; (2) an overview of how the lesson illuminates a general concept of dancing; (3) musical equipment needed; (4) introductory activities; (5) tasks for skill development; (6) suggestions for the…

  2. Seals. Grades 3-6.

    ERIC Educational Resources Information Center

    New England Aquarium, Boston, MA.

    Explanations of a marine mammal rescue program and information on seals and sea lions are presented in this curriculum package for intermediate grade teachers. Activities are highlighted which focus on the natural history of harbor seals. This unit contains: (1) pre-trip activities (including fact sheets and worksheets on the different types of…

  3. Speaking Aids Through the Grades.

    ERIC Educational Resources Information Center

    Carlson, Ruth Kearney

    This book contains a selection of activities, techniques, and sources to be used by those who are concerned with oral communication experiences of children and youth. Chapter topics are as follows: (1) multi-sensory awareness: speaking and acting for kindergarten through third grade; (2) kinesics and drama for primary children; (3) imaginative…

  4. Writing Assessment Handbook, Grade 8.

    ERIC Educational Resources Information Center

    California State Dept. of Education, Sacramento.

    This handbook, intended for English language arts teachers, principals, curriculum and testing specialists, superintendents, and all educators interested in preparing students for the grade 8 California Assessment Program (CAP) writing assessment, provides the practitioner with information about the content of the test, the rationale underlying…

  5. Transportation: Grade 8. Cluster IV.

    ERIC Educational Resources Information Center

    Calhoun, Olivia H.

    A curriculum guide for grade 8, the document is devoted to the occupational cluster "Transportation." It is divided into five units: surface transportation, interstate transportation, air transportation, water transportation, and subterranean transportation (the Metro). Each unit is introduced by a statement of the topic, the unit's…

  6. Teacher's Guide, Ecology, Grade 4.

    ERIC Educational Resources Information Center

    Yadkin Valley Economic Development District, Inc., Walnut Cove, NC.

    This teacher's guide has been constructed to assist in developing and implementing a life science course with an environment/ecological unit for Grade 4. Designed primarily for use with other science units, it offers numerous multidisciplinary activities which emphasize involvement in problem-solving through open-ended investigation rather than…

  7. Marine Science Activities, Grade Two.

    ERIC Educational Resources Information Center

    Kolb, James A.

    This unit, one of a series designed to develop and foster an understanding of the marine environment, presents marine science activities for second grade students. The unit, focusing on awareness of living/non-living factors shaping life of the sea, is divided into sections dealing with: physical characteristics of oceans; fish; sea anemone;…

  8. Woodworking: Grades 7-12.

    ERIC Educational Resources Information Center

    Instructional Objectives Exchange, Los Angeles, CA.

    The woodworking collection is composed of 55 objectives and related evaluation items for use in grades 7 through 12. Each sample contains the objective, test items, and criteria for judging the adequacy of the response. Woodworking categories being measured include sharpening, adjusting, using and caring for tools; reading a working drawing; stock…

  9. Third Grade Social Studies Unit.

    ERIC Educational Resources Information Center

    Park Forest Public Schools District 163, IL.

    As in other units in this series, this teaching guide is structured on the basis of one major generalization, supporting generalizations, and suggestions of learning activities and materials leading to an understanding of these ideas. For Grade 3, the major generalization is, "Skin color is only one of many obvious physical differences among…

  10. Teaching Literacy in Fifth Grade

    ERIC Educational Resources Information Center

    McMahon, Susan I.; Wells, Jacqueline

    2007-01-01

    For students, fifth grade is a time of increasing independence and responsibility. Yet fifth-graders vary widely in their reading and writing abilities--and they are still young enough to require considerable teacher support. Depicting an exemplary teacher in action, this indispensable book presents innovative, practical strategies for creating an…

  11. Metric Measurement: Grades K-8.

    ERIC Educational Resources Information Center

    Instructional Objectives Exchange, Los Angeles, CA.

    This collection is comprised of 63 objectives and corresponding sample test items for evaluation of students in grades K-8. Correct answers or criteria for judging the adequacy of student responses are provided. Major categories in the collection are: (1) preparing to use the metric system--decimal and fractional notation; (2) measurement--length,…

  12. THE PANC 3 SCORE PREDICTING SEVERITY OF ACUTE PANCREATITIS

    PubMed Central

    BEDUSCHI, Murilo Gamba; MELLO, André Luiz Parizi; VON-MÜHLEN, Bruno; FRANZON, Orli

    2016-01-01

    Background : About 20% of cases of acute pancreatitis progress to a severe form, leading to high mortality rates. Several studies suggested methods to identify patients that will progress more severely. However, most studies present problems when used on daily practice. Objective : To assess the efficacy of the PANC 3 score to predict acute pancreatitis severity and its relation to clinical outcome. Methods : Acute pancreatitis patients were assessed as to sex, age, body mass index (BMI), etiology of pancreatitis, intensive care need, length of stay, length of stay in intensive care unit and mortality. The PANC 3 score was determined within the first 24 hours after diagnosis and compared to acute pancreatitis grade of the Revised Atlanta classification. Results : Out of 64 patients diagnosed with acute pancreatitis, 58 met the inclusion criteria. The PANC 3 score was positive in five cases (8.6%), pancreatitis progressed to a severe form in 10 cases (17.2%) and five patients (8.6%) died. Patients with a positive score and severe pancreatitis required intensive care more often, and stayed for a longer period in intensive care units. The PANC 3 score showed sensitivity of 50%, specificity of 100%, accuracy of 91.4%, positive predictive value of 100% and negative predictive value of 90.6% in prediction of severe acute pancreatitis. Conclusion : The PANC 3 score is useful to assess acute pancreatitis because it is easy and quick to use, has high specificity, high accuracy and high predictive value in prediction of severe acute pancreatitis. PMID:27120730

  13. [Acute thrombosis of lower-limb arteries: contemporary approaches to therapeutic decision making].

    PubMed

    Zatevakhin, I I; Zolkin, V N; Gorbenko, M Iu

    2010-01-01

    Analysed herein are therapeutic outcomes in a total of 499 patients presenting with acute thrombosis of the aorta and lower-limb arteries and having previously no reconstructive operations on limb arteries on the affected side. Group I was composed of the patients who had during the first 24 hours of hospitalization undergone an emergency operation (n = 146), and Group II comprised those subjected to medical treatment only (n = 353). In Group I, the number of the patients who survived with a preserved extremity amounted to 91.5% of those presenting with grade I ischaemia, equalling 76.5% of those diagnosed with grade IIA, 48.5% of those having grade IIB, and 12.5% for those with grade IIIA. Using conservative measures alone, we had managed to attain complete regression of acute ischaemia in as few as 38% of patients found to have grade I ischaemia and in only 1.5% of grade II patients, with the remaining subjects found to either continue suffering from ischaemic impairments or even have them progressed, which later on required performing a reconstructive operation or primary amputation. The outcomes of surgery in patients operated on later than the first 24 hours after admission to hospital were also much worse: the number of amputations was two times higher as compared with that in Group I. The statistical analysis showed a significant dependence of the acute ischaemia pattern on localization and dissemination of the occlusive lesion. Hence, an emergency reconstructive operation appears to be treatment of choice for acute thromboses of lower limb arteries. An exception may only be made for patients presenting with grade I acute ischaemia, running high operative risk, and having a favourable prognosis of the acute ischaemia course, based on the data concerning localization of the occlusive lesion.

  14. Hypofractionated IMRT of the Prostate Bed After Radical Prostatectomy: Acute Toxicity in the PRIAMOS-1 Trial

    SciTech Connect

    Katayama, Sonja; Striecker, Thorbjoern; Kessel, Kerstin; Sterzing, Florian; Habl, Gregor; Edler, Lutz; Debus, Juergen; Herfarth, Klaus

    2014-11-15

    Purpose: Hypofractionated radiation therapy as primary treatment for prostate cancer is currently being investigated in large phase 3 trials. However, there are few data on postoperative hypofractionation. The Radiation therapy for the Prostate Bed With or Without the Pelvic Lymph Nodes (PRIAMOS 1) trial was initiated as a prospective phase 2 trial to assess treatment safety and toxicity of a hypofractionated intensity modulated radiation therapy (IMRT) of the prostate bed. Methods and Materials: From February to September 2012, 40 patients with indications for adjuvant or salvage radiation therapy were enrolled. One patient dropped out before treatment. Patients received 54 Gy in 18 fractions to the prostate bed with IMRT and daily image guidance. Gastrointestinal (GI) and genitourinary (GU) toxicities (according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) were recorded weekly during treatment and 10 weeks after radiation therapy. Results: Overall acute toxicity was favorable, with no recorded adverse events grade ≥3. Acute GI toxicity rates were 56.4% (grade 1) and 17.9% (grade 2). Acute GU toxicity was recorded in 35.9% of patients (maximum grade 1). Urinary stress incontinence was not influenced by radiation therapy. The incidence of grade 1 urinary urge incontinence increased from 2.6% before to 23.1% 10 weeks after therapy, but grade 2 urge incontinence remained unchanged. Conclusions: Postoperative hypofractionated IMRT of the prostate bed is tolerated well, with no severe acute side effects.

  15. Pre-transplantation risk factors to develop sclerotic chronic GvHD after allogeneic HSCT: a multicenter retrospective study from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

    PubMed

    Detrait, M Y; Morisset, S; Peffault de Latour, R; Yakoub-Agha, I; Crocchiolo, R; Tabrizi, R; Bay, J-O; Chevalier, P; Barraco, F; Raus, N; Vigouroux, S; Magro, L; Mohty, M; Milpied, N; Blaise, D; Socié, G; Michallet, M

    2015-02-01

    Sclerotic chronic GvHD (cGvHD) is one of the most severe complications after allo-hematopoietic stem cell transplantation (HSCT). Risk factors associated with this complication remain not very well defined. With the aim to define a pre-transplantation risk profile, we have conducted a French retrospective analysis in 705 consecutive patients between 2005 and 2010. Analyses to determine pre-transplantation risk factors included as variables: patient and donor age, kind of donor, HLA matching, ABO matching, sex-matching, diagnosis, stem cell source, gender, GvHD prophylaxis and antithymocyte globulin (ATG) in the conditioning regimen. The cumulative incidence of sclerotic cGvHD was 18% (95% CI, 16.6-19.6) 3 years after onset of cGvHD. In univariate analysis, we found a significantly lower number of sclerotic cGvHD form in patients transplanted from cord blood cells (P=0.0021), in patients with a one mismatched donor (P=0.041) and in patients who had received ATG in the conditioning regimen (P=0.002). In multivariate analysis, factors associated with an increased risk of sclerotic cGvHD were young patient age, multiple myeloma and PBSC as the stem cell source. ATG in conditioning regimen and cord blood unit as the stem cell source were associated with a lower risk.

  16. Are antibiotics a safe and effective treatment for acute uncomplicated appendicitis?

    PubMed

    Moraga, Felipe; Ahumada, Vanessa; Crovari, Fernando

    2016-01-26

    Acute appendicitis is a common cause of acute abdominal pain and the most frequent cause of emergency abdominal surgery. In the last two decades, growing evidence has been published about the use of antibiotics as the exclusive treatment for acute appendicitis. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified only one systematic review including one pertinent randomized trial. We generated a summary of findings following the GRADE approach. We concluded the use of antibiotics to treat acute uncomplicated appendicitis may be less effective than appendectomy and probably increases major complications compared with appendectomy.

  17. Acute loss of consciousness.

    PubMed

    Tristán, Bekinschtein; Gleichgerrcht, Ezequiel; Manes, Facundo

    2015-01-01

    Acute loss of consciousness poses a fascinating scenario for theoretical and clinical research. This chapter introduces a simple yet powerful framework to investigate altered states of consciousness. We then explore the different disorders of consciousness that result from acute brain injury, and techniques used in the acute phase to predict clinical outcome in different patient populations in light of models of acute loss of consciousness. We further delve into post-traumatic amnesia as a model for predicting cognitive sequels following acute loss of consciousness. We approach the study of acute loss of consciousness from a theoretical and clinical perspective to conclude that clinicians in acute care centers must incorporate new measurements and techniques besides the classic coma scales in order to assess their patients with loss of consciousness.

  18. Decitabine in Treating Children With Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2013-01-22

    Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Promyelocytic Leukemia (M3); Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  19. Lies; Damned Lies; Statistics; and Law School Grades. Grade Conferences from Hell: Measurement Error in Law School Grading.

    ERIC Educational Resources Information Center

    Wangerin, Paul T.

    This paper addresses problems confronting law school teachers in grading law school exams and assigning letter grades. Using prototypical dialogue and scenarios, the paper examines mathematical and statistical issues that contribute to grading errors. Discussed in relation to real world data and the bar exam are: differential weighting, combining…

  20. Early identification of 'acute-onset' chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Sung, Jia-Ying; Tani, Jowy; Park, Susanna B; Kiernan, Matthew C; Lin, Cindy Shin-Yi

    2014-08-01

    Distinguishing patients with acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy prior to relapse is often challenging at the onset of their clinical presentation. In the present study, nerve excitability tests were used in conjunction with the clinical phenotype and disease staging, to differentiate between patients with acute-onset chronic inflammatory demyelinating polyneuropathy and patients with acute inflammatory demyelinating polyneuropathy at an early stage, with the aim to better guide treatment. Clinical assessment, staging and nerve excitability tests were undertaken on patients initially fulfilling the diagnostic criteria of acute inflammatory demyelinating polyneuropathy soon after symptom onset and their initial presentation. Patients were subsequently followed up for minimum of 12 months to determine if their clinical presentations were more consistent with acute-onset chronic inflammatory demyelinating polyneuropathy. Clinical severity as evaluated by Medical Research Council sum score and Hughes functional grading scale were not significantly different between the two cohorts. There was no difference between the time of onset of initial symptoms and nerve excitability test assessment between the two cohorts nor were there significant differences in conventional nerve conduction study parameters. However, nerve excitability test profiles obtained from patients with acute inflammatory demyelinating polyneuropathy demonstrated abnormalities in the recovery cycle of excitability, including significantly reduced superexcitability (P < 0.001) and prolonged relative refractory period (P < 0.01), without changes in threshold electrotonus. In contrast, in patients with acute-onset chronic inflammatory demyelinating polyneuropathy, a different pattern occurred with the recovery cycle shifted downward (increased superexcitability, P < 0.05; decreased subexcitability, P < 0.05) and increased

  1. Acute otitis media and acute bacterial sinusitis.

    PubMed

    Wald, Ellen R

    2011-05-01

    Acute otitis media and acute bacterial sinusitis are 2 of the most common indications for antimicrobial agents in children. Together, they are responsible for billions of dollars of health care expenditures. The pathogenesis of the 2 conditions is identical. In the majority of children with each condition, a preceding viral upper respiratory tract infection predisposes to the development of the acute bacterial complication. It has been shown that viral upper respiratory tract infection predisposes to the development of acute otitis media in 37% of cases. Currently, precise microbiologic diagnosis of acute otitis media and acute bacterial sinusitis requires performance of tympanocentesis in the former and sinus aspiration in the latter. The identification of a virus from the nasopharynx in either case does not obviate the need for antimicrobial therapy. Furthermore, nasal and nasopharyngeal swabs are not useful in predicting the results of culture of the middle ear or paranasal sinus. However, it is possible that a combination of information regarding nasopharyngeal colonization with bacteria and infection with specific viruses may inform treatment decisions in the future.

  2. 7 CFR 932.11 - Grade.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE OLIVES GROWN IN CALIFORNIA Order Regulating Handling Definitions § 932.11 Grade. Grade means the classification of olives as to quality according...

  3. 7 CFR 932.11 - Grade.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE OLIVES GROWN IN CALIFORNIA Order Regulating Handling Definitions § 932.11 Grade. Grade means the classification of olives as to quality according...

  4. 7 CFR 932.11 - Grade.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE OLIVES GROWN IN CALIFORNIA Order Regulating Handling Definitions § 932.11 Grade. Grade means the classification of olives as to quality according...

  5. 7 CFR 932.11 - Grade.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE OLIVES GROWN IN CALIFORNIA Order Regulating Handling Definitions § 932.11 Grade. Grade means the classification of olives as to quality according...

  6. 7 CFR 932.11 - Grade.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE OLIVES GROWN IN CALIFORNIA Order Regulating Handling Definitions § 932.11 Grade. Grade means the classification of olives as to quality according...

  7. Academic Interest Rates and Grade Inflation

    ERIC Educational Resources Information Center

    Davidson, James F.

    1975-01-01

    Traces the causes and effects of the devaluation of honors grades over the past fifteen years noting particularly effects on transcripts and grades as a means of exchange and suggesting faculty responsibility for restoration of academic standards. (JT)

  8. Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors

    PubMed Central

    Kanate, Abraham S.; Mussetti, Alberto; Kharfan-Dabaja, Mohamed A.; Ahn, Kwang W.; DiGilio, Alyssa; Beitinjaneh, Amer; Chhabra, Saurabh; Fenske, Timothy S.; Freytes, Cesar; Gale, Robert Peter; Ganguly, Siddhartha; Hertzberg, Mark; Klyuchnikov, Evgeny; Lazarus, Hillard M.; Olsson, Richard; Perales, Miguel-Angel; Rezvani, Andrew; Riches, Marcie; Saad, Ayman; Slavin, Shimon; Smith, Sonali M.; Sureda, Anna; Yared, Jean; Ciurea, Stefan; Armand, Philippe; Salit, Rachel; Bolaños-Meade, Javier

    2016-01-01

    We evaluated 917 adult lymphoma patients who received haploidentical (n = 185) or HLA-matched unrelated donor (URD) transplantation either with (n = 241) or without antithymocyte globulin (ATG; n = 491) following reduced-intensity conditioning regimens. Haploidentical recipients received posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, whereas URD recipients received calcineurin inhibitor-based prophylaxis. Median follow-up of survivors was 3 years. The 100-day cumulative incidence of grade III-IV acute GVHD on univariate analysis was 8%, 12%, and 17% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .44). Corresponding 1-year rates of chronic GVHD on univariate analysis were 13%, 51%, and 33%, respectively (P < .001). On multivariate analysis, grade III-IV acute GVHD was higher in URD without ATG (P = .001), as well as URD with ATG (P = .01), relative to haploidentical transplants. Similarly, relative to haploidentical transplants, risk of chronic GVHD was higher in URD without ATG and URD with ATG (P < .0001). Cumulative incidence of relapse/progression at 3 years was 36%, 28%, and 36% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .07). Corresponding 3-year overall survival (OS) was 60%, 62%, and 50% in the 3 groups, respectively, with multivariate analysis showing no survival difference between URD without ATG (P = .21) or URD with ATG (P = .16), relative to haploidentical transplants. Multivariate analysis showed no difference between the 3 groups in terms of nonrelapse mortality (NRM), relapse/progression, and progression-free survival (PFS). These data suggest that reduced-intensity conditioning haploidentical transplantation with posttransplant cyclophosphamide does not compromise early survival outcomes compared with matched URD transplantation, and is associated with significantly reduced risk of chronic GVHD. PMID:26670632

  9. Fair & Accurate Grading for Exceptional Learners

    ERIC Educational Resources Information Center

    Jung, Lee Ann; Guskey, Thomas R.

    2011-01-01

    Despite the many changes in education over the past century, grading and reporting practices have essentially remained the same. In part, this is because few teacher preparation programs offer any guidance on sound grading practices. As a result, most current grading practices are grounded in tradition, rather than research on best practice. In an…

  10. Student Perspectives of Grading in Physical Education

    ERIC Educational Resources Information Center

    Zhu, Xihe

    2015-01-01

    Recent state and federal legislations on educational accountability push evaluation and grading to the frontline. This study examined students' perspectives of grading in physical education. The participants included students (N = 39) from two middle schools. Data were collected through observation, student profile grading sheets and interviews.…

  11. Contract Grading in Speech Communication Courses.

    ERIC Educational Resources Information Center

    Book, Cassandra L.; And Others

    This document presents contract grading as a system of evaluation for speech communication courses at the high school or college level. Contract grading can provide the means to reduce the element of threat that impedes effective interpersonal communication between teacher and student. Contract grading is a business like arrangement whereby the…

  12. Grade Inflation: Magnitude, Causes, and Consequences.

    ERIC Educational Resources Information Center

    Garten, Edward D.; Olday, David B.

    The extent of grade inflation at the college level, possible causes of the phenomenon, and its potential consequences for colleges and universities and the individual student are discussed. Grade inflation since 1965 has been attributed to the following possible causes: grade point averages (GPA) have increased because of real changes in high…

  13. Grade Inflation: An Issue for Higher Education?

    ERIC Educational Resources Information Center

    Caruth, Donald L.; Caruth, Gail D.

    2013-01-01

    Grade inflation impacts university credibility, student courses of study, choices of institution, and other areas. There has been an upward shift in grades without a corresponding upward shift in knowledge gained. Some of the most frequently mentioned causes of grade inflation are: (1) student evaluations of professors; (2) student teacher…

  14. Investigating Grade Inflation and Non-Equivalence

    ERIC Educational Resources Information Center

    Godfrey, Kelly E.

    2009-01-01

    [Slides] presented at the American Educational Research Association (AERA) in 2009. This study investigated the presence of a general rise in high school grades without a corresponding rise in SAT scores, as well as different grading criteria between schools, as shown by differential relationships between AP course grades and exam scores. These…

  15. Grade Inflation in Higher Education. ERIC Digest.

    ERIC Educational Resources Information Center

    Young, Carol

    Grade inflation has commanded increasing attention in the academic world in recent years, with administrators, faculty, and academic analysts unable to agree on whether grade inflation actually exists or is a myth to be debunked. This Digest reviews research in support of and against the existence of grade inflation. A statistical analysis report…

  16. Demystify Learning Expectations to Address Grade Inflation

    ERIC Educational Resources Information Center

    Hodges, Linda C.

    2014-01-01

    This article describes the subject of "grade inflation," a reference to educators giving higher grades to student work than their expectations for student achievement warrant. Of the many reasons why this practice happens, Hodges specifically discusses inflating grades as "a natural consequence" when the faculty really…

  17. Does Competition among Schools Encourage Grade Inflation?

    ERIC Educational Resources Information Center

    Walsh, Patrick

    2010-01-01

    This paper considers whether high schools in competitive environments use grade inflation to attract and retain families, perhaps in addition to more constructive responses. Two measures of grade inflation are used: the cutoffs used by each school to assign a letter grade to a percent score; and high school GPA after controlling for test scores, a…

  18. Is Grade Inflation Related to Faculty Status?

    ERIC Educational Resources Information Center

    Kezim, Boualem; Pariseau, Susan E.; Quinn, Frances

    2005-01-01

    The authors performed a statistical analysis to investigate whether grade inflation existed in the business school at a small private college in the northeast region of the United States. The results showed that grade inflation existed and exhibited a linear trend over a 20-year period. The authors found that grade inflation was related to faculty…

  19. Examining Text Complexity in the Early Grades

    ERIC Educational Resources Information Center

    Fitzgerald, Jill; Elmore, Jeff; Hiebert, Elfrieda H.; Koons, Heather H.; Bowen, Kimberly; Sanford-Moore, Eleanor E.; Stenner, A. Jackson

    2016-01-01

    The Common Core raises the stature of texts to new heights, creating a hubbub. The fuss is especially messy at the early grades, where children are expected to read more complex texts than in the past. But early-grades teachers have been given little actionable guidance about text complexity. The authors recently examined early-grades texts to…

  20. Best Practices in Grading. Research into Practice

    ERIC Educational Resources Information Center

    Johnston, Howard

    2011-01-01

    Grading is one of the most enduring features of schooling. No matter what other reforms occur in a school, grading remains as one of the cornerstones of educational practice. But recently this long-standing tradition has come under scrutiny with some alarming results. Many traditional grading practices actually "depress" achievement, and may, in…