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Sample records for acute gvhd grade

  1. Acute gut GVHD in children: does skin involvement matter?

    PubMed

    Gassas, A; Sung, L; Dupuis, A; Schechter, T; Egeler, M; Ali, M

    2013-08-01

    Gut GVHD (G-GVHD) is frequently the most severe and difficult to treat compared with skin GVHD. It is unknown if skin involvement with G-GVHD has prognostic significance. To compare the prognosis of acute isolated G-GVHD vs acute gut and skin GVHD (GS-GVHD) in children following allo-SCT. Allo-SCT recipients from Jan 2000-Dec 2009 were included and patients who underwent endoscopy and gut biopsy for G-GVHD were identified. Four hundred and fifty children (0-18 years) underwent allo-SCT during the study period. Seventy-nine (17.5%) patients underwent endoscopy and biopsy. At least stage II was required for skin involvement. Forty nine patients had G-GVHD and 30 had combined, GS-GVHD. The majority of patients received CsA and MTX for GVHD prophylaxis. Sixty-seven percent of patients with GS-GVHD had grade III-IV while only 31% had grade III-IV in the G-GVHD group. Median follow-up was 6.3 years (range 3.6-11.9 years). Relapse rate was similar in both the groups. However, children with G-GVHD had a significantly higher risk of dying from GVHD related complications (37% vs 16%) resulting in superior survival for those with skin involvement (79% vs 49% P=0.02). Extension of G-GVHD to the skin may suggest a better outcome.

  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. PMID:27338097

  3. 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.

  4. A refined risk score for acute GVHD that predicts response to initial therapy, survival and transplant-related mortality

    PubMed Central

    MacMillan, Margaret L.; Robin, Marie; Harris, Andrew C.; DeFor, Todd E.; Martin, Paul J.; Alousi, Amin; Ho, Vincent T.; Bolaños-Meade, Javier; Ferrara, James L.M.; Jones, Richard; Arora, Mukta; Blazar, Bruce R.; Holtan, Shernan G.; Jacobsohn, David; Pasquini, Marcelo; Socie, Gerard; Antin, Joseph H.; Levine, John E.; Weisdorf, Daniel J.

    2015-01-01

    To develop a novel acute graft-versus-host disease (GVHD) Risk Score, we examined the GVHD clinical stage and grade of 1723 patients at the onset of treatment with systemic steroids. Using clinical grouping, descriptive statistics and recursive partitioning, we identified poorly responsive, high-risk (HR) acute GVHD by the number of involved organs and severity of GVHD at onset. The overall response [(complete response/partial response (CR/PR)] rate 28 days after initiation of steroid therapy for acute GVHD was lower in the 269 patients with HR-GVHD than in the 1454 patients with standard risk (SR)-GVHD [44% (95% CI 38–50%) vs. 68% (95% CI 66–70%), p<0.001. Patients with HR-GVHD were less likely to respond at day 28 [odds ratio (OR), 0.3, 95% CI 0.2–0.4, p<0.001], and had higher risks of mortality [relative risk (RR) 2.1, 95% CI 1.7–2.6, P<0.001] and transplant-related mortality (RR 2.5, 95% CI 2.0–3.2%, p<0.001) compared to patients with SR-GVHD. This refined definition of acute GVHD risk is a better predictor of response, survival and transplant-related mortality than other published acute GVHD risk scores. Patients with HR-GVHD are candidates for studies investigating new treatment approaches. Likewise, patients with SR-GVHD are candidates for studies investigating less toxic therapy. PMID:25585275

  5. Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation

    PubMed Central

    Brennan, Todd V.; Lin, Liwen; Huang, Xiaopei; Cardona, Diana M.; Li, Zhiguo; Dredge, Keith; Chao, Nelson J.

    2012-01-01

    Graft-versus-host disease (GVHD) remains the most common cause of nonrelapse-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although T-cell depletion and intensive immunosuppression are effective in the control of GVHD, they are often associated with higher rates of infection and tumor recurrence. In this study, we showed that heparan sulfate (HS), an extracellular matrix component, can activate Toll-like receptor 4 on dendritic cells in vitro, leading to the enhancement of dendritic cell maturation and alloreactive T-cell responses. We further demonstrated in vivo that serum HS levels were acutely elevated at the onset of clinical GVHD in mice after allo-HSCT. Treatment with the serine protease inhibitor α1-antitrypsin decreased serum levels of HS, leading to a reduction in alloreactive T-cell responses and GVHD severity. Conversely, an HS mimetic that increased serum HS levels accelerated GVHD. In addition, in patients undergoing allo-HSCT for hematologic malignancies, serum HS levels were elevated and correlated with the severity of GVHD. These results identify a critical role for HS in promoting acute GVHD after allo-HSCT, and they suggest that modulation of HS release may have therapeutic potential for the control of clinical GVHD. PMID:22760779

  6. 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. PMID:25704053

  7. Risk factors and prognosis of hepatic acute GvHD after allogeneic hematopoietic cell transplantation.

    PubMed

    Arai, Y; Kanda, J; Nakasone, H; Kondo, T; Uchida, N; Fukuda, T; Ohashi, K; Kaida, K; Iwato, K; Eto, T; Kanda, Y; Nakamae, H; Nagamura-Inoue, T; Morishima, Y; Hirokawa, M; Atsuta, Y; Murata, M

    2016-01-01

    Hepatic acute GvHD (aGvHD) is associated with high mortality owing to poor response to immunosuppressive therapy. The pathogenesis of hepatic aGvHD differs from that of other lesions, and specific risk factors related to pre-transplant liver conditions should be determined. We conducted a cohort study by using a Japanese transplant registry database (N=8378). Of these subjects, 1.5% had hepatitis C virus Ab (HCV-Ab) and 9.4% had liver dysfunction (elevated transaminase or bilirubin levels) before hematopoietic cell transplantation (HCT). After HCT, the cumulative incidence of hepatic aGvHD was 6.7%. On multivariate analyses, HCV-Ab positivity (hazard ratio (HR), 1.93; P=0.02) and pre-transplant liver dysfunction (HR, 1.85; P<0.01), as well as advanced HCT risk, unrelated donors, HLA mismatch and cyclosporine as GvHD prophylaxis, were significant risk factors for hepatic aGvHD, whereas hepatitis B virus surface Ag was not. Hepatic aGvHD was a significant risk factor for low overall survival and high transplant-related mortality in all aGvHD grades (P<0.01). This study is the first to show the relationship between pre-transplant liver conditions and hepatic aGvHD. A prospective study is awaited to validate the results of this study and establish a new strategy especially for high-risk patients. PMID:26367230

  8. Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality

    PubMed Central

    Wang, Tao; Haagenson, Michael; Spellman, Stephen R.; Askar, Medhat; Battiwalla, Minoo; Baxter-Lowe, Lee Ann; Bitan, Menachem; Fernandez-Viña, Marcelo; Gandhi, Manish; Jakubowski, Ann A.; Maiers, Martin; Marino, Susana R.; Marsh, Steven G. E.; Oudshoorn, Machteld; Palmer, Jeanne; Prasad, Vinod K.; Reddy, Vijay; Ringden, Olle; Saber, Wael; Santarone, Stella; Schultz, Kirk R.; Setterholm, Michelle; Trachtenberg, Elizabeth; Turner, E. Victoria; Woolfrey, Ann E.; Lee, Stephanie J.; Anasetti, Claudio

    2013-01-01

    HLA disparity has a negative impact on the outcomes of hematopoietic cell transplantation (HCT). We studied the independent impact of amino acid substitution (AAS) at peptide-binding positions 9, 99, 116, and 156, and killer immunoglobulin-like receptor binding position 77 of HLA-A, B, or C, on the risks for grade 3-4 acute graft-versus-host disease (GVHD), chronic GVHD, treatment-related mortality (TRM), relapse, and overall survival. In multivariate analysis, a mismatch at HLA-C position 116 was associated with increased risk for severe acute GVHD (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.15-1.82, P = .0016). Mismatch at HLA-C position 99 was associated with increased transplant-related mortality (HR = 1.37, 95% CI = 1.1-1.69, P = .0038). Mismatch at HLA-B position 9 was associated with increased chronic GVHD (HR = 2.28, 95% CI = 1.36-3.82, P = .0018). No AAS were significantly associated with outcome at HLA-A. Specific AAS pair combinations with a frequency >30 were tested for association with HCT outcomes. Cysteine to tyrosine substitution at position 99 of HLA-C was associated with increased TRM (HR = 1.78, 95% = CI 1.27-2.51, P = .0009). These results demonstrate that donor-recipient mismatch for certain peptide-binding residues of the HLA class I molecule is associated with increased risk for acute and chronic GVHD and death. PMID:23982174

  9. Numerical impairment of nestin(+) bone marrow niches in acute GvHD after allogeneic hematopoietic stem cell transplantation for AML.

    PubMed

    Medinger, M; Krenger, W; Jakab, A; Halter, J; Buser, A; Bucher, C; Passweg, J; Tzankov, A

    2015-11-01

    The nestin(+) perivascular bone marrow (BM) stem cell niche (N(+)SCN) may be involved in GvHD. To investigate whether acute GvHD (aGvHD) reduces the number of N(+)SCN, we examined patients with AML who had undergone allogeneic hematopoietic stem cell transplantation. In the test cohort (n=8), the number of N(+)SCN per mm(2) in BM biopsies was significantly reduced in aGvHD patients at the time of aGvHD compared with patients who did not have aGvHD (1.2±0.78 versus 2.6±0.93, P=0.04). In the validation cohort (n=40), the number of N(+)SCN was reduced (1.9±0.99 versus 2.6±0.90 N(+)SCN/mm(2), P=0.05) in aGvHD patients. Receiver operating curves suggested that the cutoff score that best discriminated between patients with and without aGvHD was 2.29 N(+)SCN/mm(2). Applying this cutoff score, 9/11 patients with clinically relevant aGvHD (⩾grade 2) and 13/20 with any type of GvHD had decreased N(+)SCN numbers compared with only 10/29 patients without clinically relevant aGvHD (P=0.007) and 6/20 patients without any type of GvHD (P=0.028). In patients tracked over time, N(+)SCN density returned to normal after aGvHD resolved or remained stable in patients who did not have aGvHD. Our results show a decrease in the number of N(+)SCN in aGvHD.

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

    PubMed

    Chopra, Martin; Biehl, Marlene; Steinfatt, Tim; Brandl, Andreas; Kums, Juliane; Amich, Jorge; Vaeth, Martin; Kuen, Janina; Holtappels, Rafaela; Podlech, Jürgen; Mottok, Anja; Kraus, Sabrina; Jordán-Garrote, Ana-Laura; Bäuerlein, Carina A; Brede, Christian; Ribechini, Eliana; Fick, Andrea; Seher, Axel; Polz, Johannes; Ottmüller, Katja J; Baker, Jeanette; Nishikii, Hidekazu; Ritz, Miriam; Mattenheimer, Katharina; Schwinn, Stefanie; Winter, Thorsten; Schäfer, Viktoria; Krappmann, Sven; Einsele, Hermann; Müller, Thomas D; Reddehase, Matthias J; Lutz, Manfred B; Männel, Daniela N; Berberich-Siebelt, Friederike; Wajant, Harald; Beilhack, Andreas

    2016-08-22

    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

  11. 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

  12. Acute GVHD is a strong predictor of full donor CD3+ T cell chimerism after reduced intensity conditioning allogeneic stem cell transplantation.

    PubMed

    El-Cheikh, Jean; Vazquez, Alberto; Crocchiolo, Roberto; Furst, Sabine; Calmels, Boris; Castagna, Luca; Lemarie, Claude; Granata, Angela; Ladaique, Patrick; Oudin, Claire; Faucher, Catherine; Chabannon, Christian; Blaise, Didier

    2012-12-01

    The monitoring of chimerism is a standard procedure to assess engraftment and achievement of full donor lymphoid cells after reduced intensity conditioning (RIC) stem cell transplantation (Allo-SCT). However, there is no consensus on when and how often to monitor post-transplant chimerism. We retrospectively analyzed our experience regarding the impact of acute graft versus host disease (GVHD) for the prediction of allograft chimerism. One-hundred-and-fifteen patients transplanted between 2001 and 2010 were identified. This group included 57 females and 58 males with a median age of 50 years (range: 26-68). Patients evaluated in this study were adult patients with hematologic malignancies, who received transplants from an HLA-matched sibling donor or matched unrelated donor (MUD) at allele level so-called 10/10, and received the RIC regimen including fludarabine/busulfan and anti-thymoglobulin (ATG). Mixed T-cell chimerism was defined as between 5 and 94% recipient cells, and full chimerism was defined as the presence of more than 95% donor T-cell chimerism (TCC). Full donor TCC was achieved in 93 patients (81%) at a median of 77 days (range: 30-120) post-transplant. The cumulative incidence of Grade 2-4 GVHD in our population was 25% (95% CI 17-34). The analysis of the population of patients with acute GVHD grade ≥2 showed that at day 120 after Allo-SCT they all had a total full donor TCC. On the other hand, 78 (68%) patients without acute GVHD grade ≥2 presented with mixed chimerism (p = 0.002) on day 120 post-transplant. Interestingly, patients who received ATG 5 mg/kg obtained a higher probability of complete chimerism compared with those receiving 2.5 mg/kg (p = 0.03). In conclusion, our study demonstrates that acute GVHD was predictive of full donor TCC after RIC Allo-SCT. Therefore, our data may challenge the concept of the frequent or close monitoring of donor chimerism in some patients with ongoing acute GVHD. However, chimerism testing could represent

  13. Hydrogen therapy may be an effective and specific novel treatment for Acute Graft-versus-host disease (GVHD)

    PubMed Central

    Qian, Liren; Shen, Jianliang

    2013-01-01

    Allogeneic haematopoietic stem cell transplantation (HSCT) has been widely used for the treatment of haematological malignant and non-malignant haematologic diseases. However, acute graft-versus-host disease (aGVHD) is a kind of severe complication of HSCT limiting its application. Cytokines such as tumour necrosis factor-α (TNF-α), IL-6 play an extremely important role in the formation and development of aGVHD. Besides, the oxidation phenomena and/or the formation of free radicals have been suggested to be causally related to various haematological disorders including aGVHD. Reactive oxygen species (ROS), such as hydroxyl radicals, play an important role in the formation and development of aGVHD. Hydrogen has been reported to have the ability to inhibit levels of cytokines such as TNF, IL-6 in vivo. Our recent studies provided evidence that hydrogen inhalation can selectively reduce cytotoxic oxygen radicals and exert antioxidant effects. Therefore, we suggested that hydrogen may have therapeutic effects on aGVHD. This hypothesis entails many experimentally testable predictions. We propose the experimental study by detecting complete blood counts (CBC) and Clinic signs of aGVHD mice. We also propose to detect the levels of TNF-α, IL-2, IL-1β, IL-6 which play important roles in the pathogenesis of aGVHD. To discover potential mechanisms of the therapeutic effects of hydrogen on the aGVHD model, we will examine gene-expression profiles. This study will open a new therapeutic avenue combining the field of therapeutic medical gases and aGVHD. This theory is original and probably of importance, because therapeutic medical gases have never been used for aGVHD previously. PMID:23742028

  14. 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. PMID:25452614

  15. 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

  16. 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.

  17. Comparison of Tacrolimus and Sirolimus (Tac/Sir) versus Tacrolimus, Sirolimus, and mini-methotrexate (Tac/Sir/Mtx) as Acute GVHD Prophylaxis after Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation

    PubMed Central

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

    2009-01-01

    Previous studies have shown that the addition of sirolimus to tacrolimus/mini-methotrexate (tac/sir/mtx) as GVHD prophylaxis produces low rates of acute GVHD after reduced intensity (RIC) allogeneic SCT. To assess whether the post transplant methotrexate can be safely eliminated altogether, we conducted a prospective clinical trial testing the combination of tacrolimus and silrolimus (tac/sir) alone as GVHD prophylaxis after RIC SCT from matched related donors. We compare 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 on both trials received fludarabine 30 mg/m2/d IV and intravenous busulfan 0.8 mg/kg/d IV from day −5 through day −2 as conditioning, followed by transplantation of unmanipulated filgrastim mobilized peripheral blood stem cells. Both cohorts received tacrolimus and sirolimus orally starting on day-3, with doses adjusted to achieve trough serum levels of 5–10 ng/ml and 3–12 ng/ml, respectively. The tac/sir/mtx cohort received additional mini-methotrexate (5 mg/m2 IV) on day +1,3,6. Filgrastim 5 mcg/kg SC QD was started on day +1 until neutrophil engraftment. Twenty nine patients were transplanted on tac/sir, and 46 were transplanted on tac/sir/mtx. The two groups were balanced in age, gender, and disease characteristics. Engraftment was brisk and donor chimerism after transplant was robust in both groups. The cumulative incidence of grade II–IV acute GVHD were similar, 17% vs 11% for the tac/sir and tac/sir/mtx cohorts, respectively (p=0.46). There was also no difference in cumulative incidence of extensive chronic GVHD, treatment related mortality, disease relapse, or survival. The GVHD prophylaxis combination of tacrolimus and sirolimus is well tolerated, and is associated with a low incidence of acute GVHD in matched related donor RIC transplantation. The omission of mini-methotrexate from the tacrolimus and sirolimus GVHD

  18. The Effect of GVHD on Long-term Outcomes after Peripheral Blood Allogeneic Stem Cell Transplantation from an HLA-identical Sibling in Adult Acute Lymphocytic Leukemia: A Landmark Analysis Approach in Competing Risks.

    PubMed

    Jalali, Arash; Alimoghaddam, Kamran; Mahmoudi, Mahmood; Mohammad, Kazem; Mousavi, Seied Asadollah; Bahar, Babak; Vaezi, Mohammad; Zeraati, Hojjat; Jahani, Mohammad; Ghavamzadeh, Ardeshir

    2014-01-01

    Allogeneic Hematopoietic stem cell transplantation (HSCT) is the most effective therapy to prevent relapse in acute lymphocytic leukemia (ALL). This benefit is affected by non-relapse mortality (NRM) due to complications such as graft versus host disease (GVHD). A new approach in analyzing time-dependent covariates in competing risks is landmark analysis. So, the aim of this study is to evaluate the effect of acute and chronic GVHD on long-term outcomes, relapse and NRM, after allogeneic HSCT in adult ALL using landmark analysis. This study was conducted on 252 ALL patients who were allogeneic transplanted from an HLA-identical sibling with peripheral blood (PB) as the source of stem cell from 2004 to 2012 and were followed-up until 2013. In the first 100 days after transplant, a landmark analysis on days +10, +11, +12, +17, +24, and +31 was applied to assess the effect of acute GVHD on early relapse and NRM. Similarly, for patients alive and event-free at day +100 after transplant, a landmark analysis at time points day +101, months +4, +5, +6, +9, and +12 was applied to evaluate the effect of chronic GVHD on late relapse and NRM. Five-year LFS and OS were 35.0% (95% CI: 29.1, 42.2%) and 37.5% (95% CI: 31.3, 45.0%), respectively. Five-year cumulative incidence of relapse was 44.5% (95% CI: 37.9, 51.0%) while this was 20.4% (95% CI: 15.4, 26.0%) for NRM. The landmark analysis in the first 100 days after transplant showed that the grade III/IV of aGVHD has a lower risk of relapse but higher risk of NRM after adjustment for the EBMT risk score. For patients alive at day +100, cGVHD had no significant effect on relapse. Limited cGVHD had lower risk of NRM and after 6 month post-transplant the risk of NRM decreased and there were not important difference between the groups of cGVHD. Using advanced models enables us to estimate the effects more precisely and ultimately make inference more accurately.

  19. Intestinal aGVHD and infection after hematopoietic stem cell transplantation

    PubMed Central

    Hou, Cai-yan; Xu, Li-li; Chen, Hu; Liu, Na; Jiang, Ming; Wang, Guo-quan; Zhang, Linlin; Wang, Xiao-hong; Zeng, Yan-jun

    2013-01-01

    Background We aimed to guide clinical nursing by studying the relationship between intestinal acute graft-versus-host disease and intestinal infection after hematopoietic stem cell transplantation. Material/Methods We present an effective nursing method by comparing and analyzing the degree, duration time, and volume of diarrhea, and the distribution of pathogens in 44 patients who developed intestinal aGVHD after hematopoietic stem cell transplantation (24 patients with no intestinal infection). Results 21.4% of patients with grade I–II intestinal aGVHD developed into intestinal infection and 87.5% of patients with grade III–IV intestinal aGVHD developed into intestinal infection (P<0.05). Higher mortality was found in the grade III–IV intestinal aGVHD patients with intestinal infection. Patient age had no effect on the incidence of GVHD according to our data (P<0.05). We found remarkable differences in the amount and duration of diarrhea between patients with and without intestinal infection (P<0.05). The most common pathogens cultivated were Candida glabrata (24%) and Candida albicans (22.67%). Conclusions The incidence of intestinal infection increased remarkably after intestinal aGVHD occurred. Severe aGVHD can easily lead to fungus infection. Nursing care can decrease the incidence of intestinal infection in aGVHD. PMID:24077343

  20. Protection of acute GVHD by all-trans retinoic acid through suppression of T cell expansion and induction of regulatory T cells through IL-2 signaling.

    PubMed

    Yang, Haojun; Gu, Jian; Zhu, Qin; Lu, Hao; Wang, Kunpeng; Ni, Xuhao; Lu, Yunjie; Lu, Ling

    2015-10-01

    All-trans retinoic acid (atRA), the active derivative of vitamin A, has been shown to regulate Treg and T effector cell differentiation. However, the potential use of atRA as a treatment for acute graft-verse-host disease (aGVHD) has not been realized. Here we studied the ability of atRA to prevent and treat acute-GVHD in the B6-to-F1(D2B6F1) murine model. Our results showed that atRA consistently displayed a potent ability to control aGVHD development and reduce mortality by suppressing the expansion of donor T cells and inhibiting cytokine expression from donor CD8 cells. Interestingly, CD4(+)Foxp3(+) regulatory T cells were markedly increased in the spleens of atRA-treated mice. In vitro treatment with atRA inhibited T cell proliferation in a dose-dependent manner. Injection of an anti-IL-2 antibody impaired the protection by atRA in aGVHD. Therefore, these results strongly implicate atRA as a novel therapeutic strategy for controlling aGVHD progression and treating other inflammatory diseases. PMID:25864619

  1. Skin and kidney histological changes in graft-versus-host disease (GVHD) after kidney transplantation.

    PubMed

    Pintar, Tadeja; Alessiani, Mario; Pleskovič, Alojz; Pleskovič, Aleš; Zorc-Pleskovič, Ruda; Milutinović, Aleksandra

    2011-05-01

    Kidney transplantation (Ktx) is generally performed during end stage renal disease due to a loss of the kidneys' ability to filter wastes from the circulatory system. Acute graft-versus-host disease (GVHD) after Ktx is a life-threatening complication that progresses to organ failure, systemic complications, and death. The current study evaluated the significance of histologic findings of GVHD as obtained from skin biopsies following Ktx in swine. A swine model of Ktx with tacrolimus-based immunosuppression was used to assess possible correlations between acute-graft-cellular rejection and skin histological findings for prediction of GVHD. Animals were divided into a Ktx treatment group or a control group with no Ktx and skin and kidney biopsies were histologically assessed at postoperative days 0, 15, 30, 45 and 60. Skin samples were analyzed and classified from grade 1 to 4 of skin GVHD and the major histopathological changes of kidney acute cellular rejection were described using Banff's score system. We observed a significant linear correlation between the histological grading values of skin biopsy changes and the histological grading values of kidney biopsies (Kendall's tau_b=0.993) in the Ktx experimental group. No histological changes were observed in controls. Our findings demonstrate the diagnostic value of staging skin GVHD after Ktx and suggest it's future utility for monitoring long term Ktx-induced changes.

  2. Double umbilical cord blood transplantation with reduced intensity conditioning and sirolimus-based GVHD prophylaxis.

    PubMed

    Cutler, C; Stevenson, K; Kim, H T; Brown, J; McDonough, S; Herrera, M; Reynolds, C; Liney, D; Kao, G; Ho, V; Armand, P; Koreth, J; Alyea, E; Dey, B R; Attar, E; Spitzer, T; Boussiotis, V A; Ritz, J; Soiffer, R; Antin, J H; Ballen, K

    2011-05-01

    The main limitations to umbilical cord blood (UCB) 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 GVHD remains a significant problem. We describe our experience in 32 subjects, who underwent DUCBT after reduced-intensity conditioning with fludarabine/melphalan/antithymocyte 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 four subjects (cumulative incidence 12.5%). No deaths were caused by GVHD and NRM at 100 days was 12.5%. At 2 years, NRM, PFS and 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 the 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.

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

    ClinicalTrials.gov

    2016-04-28

    Aggressive Non-Hodgkin Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm; 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 Diffuse Large B-Cell Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Plasma Cell Myeloma; Waldenstrom Macroglobulinemia

  4. Risk Factors, Pattern and Clinical Outcome of Acute Graft Versus Host Disease in Acute Leukemia Patients Undergoing Allogeneic Stem Cell Transplant.

    PubMed

    Gupta, Alok; Punatar, Sachin; Gawande, Jayant; Mathew, Libin; Bagal, Bhausaheb; Kannan, Sadhana; Khattry, Navin

    2015-12-01

    We sought to determine risk factors, pattern and outcome of acute graft versus host disease (aGVHD) in seventy-seven acute leukemia patients who underwent allogeneic stem cell transplant at our centre from January 2008 to March 2013. GVHD prophylaxis with cyclosporine-methotrexate or cyclosporine-mycophenolate mofetil was used. Patients were divided in 2 groups, grade II-IV aGVHD (group A) and grade 0-I aGVHD (group B). Incidence of any grade and grade II-IV aGVHD was 44 and 18 %, respectively. The most common site of aGVHD was gastro-intestinal tract (65 %) followed by skin (35 %). Higher total nucleated cell (TNC) dose infused was associated with increased incidence of grade II-IV aGVHD. Incidence of relapse and incidence of slippage of chimerism was 21 and 36 % in group A while 37 and 27 % in group B respectively. Transplant related mortality (TRM) was 21 % in group A and 13 % in group B. Probability of OS and RFS at 4 years was 63 and 34 % in group A compared with 40 and 38 % in group B, respectively. We conclude that higher TNC dose infused is a risk factor for grade II-IV aGVHD with gut being the commonest site. Grade II-IV aGVHD did not have a significant impact on incidence of relapse, TRM and OS.

  5. Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS

    PubMed Central

    Kanakry, Christopher G.; Tsai, Hua-Ling; Bolaños-Meade, Javier; Smith, B. Douglas; Gojo, Ivana; Kanakry, Jennifer A.; Kasamon, Yvette L.; Gladstone, Douglas E.; Matsui, William; Borrello, Ivan; Huff, Carol Ann; Swinnen, Lode J.; Powell, Jonathan D.; Pratz, Keith W.; DeZern, Amy E.; Showel, Margaret M.; McDevitt, Michael A.; Brodsky, Robert A.; Levis, Mark J.; Ambinder, Richard F.; Fuchs, Ephraim J.; Rosner, Gary L.; Jones, Richard J.

    2014-01-01

    High-dose, posttransplantation cyclophosphamide (PTCy) reduces severe graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT), but the impact of PTCy on long-term, disease-specific outcomes is unclear. We conducted a retrospective study of 209 consecutive adult patients transplanted for acute myeloid leukemia (AML, n = 138), myelodysplastic syndrome (n = 28), or acute lymphoblastic leukemia (ALL, n = 43) using PTCy as sole GVHD prophylaxis after myeloablative conditioning and HLA-matched–related or –unrelated T-cell–replete allografting. At alloBMT, 30% of patients were not in morphologic complete remission. The cumulative incidences of grades II to IV and III to IV acute GVHD at 100 days and chronic GVHD at 2 years were 45%, 11%, and 13%, respectively. Forty-three percent of patients did not require immunosuppression for any reason beyond PTCy. At 3 years, relapse cumulative incidence was 36%, disease-free survival was 46%, survival free of disease and chronic GVHD was 39%, and overall survival was 58%. Lack of remission at alloBMT, adverse cytogenetics, and low allograft nucleated cell dose were associated with inferior survival for AML patients. Minimal residual disease but not t(9;22) was associated with inferior outcomes for ALL patients. The ability to limit posttransplantation immunosuppression makes PTCy a promising transplantation platform for the integration of postgrafting strategies to prevent relapse. PMID:25316679

  6. PHASE II TRIAL OF GVHD PROPHYLAXIS WITH POST-TRANSPLANTATION CYCLOPHOSPHAMIDE FOLLOWING REDUCED-INTENSITY BUSULFAN/FLUDARABINE (BU/FLU) CONDITIONING FOR HEMATOLOGICAL MALIGNANCIES

    PubMed Central

    Alousi, Amin M.; Brammer, Jonathan E.; Saliba, Rima M.; Andersson, Borje; Popat, Uday; Hosing, Chitra; Jones, Roy; Shpall, Elizabeth J; Khouri, Issa; Qazilbash, Muzaffar; Nieto, Yago; Shah, Nina; Ahmed, Sairah; Oran, Betul; Atrash, Gheath Al; Ciurea, Stefan; Kebriaei, Partow; Chen, Julianne; Rondon, Gabriela; Champlin, Richard

    2016-01-01

    GVHD-prophylaxis with post-transplant cyclophosphamide (CY) following ablative HLA-matched bone marrow (BM) transplantation has been reported to have comparable rates of acute GVHD with an apparent reduction in chronic GVHD and infections. We conducted a phase II trial of post-CY following reduced-intensity conditioning (RIC) using intravenous busulfan (AUC of 4,000 micromolar-minutes), Fludarabine (40mg/m2) for 4 days and CY 50mg/kg on days +3 and +4 following BM or peripheral blood (PB) transplants from matched related (MRD) or unrelated donors (MUD). MUD- recipients received anti-thymocyte globulin (ATG); however, a later amendment removed ATG. 49 patients were treated (AML/MDS: 82%). Median age was 62 years (range, 39–72). Fifteen patients received a MRD (9 PB/6 BM); 34 had a MUD (2 PB/32 BM). The cumulative incidence of grade II–IV, III–IV acute and chronic GVHD was 58%, 22% and 18%. A matched-cohort analysis compared outcomes to tacrolimus/methotrexate GVHD prophylaxis and indicated higher rates of acute GVHD grade II–IV (46% versus 19%, HR=2.8, p=0.02) and treatment-related mortality (HR 3.3, p=0.035) and worse overall survival (HR=1.9, p=0.04) with post-Cy. The incidence of chronic GVHD and CMV reactivation did not differ. This study suggests that post-transplant CY should not be used as sole GVHD-prophylaxis following a RIC transplant from HLA matched donors. PMID:25667989

  7. Etiology of GVHD: alloreactivity or impaired cellular adaptation?

    PubMed

    Manjili, Masoud H; Toor, Amir A

    2014-01-01

    According to the self-nonself model of immunity, allogeneic T cells are considered as major cause of graft versus host disease (GVHD) following allogeneic stem cell transplantation (SCT). On the other hand, the danger model of immunity suggests that transplant-associated recipient tissue injury rather than donor-derived alloreactive T cells is the main cause of GVHD. What has been less appreciated are the early, both conditioning-dependent and conditioning-independent, events that impair homeostatic cellular adaptations and host-protective immune responses leading to the development of tissue-specific GVHD. The notion of gut injury precipitating in GVHD has been acknowledged by clinicians, with the shift to reduced intensity-conditioning regimens that prevent acute tissue injury and are less disruptive of tissue adaptation to T cell attack. Also, the role of host-protective immune response against pathogens in preventing GVHD has been shown by the lack of severe GVHD in germ free mice as well as an impaired anti-viral immune response during chronic GVHD. This article provides a brief review of the literature on GVHD and suggests that transplant-induced dysregulation of the protective immune response in the recipient of SCT is more important than allogeneic T cells in causing GVHD. PMID:25296238

  8. Acute GVHD results in a severe DC defect that prevents T-cell priming and leads to fulminant cytomegalovirus disease in mice.

    PubMed

    Wikstrom, Matthew E; Fleming, Peter; Kuns, Rachel D; Schuster, Iona S; Voigt, Valentina; Miller, Gregory; Clouston, Andrew D; Tey, Siok-Keen; Andoniou, Christopher E; Hill, Geoffrey R; Degli-Esposti, Mariapia A

    2015-09-17

    Viral infection is a common, life-threatening complication after allogeneic bone marrow transplantation (BMT), particularly in the presence of graft-versus-host disease (GVHD). Using cytomegalovirus (CMV) as the prototypic pathogen, we have delineated the mechanisms responsible for the inability to mount protective antiviral responses in this setting. Although CMV infection was self-limiting after syngeneic BMT, in the presence of GVHD after allogeneic BMT, CMV induced a striking cytopathy resulting in universal mortality in conjunction with a fulminant necrotizing hepatitis. Critically, GVHD induced a profound dendritic cell (DC) defect that led to a failure in the generation of CMV-specific CD8(+) T-cell responses. This was accompanied by a defect in antiviral CD8(+) T cells. In combination, these defects dramatically limited antiviral T-cell responses. The transfer of virus-specific cells circumvented the DC defects and provided protective immunity, despite concurrent GVHD. These data demonstrate the importance of avoiding GVHD when reconstructing antiviral immunity after BMT, and highlight the mechanisms by which the adoptive transfer of virus-specific T cells overcome the endogenous defects in priming invoked by GVHD.

  9. Quantitative analysis of eosinophils in acute graft-versus-host disease compared with drug hypersensitivity reactions.

    PubMed

    Weaver, Joshua; Bergfeld, Wilma F

    2010-02-01

    Acute graft-versus-host disease (aGVHD), if not detected and treated early, is a common cause of morbidity and mortality. Drug hypersensitivity reactions (DHRs), the most frequent clinical and histopathological mimickers of early aGVHD, are often still distinguished from aGVHD by the presence of eosinophils within the inflammatory infiltrate on skin biopsy. Distinguishing these entities is important because the delay of appropriate treatment of aGVHD may lead to advanced stages of the disease process with a poor prognosis. To determine whether the existence or amount of eosinophilic infiltrate could be used to differentiate these entities, we employed a quantitative method of analyzing eosinophils in skin biopsies of rashes from patients with aGVHD and DHR. Eosinophils were counted in 50 high-power fields (HPFs) in skin biopsies of patients with clinical grade >or=2 aGVHD (+aGVHD), with clinical grade <2 aGVHD (-aGVHD), and those with clinical DHR (+DHR). The average number of eosinophils per 10 HPFs (ave. eos/10 HPFs) increased throughout each group. The ave. eos/10 HPFs in +DHR was significantly different from both aGVHD groups (P < 0.001). The specificity to completely rule out aGVHD did not reach 100% until 16.0 ave. eos/10 HPFs was observed. There is a significant difference between the numbers of eosinophils found in differentiating DHR from aGVHD, but a very high number (>16.0 ave. eos/10 HPFs) is necessary to rule out aGVHD completely. Therefore, a quantitative analysis of eosinophils in all biopsies to rule out aGVHD would be of limited value and should only be considered in those biopsies with significant eosinophilia.

  10. Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival.

    PubMed

    Malard, Florent; Labopin, Myriam; Chevallier, Patrice; Guillaume, Thierry; Duquesne, Alix; Rialland, Fanny; Derenne, Sophie; Peterlin, Pierre; Leauté, Anne-Gaelle; Brissot, Eolia; Gregoire, Marc; Moreau, Philippe; Saas, Philippe; Gaugler, Béatrice; Mohty, Mohamad

    2016-04-01

    We studied the impact of a set of immune cells contained within granulocyte colony-stimulating factor-mobilized peripheral blood stem cell grafts (naïve and memory T-cell subsets, B cells, regulatory T cells, invariant natural killer T cells [iNKTs], NK cells, and dendritic cell subsets) in patients (n = 80) undergoing allogeneic stem cell transplantation (SCT), using the composite end point of graft-versus-host disease (GVHD)-free and progression-free survival (GPFS) as the primary end point. We observed that GPFS incidences in patients receiving iNKT doses above and below the median were 49% vs 22%, respectively (P= .007). In multivariate analysis, the iNKT dose was the only parameter with a significant impact on GPFS (hazard ratio = 0.48; 95% confidence interval, 0.27-0.85;P= .01). The incidences of severe grade III to IV acute GVHD and National Institutes of Health grade 2 to 3 chronic GVHD (12% and 16%, respectively) were low and associated with the use of antithymocyte globulin in 91% of patients. No difference in GVHD incidence was reported according to the iNKT dose. In conclusion, a higher dose of iNKTs within the graft is associated with an improved GPFS. These data may pave the way for prospective and active interventions aiming to manipulate the graft content to improve allo-SCT outcome.

  11. IL-35 mitigates murine acute graft-versus-host disease with retention of graft-versus-leukemia effects.

    PubMed

    Liu, Y; Wu, Y; Wang, Y; Cai, Y; Hu, B; Bao, G; Fang, H; Zhao, L; Ma, S; Cheng, Q; Song, Y; Liu, Y; Zhu, Z; Chang, H; Yu, X; Sun, A; Zhang, Y; Vignali, D A A; Wu, D; Liu, H

    2015-04-01

    IL-35 is a newly discovered inhibitory cytokine secreted by regulatory T cells (Tregs) and may have therapeutic potential in several inflammatory disorders. Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation and caused by donor T cells and inflammatory cytokines. The role of IL-35 in aGVHD is still unknown. Here we demonstrate that IL-35 overexpression suppresses CD4(+) effector T-cell activation, leading to a reduction in alloreactive T-cell responses and aGVHD severity. It also leads to the expansion of CD4(+)Foxp3(+) Tregs in the aGVHD target organs. Furthermore, IL-35 overexpression results in a selective decrease in the frequency of Th1 cells and an increase of IL-10-producing CD4(+) T cells in aGVHD target tissues. Serum levels of TNF-α, IFN-γ, IL-6, IL-22 and IL-23 decrease and IL-10 increases in response to IL-35. Most importantly, IL-35 preserves graft-versus-leukemia effect. Finally, aGVHD grade 2-4 patients have decreased serum IL-35 levels comparing with time-matched patients with aGVHD grade 0-1. Our findings indicate that IL-35 has an important role in reducing aGVHD through promoting the expansion of Tregs and repressing Th1 responses, and should be investigated as the therapeutic strategy for aGVHD.

  12. 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.

  13. Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention.

    PubMed

    Furlan, Scott N; Watkins, Benjamin; Tkachev, Victor; Flynn, Ryan; Cooley, Sarah; Ramakrishnan, Swetha; Singh, Karnail; Giver, Cindy; Hamby, Kelly; Stempora, Linda; Garrett, Aneesah; Chen, Jingyang; Betz, Kayla M; Ziegler, Carly G K; Tharp, Gregory K; Bosinger, Steven E; Promislow, Daniel E L; Miller, Jeffrey S; Waller, Edmund K; Blazar, Bruce R; Kean, Leslie S

    2015-11-25

    Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplant (HCT). However, our understanding of the molecular pathways that cause this disease remains incomplete, leading to inadequate treatment strategies. To address this, we measured the gene expression profile of nonhuman primate (NHP) T cells during acute GVHD. Utilizing microarray technology, we measured the expression profiles of CD3(+) T cells from five cohorts: allogeneic transplant recipients receiving (i) no immunoprophylaxis (No Rx), (ii) sirolimus monotherapy (Siro), (iii) tacrolimus-methotrexate (Tac-Mtx), as well as (iv) autologous transplant recipients (Auto) and (v) healthy controls (HC). This comparison allowed us to identify transcriptomic signatures specific for alloreactive T cells and determine the impact of both mTOR (mechanistic target of rapamycin) and calcineurin inhibition on GVHD. We found that the transcriptional profile of unprophylaxed GVHD was characterized by significant perturbation of pathways regulating T cell proliferation, effector function, and cytokine synthesis. Within these pathways, we discovered potentially druggable targets not previously implicated in GVHD, prominently including aurora kinase A (AURKA). Utilizing a murine GVHD model, we demonstrated that pharmacologic inhibition of AURKA could improve survival. Moreover, we found enrichment of AURKA transcripts both in allo-proliferating T cells and in sorted T cells from patients with clinical GVHD. These data provide a comprehensive elucidation of the T cell transcriptome in primate acute GVHD and suggest that AURKA should be considered a target for preventing GVHD, which, given the many available AURKA inhibitors in clinical development, could be quickly deployed for the prevention of GVHD. PMID:26606970

  14. Dermoscopic Follow-Up of the Skin towards Acute Graft-versus-Host-Disease in Patients after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Kaminska-Winciorek, Grazyna; Czerw, Tomasz; Kruzel, Tomasz; Giebel, Sebastian

    2016-01-01

    Background. Acute graft-versus-host disease (aGVHD) involving skin is one of the most frequent complications of allogeneic hematopoietic stem cell transplantation (alloHSCT), usually diagnosed based on clinical manifestations. So far, skin biopsy with histopathological evaluation is the only method to confirm the diagnosis. Objective. In this prospective study we monitored alloHSCT recipients by dermoscopy in order to assess its utility as an alternative noninvasive tool to early diagnose acute GVHD. Methods. Thirteen consecutive patients who received alloHSCT were examined clinically and dermoscopically towards aGVHD [days 28 (±7), 56 (±7), and 100 (±7)], as well as in each patient who developed cutaneous aGVHD diagnosed according to clinical criteria (Glucksberg scale). Results. Six patients (46%) developed symptoms of cutaneous acute GVHD (grade 1, n = 3; grade 2, n = 3). Dermoscopic evaluation revealed pinkish or reddish background and well-visible, multiple thin telangiectasias. Conclusion. To our knowledge, this is the first report on the use of dermoscopy to evaluate skin involvement in the course of acute GVHD suggesting its role as a diagnostic tool in follow-up of GVHD, which can be also used before clinical symptoms occur. PMID:27446950

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

    PubMed Central

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

    2016-01-01

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

  16. Early changes in gene expression profiles of hepatic GVHD uncovered by oligonucleotide microarrays.

    PubMed

    Ichiba, Tamotsu; Teshima, Takanori; Kuick, Rork; Misek, David E; Liu, Chen; Takada, Yuichiro; Maeda, Yoshinobu; Reddy, Pavan; Williams, Debra L; Hanash, Samir M; Ferrara, James L M

    2003-07-15

    The liver, skin, and gastrointestinal tract are major target organs of acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT). In order to gain a better understanding of acute GVHD in the liver, we compared the gene expression profiles of livers after experimental allogeneic and syngeneic BMT using oligonucleotide microarray. At 35 days after allogeneic BMT when hepatic GVHD was histologically evident, genes related to cellular effectors and acute-phase proteins were up-regulated, whereas genes largely related to metabolism and endocrine function were down-regulated. At day 7 after BMT before the development of histologic changes in the liver, interferon gamma (IFN-gamma)-inducible genes, major histocompatibility (MHC) class II molecules, and genes related to leukocyte trafficking had been up-regulated. Immunohistochemistry demonstrated that expression of IFN-gamma protein itself was increased in the spleen but not in hepatic tissue. These results suggest that the increased expression of genes associated with the attraction and activation of donor T cells induced by IFN-gamma early after BMT is important in the initiation of hepatic GVHD in this model and provide new potential molecular targets for early detection and intervention of acute GVHD.

  17. [Differential regulation of CCR5 expression on T lymphocytes in healthy donors after mobilization with rhG-CSF and its correlation with aGVHD].

    PubMed

    Wang, Meng; Ma, Xiang-Juan; Dong, Yu-Jun; Qiu, Zhi-Xiang; Liu, Wei; Li, Yuan; Wang, Mang-Ju; Sun, Yu-Hua; Ren, Han-Yun

    2013-08-01

    This study was to investigate the differential regulation of CCR5 expression on T cells in healthy donors after mobilization with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and analyze its correlation with acute graft-versus-host disease (aGVHD) so as to understand the possible mechanisms underlying rhG-CSF-induced immune tolerance. Sixty-eight related healthy donor and their corresponding recipient for allogeneic hematopoietic stem cell transplantation (allo-HSCT) were enrolled in this study. The expression of CCR5 on CD4(+) and CD8(+) T cells in the peripheral blood (PB) before and after mobilization were detected by using flow cytometry (FCM) respectively. According to the changes of CCR5 expression on CD4(+) and CD8(+) T cells, the Sixty-two evaluable donors were divided into the downregulated and unchanged/upregulated (non-downregulated) groups, and the incidence of grades II to IV aGVHD in two groups were compared. The results showed that the mean value of CCR5 expression on CD4(+) and CD8(+) T cells in PB was not different significantly after mobilization (P > 0.05). Apparent inconsistency was showed among different individuals. Thirty-four (50%) donors displayed downregulation of CCR5 expression, while 34 (50%) donors manifested unchanged or upregulated CCR5 expression on CD4(+) T cells. CCR5 expression on CD8(+) T cells was downregulated in 42 (61.8%), unchanged or upregulated in 26 (38.3%) donors. The cumulative incidence of grades II to IV aGVHD in the downregulated and non-downregulated groups for CD4(+) T cells were 16.1% and 41.9% (P = 0.032), and recipients with CCR5 downregulation on CD8(+) T cells showed an increased tendency of developing aGVHD (37.8% vs 16.0%, P = 0.065). In conclusion, rhG-CSF mobilization could lead to differential regulation of CCR5 expression on T cells, which might influence the migration of T cells in vivo, decrease T cell trafficking towards GVHD target organs, and thus reduce the incidence of aGVHD

  18. [Differential regulation of CCR5 expression on T lymphocytes in healthy donors after mobilization with rhG-CSF and its correlation with aGVHD].

    PubMed

    Wang, Meng; Ma, Xiang-Juan; Dong, Yu-Jun; Qiu, Zhi-Xiang; Liu, Wei; Li, Yuan; Wang, Mang-Ju; Sun, Yu-Hua; Ren, Han-Yun

    2013-08-01

    This study was to investigate the differential regulation of CCR5 expression on T cells in healthy donors after mobilization with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and analyze its correlation with acute graft-versus-host disease (aGVHD) so as to understand the possible mechanisms underlying rhG-CSF-induced immune tolerance. Sixty-eight related healthy donor and their corresponding recipient for allogeneic hematopoietic stem cell transplantation (allo-HSCT) were enrolled in this study. The expression of CCR5 on CD4(+) and CD8(+) T cells in the peripheral blood (PB) before and after mobilization were detected by using flow cytometry (FCM) respectively. According to the changes of CCR5 expression on CD4(+) and CD8(+) T cells, the Sixty-two evaluable donors were divided into the downregulated and unchanged/upregulated (non-downregulated) groups, and the incidence of grades II to IV aGVHD in two groups were compared. The results showed that the mean value of CCR5 expression on CD4(+) and CD8(+) T cells in PB was not different significantly after mobilization (P > 0.05). Apparent inconsistency was showed among different individuals. Thirty-four (50%) donors displayed downregulation of CCR5 expression, while 34 (50%) donors manifested unchanged or upregulated CCR5 expression on CD4(+) T cells. CCR5 expression on CD8(+) T cells was downregulated in 42 (61.8%), unchanged or upregulated in 26 (38.3%) donors. The cumulative incidence of grades II to IV aGVHD in the downregulated and non-downregulated groups for CD4(+) T cells were 16.1% and 41.9% (P = 0.032), and recipients with CCR5 downregulation on CD8(+) T cells showed an increased tendency of developing aGVHD (37.8% vs 16.0%, P = 0.065). In conclusion, rhG-CSF mobilization could lead to differential regulation of CCR5 expression on T cells, which might influence the migration of T cells in vivo, decrease T cell trafficking towards GVHD target organs, and thus reduce the incidence of aGVHD

  19. Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity.

    PubMed

    Vaeth, Martin; Bäuerlein, Carina A; Pusch, Tobias; Findeis, Janina; Chopra, Martin; Mottok, Anja; Rosenwald, Andreas; Beilhack, Andreas; Berberich-Siebelt, Friederike

    2015-01-27

    Graft-versus-host disease (GvHD) is a life-threatening immunological complication after allogenic hematopoietic stem cell transplantation (allo-HCT). The intrinsic graft-versus-leukemia (GvL) effect, however, is the desirable curative benefit. Patients with acute GvHD are treated with cyclosporine A (CsA) or tacrolimus (FK506), which not only often causes severe adverse effects, but also interferes with the anticipated GvL. Both drugs inhibit calcineurin, thus at first suppressing activation of the nuclear factor of activated T cells (NFAT). Therefore, we explored the specific contribution of individual NFAT factors in donor T cells in animal models of GvHD and GvL. Ablation of NFAT1, NFAT2, or a combination of both resulted in ameliorated GvHD, due to reduced proliferation, target tissue homing, and impaired effector function of allogenic donor T cells. In contrast, the frequency of Foxp3(+) regulatory T (Treg) cells was increased and NFAT-deficient Tregs were fully protective in GvHD. CD8(+) T-cell recall response and, importantly, the beneficial antitumor activity were largely preserved in NFAT-deficient effector T cells. Thus, specific inhibition of NFAT opens an avenue for an advanced therapy of GvHD maintaining protective GvL.

  20. Haploidentical hematopoietic stem cell transplantation without total body irradiation for pediatric acute leukemia: a single-center experience

    PubMed Central

    Mu, Yanshun; Qin, Maoquan; Wang, Bin; Li, Sidan; Zhu, Guanghua; Zhou, Xuan; Yang, Jun; Wang, Kai; Lin, Wei; Zheng, Huyong

    2016-01-01

    Hematopoietic stem cell transplantation (HSCT) is a promising method for therapy of pediatric patients with acute leukemia. However, less availability of matched donors limited its wide application. Recently, haploidentical HSCT has become a great resource. Here, we have retrospectively reported our experience of 20 pediatric patients with acute leukemia who underwent haploidentical HSCT without total body irradiation (TBI) myeloablative regimen in our center from November 2007 to June 2014. All the patients attained successful HSCT engraftment in terms of myeloid and platelet recovery. Thirteen patients developed grade I–IV acute graft-versus-host disease (a-GVHD). The incidence of grade I–II a-GVHD, grade III–IV a-GVHD, and chronic GVHD (c-GVHD) was 45%, 20%, and 25%, respectively. The mean myeloid and platelet recovery time was 13.20±2.41 and 19.10±8.37 days. The median follow-up time was 43.95±29.26 months. During the follow-up, three patients died. The overall survival (OS) rate was 85%. The present study indicated that haploidentical HSCT without TBI myeloablative regimen significantly improved the OS rate of pediatric patients with acute leukemia. PMID:27217774

  1. [Correlation of the level of Reg3α protein in plasma with gastrointestinal acute graft-versus-host disease].

    PubMed

    Cai, Cheng-Sen; Chen, Guang-Hua; Sun, Ai-Ning; Qiao, Man; Liu, Hui-Wen; Chen, Feng; Wang, Ying; Qiu, Hui-Ying; Han, Yue; Ma, Xiao; Tang, Xiao-Wen; Jin, Zheng-Ming; Fu, Cheng-Cheng; Wu, De-Pei

    2014-06-01

    This study was purposed to explore the correlation of regenerating Islet-derived 3-alpha(Reg3α) protein level in plasma with the diagnosis and prognosis of the gastrointestinal acute graft-versus-host disease (GI-aGVHD) after all-HSCT, 103 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) were observed in our hospital from December 2011 to December 2012. Peripheral blood samples were routinely collected at 9 d before allo-HSCT, 0 d, 14 d, 28 d after allo-HSCT as well as in aGVHD and at the 1 and 4 weeks after aGVHD therapy. The plasma concentrations of Reg3α were measured by using ELISA kit. The results indicated that among the 103 patients, 17 cases never developed aGVHD symptoms (no-aGVHD), 27 cases presented with non-aGVHD associated diarrhea, 10 cases presented with isolated skin aGVHD, 17 cases developed grades I-II GI-aGVHD, 32 cases with grades III-IV GI-aGVHD. The plasma concentrations of Reg3α in group of patients with GI-aGVHD and group of non-aGVHD diarrhea were 111.5 (54.7-180.2) and 23.9 (14.5-89.5) ng/ml respectively with significant difference (P < 0.001). The plasma concentrations of Reg3α in 17 patients of grades III-IV GI-aGVHD who experienced a complete or partial response and 7 patients who had no response to therapy at 4 weeks were 137.2(51.7-205.4) and 679.4(122.3-896.8) ng/ml respectively with the significant difference (P = 0.028). All of the patients who had no response to therapy died of aGVHD associated multiple organ failure. The area under the ROC curve was 0.902 when plasma concentration of Reg3α was set at 87.73 ng/ml. The sensitivity was 81.48% and the specificity was 82.86% when the critical value was used in diagnosis of grades III-IV GI-aGVHD. The probability of grades III-IV GI-aGVHD had statistical difference above and below 87.73 ng/ml after allo-HSCT (P < 0.001). It is concluded that the increase of plasma Reg3α level after transplantation suggests the incidence of grades III-IV GI-aGVHD

  2. Endothelial-cell injury in cutaneous acute graft-versus-host disease.

    PubMed Central

    Dumler, J. S.; Beschorner, W. E.; Farmer, E. R.; Di Gennaro, K. A.; Saral, R.; Santos, G. W.

    1989-01-01

    The presence of an erythematous skin rash and hemorrhagic complications in acute graft-versus-host disease (GVHD) suggest that the vasculature may be involved in the immunopathologic process. We reviewed endothelial and vascular histopathologic changes on light microscopy and on immunoperoxidase stained sections of skin biopsies obtained from 41 HLA-identical allogeneic marrow transplant recipients with at least grade 2 GVHD. Biopsies taken from 14 allogeneic HLA-identical bone marrow transplant recipients who never developed GVHD were used as controls. Sections were evaluated for evidence of immunologic vascular injury using the rank file analysis of histologic features, expression of HLA-DR antigen, and the distribution of fibrin and factor VIII-related antigen (F VIII RAg). Patients with acute GVHD had significantly greater intimal lymphocytic infiltrates, perivascular nuclear dust deposition, perivascular F VIII Rag extravasation and deposition and vascular proliferation than controls. We find significantly greater endothelial injury in GVHD patients, which may represent primary immunologic injury to the vasculature. The clinical findings in acute GVHD probably result from cumulative endothelial as well as epithelial injury. Images Figure 1 Figure 2 Figure 3 PMID:2596572

  3. 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.

  4. 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

  5. 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 ...

  6. Loss of B7-H1 expression by recipient parenchymal cells leads to expansion of infiltrating donor CD8+ T cells and persistence of GVHD

    PubMed Central

    Li, Xiaofan; Deng, Ruishu; He, Wei; Liu, Can; Wang, Miao; Young, James; Meng, Zhipeng; Du, Chantal; Huang, Wendong; Chen, Lieping; Chen, Yuan-Zhong; Martin, Paul; Forman, Stephen; Zeng, Defu

    2013-01-01

    Previous experimental studies have shown that acute graft-versus-host disease (GVHD) is associated with two waves of donor CD8+ T cell expansion. In the current studies, we used in vivo bioluminescent imaging (BLI), in vivo BrdU-labeling, and three different experimental GVHD systems to show that B7-H1 expression by recipient parenchymal cells controls the second wave of alloreactive donor CD8+ T cell expansion and the associated second phase of GVHD. Loss of B7-H1 expression by parenchymal cells during the course of GVHD was associated with persistent proliferation of donor CD8+ T cells in GVHD target tissues and continued tissue injury, whereas persistent expression of B7-H1 expression by parenchymal cells led to reduced proliferation of donor CD8+ T cells in GVHD target tissues and resolution of GVHD. These studies demonstrate that parenchymal cell expression of B7-H1 is required for tolerizing infiltrating T cells and preventing the persistence of GVHD. Our results suggest that therapies designed to preserve or restore expression of B7-H1 expression by parenchymal tissues in the recipient could prevent or ameliorate GVHD in humans. PMID:22156590

  7. Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence

    PubMed Central

    Arai, Sally; Sahaf, Bita; Narasimhan, Balasubramanian; Chen, George L.; Jones, Carol D.; Lowsky, Robert; Shizuru, Judith A.; Johnston, Laura J.; Laport, Ginna G.; Weng, Wen-Kai; Benjamin, Jonathan E.; Schaenman, Joanna; Brown, Janice; Ramirez, Jessica; Zehnder, James L.; Negrin, Robert S.

    2012-01-01

    B cells are involved in the pathogenesis of chronic GVHD (cGVHD). We hypothesized that prophylactic anti–B-cell therapy delivered 2 months after transplantation would decrease allogeneic donor B-cell immunity and possibly the incidence of cGVHD. Therefore, in the present study, patients with high-risk chronic lymphocytic leukemia (n = 22) and mantle-cell lymphoma (n = 13) received a total lymphoid irradiation of 80 cGy for 10 days and antithymocyte globulin 1.5 mg/kg/d for 5 days. Rituximab (375 mg/m2) was infused weekly on days 56, 63, 70, and 77 after transplantation. The incidence of acute GVHD was 6%. The cumulative incidence of cGVHD was 20%. Nonrelapse mortality was 3%. Rituximab treatment after allogeneic transplantation significantly reduced B-cell allogeneic immunity, with complete prevention of alloreactive H-Y Ab development in male patients with female donors (P = .01). Overall survival and freedom from progression at 4 years for chronic lymphocytic leukemia patients were 73% and 47%, respectively; for mantle-cell lymphoma patients, they were 69% and 53%, respectively. This study is registered at www.clinicaltrials.gov as NCT00186628. PMID:22563089

  8. Reduced IL-35 levels are associated with increased platelet aggregation and activation in patients with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Zhang, Xiaohui; Zhou, Yi; Xu, Lanping; Han, Wei; Chen, Huan; Chen, Yuhong; Fu, Haixia; Zhou, Shiyuan; Zhao, Jingzhong; Wang, Qianming; Feng, Feier; Zhu, Xiaolu; Liu, Kaiyan; Huang, Xiaojun

    2015-05-01

    Acute graft-versus-host disease (aGVHD) is a major complication associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Interleukin (IL)-35 is a novel anti-inflammatory cytokine that suppresses the immune response. This prospective study explored IL-35 plasma levels in 65 patients after HSCT. The results revealed that the peripheral blood of patients with grades III-IV aGVHD (23.46 ng/ml) had reduced IL-35 compared to transplanted patients with grades I-II aGVHD (40.26 ng/ml, p < 0.01) or patients without aGVHD (41.40 ng/ml, p < 0.05). Allografts, including granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cell (PBPC) and G-CSF-primed bone marrow (GBM), from 38 patients were analyzed for IL-35 levels with respect to aGVHD. The patients who received lower levels of IL-35 cells in the GBM (28.0 ng/ml, p = 0.551) or lower levels of IL-35 in PBPC (53.46 ng/ml, p = 0.03) exhibited a higher incidence of aGVHD. Patients with aGVHD have increased platelet aggregation. IL-35 was added to patient blood in vitro, and platelet aggregation was inhibited by IL-35 in a dose-dependent manner. The markers of platelet activation (CD62P/PAC-1) can also be inhibited by IL-35. The results indicate that IL-35 may affect the development of aGVHD by inhibiting platelet activation and aggregation. Our data suggests that IL-35 represents a potentially effective therapeutic agent against aGVHD after allo-HSCT.

  9. Viral PCR positivity in stool before allogeneic hematopoietic cell transplantation is strongly associated with acute intestinal graft-versus-host disease.

    PubMed

    van Montfrans, Joris; Schulz, Laura; Versluys, Birgitta; de Wildt, Arianne; Wolfs, Tom; Bierings, Marc; Gerhardt, Corinne; Lindemans, Caroline; Wensing, Anne; Boelens, Jaap Jan

    2015-04-01

    Acute graft-versus-host disease (aGVHD) can be triggered by inflammatory conditions, including infections and mucositis. We investigated the association between PCR positivity for gastrointestinal (GI) viruses in stool before hematopoietic cell transplantation (HCT) and intestinal aGVHD using Cox proportional hazard models. We included 48 consecutive HCT patients (28 with malignancies and 20 with nonmalignancies) without GI symptoms before HCT. Fifteen patients were GI virus positive: 9 adenovirus, 3 norovirus, 2 parechovirus, and 1 astrovirus. Overall survival was 58% ± 8%. The cumulative incidence of aGVHD grade 2 to 4 was 43% ± 8% (n = 18) after a median of 47 days (range, 14 to 140). In univariate analysis, GI virus PCR positivity was the only predictor for aGVHD (P = .008): within the group of GI virus PCR-positive patients, the cumulative incidence of aGVHD 2 to 4 was 70% ± 12% versus 29 ± 8% in the PCR-negative group (P = .004). In conclusion, GI virus PCR positivity before HCT predicted development of intestinal aGVHD. These results may ultimately affect monitoring, aGVHD prophylaxis, and treatment, as well as rescheduling of elective HCTs.

  10. Atorvastatin for the Prophylaxis of Acute Graft-versus-Host Disease in Patients Undergoing HLA-Matched Related Donor Allogeneic Hematopoietic Stem Cell Transplantation (allo-HCT).

    PubMed

    Efebera, Yvonne A; Geyer, Susan; Andritsos, Leslie; Vasu, Sumithira; Jaglowski, Samantha; Bingman, Anissa; Blum, William; Klisovic, Rebecca; Hofmeister, Craig C; Benson, Don M; Penza, Sam; Elder, Patrick; Cortright, Katie; Kitzler, Rhonda; Coombes, Kevin; O'Donnell, Lynn; Daneault, Beth; Bradbury, Hillary; Zhang, Jianying; Chen, Xilin; Garman, Sabrina; Ranganathan, Parvathi; Yu, Xueyan; Hofstetter, Jessica; Yu, Jianhua; Garzon, Ramiro; Scrape, Scott R; Lozanski, Gerard; Devine, Steven M

    2016-01-01

    Statins possess potent immunomodulatory effects that may play a role in preventing acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). We performed a phase II study of atorvastatin for aGVHD prophylaxis when given to allo-HCT recipients and their HLA-matched sibling donors. Atorvastatin (40 mg/day) was administered to sibling donors, beginning 14 days before the anticipated start of stem cell collection. Allo-HCT recipients (n = 40) received atorvastatin (40 mg/day) in addition to standard aGVHD prophylaxis. The primary endpoint was cumulative incidence of grades II to IV aGVHD at day 100. Atorvastatin was well tolerated, with no attributable grades III to IV toxicities in donors or their recipients. Day 100 and 180 cumulative incidences of grades II to IV aGVHD were 30% (95% confidence interval [CI], 17% to 45%) and 40% (95% CI, 25% to 55%), respectively. One-year cumulative incidence of chronic GVHD was 43% (95% CI, 32% to 69%). One-year nonrelapse mortality and relapse incidences were 5.5% (95% CI, .9% to 16.5%) and 38% (95% CI, 18% to 47%), respectively. One-year progression-free and overall survival rates were 54% (95% CI, 38% to 71%) and 82% (95% CI, 69% to 94%). One-year GVHD-free, relapse-free survival was 27% (95% CI, 16% to 47%). These results did not differ from our historical control subjects (n = 96). Although safe and tolerable, the addition of atorvastatin did not appear to provide any benefit to standard GVHD prophylaxis alone.

  11. 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.

  12. Serum microRNA181a: Correlates with the intracellular cytokine levels and a potential biomarker for acute graft-versus-host disease.

    PubMed

    Xie, Linna; Zhou, Fang; Liu, Ximin; Fang, Yuan; Yu, Zhe; Song, Ningxia; Kong, Fansheng

    2016-09-01

    The aim of this study was to investigate the clinical relevance of lymphocyte-related serum miRNAs to the pathogenesis of acute graft-versus-host disease (aGVHD) and evaluate the predictive and prognosis value of miRNAs. Consecutive patients who received allogeneic peripheral blood stem cell transplantation (allo-PBSCT) in General Hospital of Jinan Military District were enrolled. aGVHD patients were diagnosed and graded clinically, and divided into the training set and the testing set. Blood samples were collected, total RNA was isolated, and RT-PCR was performed for miRNA expression (miR-181a-3p, miR-214-3p and miR-326). Intracellular cytokines levels were assayed by flow cytometry, and the disease specificity assay of miRNAs for aGVHD was detected. A total of 120 patients were admitted. Serum level of miR-181a in aGVHD patients was highly increased and associated with the severity of aGVHD, but not miR-214 and miR-326. Levels of cytokines including IL-2, IL-22, and IL-17a were positively correlated with miR-181a level, while serum IL-13 level was negatively correlated with miR-181a level in aGVHD patients. Moreover, increased miR-181a level was not detected in patients with acute rejection after kidney transplantation or sepsis patients. MiR-181a level was sensitively and specifically increased, especially in severe aGVHD patients. MiR-181a may be a potential biomarker for the identification, diagnosis, and prognosis of aGVHD patients. PMID:27288630

  13. Soluble DNAM-1, as a Predictive Biomarker for Acute Graft-Versus-Host Disease

    PubMed Central

    Kanaya, Minoru; Shibuya, Kazuko; Hirochika, Rei; Kanemoto, Miyoko; Ohashi, Kazuteru; Okada, Masafumi; Wagatsuma, Yukiko; Cho, Yukiko; Kojima, Hiroshi; Teshima, Takanori; Imamura, Masahiro; Sakamaki, Hisashi; Shibuya, Akira

    2016-01-01

    Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because diagnosis of aGVHD is exclusively based on clinical symptoms and pathological findings, reliable and noninvasive laboratory tests for accurate diagnosis are required. An activating immunoreceptor, DNAM-1 (CD226), is expressed on T cells and natural killer cells and is involved in the development of aGVHD. Here, we identified a soluble form of DNAM-1 (sDNAM-1) in human sera. In retrospective univariate and multivariate analyses of allo-HSCT patients (n = 71) at a single center, cumulative incidences of all grade (grade I–IV) and sgrade II–IV aGVHD in patients with high maximal serum levels of sDNAM-1 (≥30 pM) in the 7 days before allo-HSCT were significantly higher than those in patients with low maximal serum levels of sDNAM-1 (<30 pM) in the same period. However, sDNAM-1 was not associated with other known allo-HSCT complications. Our data suggest that sDNAM-1 is potentially a unique candidate as a predictive biomarker for the development of aGVHD. PMID:27257974

  14. Soluble DNAM-1, as a Predictive Biomarker for Acute Graft-Versus-Host Disease.

    PubMed

    Kanaya, Minoru; Shibuya, Kazuko; Hirochika, Rei; Kanemoto, Miyoko; Ohashi, Kazuteru; Okada, Masafumi; Wagatsuma, Yukiko; Cho, Yukiko; Kojima, Hiroshi; Teshima, Takanori; Imamura, Masahiro; Sakamaki, Hisashi; Shibuya, Akira

    2016-01-01

    Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because diagnosis of aGVHD is exclusively based on clinical symptoms and pathological findings, reliable and noninvasive laboratory tests for accurate diagnosis are required. An activating immunoreceptor, DNAM-1 (CD226), is expressed on T cells and natural killer cells and is involved in the development of aGVHD. Here, we identified a soluble form of DNAM-1 (sDNAM-1) in human sera. In retrospective univariate and multivariate analyses of allo-HSCT patients (n = 71) at a single center, cumulative incidences of all grade (grade I-IV) and sgrade II-IV aGVHD in patients with high maximal serum levels of sDNAM-1 (≥30 pM) in the 7 days before allo-HSCT were significantly higher than those in patients with low maximal serum levels of sDNAM-1 (<30 pM) in the same period. However, sDNAM-1 was not associated with other known allo-HSCT complications. Our data suggest that sDNAM-1 is potentially a unique candidate as a predictive biomarker for the development of aGVHD. PMID:27257974

  15. [Prolonged acute pancreatitis after bone marrow transplantation].

    PubMed

    De Singly, B; Simon, M; Bennani, J; Wittnebel, S; Zagadanski, A-M; Pacault, V; Gornet, J-M; Allez, M; Lémann, M

    2008-04-01

    Acute pancreatitis is not infrequent after allogenic marrow transplantation. Several causes can predispose to pancreatitis, including Graft-Versus-Host Disease (GVHD), a condition which is probably underestimated. In the literature, few description of pancreatic GVHD can be found. Pancreatic GVHD diagnosis can be difficult if pancreatic involvement occurs without other typical manifestations of GVHD. We report the case of a woman, 54 years old, suffering from prolonged, painful pancreatitis two months after allogenic bone marrow transplantation for acute myeloid leucemia. Pancreatic GVHD diagnosis was performed after five weeks on duodenal biopsies despite the absence of diarrheoa. The patient dramatically improved within few days on corticosteroids.

  16. Tear physiology in dry eye associated with chronic GVHD.

    PubMed

    Khanal, S; Tomlinson, A

    2012-01-01

    The purpose of this study was to compare tear physiology characteristics of chronic GVHD (cGVHD)-associated dry eye to dry eye caused by Sjogren's syndrome (SS), a extreme form of aqueous-deficient dry eye, and meibomian gland dysfunction (MGD), the major cause of evaporative dry eye. Tear turnover rate, evaporation and osmolarity along with meibomian gland dropout and lipid layer interferometric patterns were assessed in the right eyes of 12 patients with dry eye associated with cGVHD, 12 age-matched patients with SS and 12 age-sex matched subjects with MGD. In cGVHD, the decrease in tear turnover rate was similar (P=0.33), but the number of non-functioning meibomian glands was significantly higher (P<0.01) than in SS. Tear evaporation rate in cGVHD dry eye was found to be similar to that in MGD (P=0.36) and significantly higher than in SS (P<0.01). The lipid layer was most unstable in cGVHD compared with other groups. There was no variation in tear volume across all groups. Although statistical significance was not detected, the mean tear osmolarity (333.51±14.67mOsm/L) was highest in cGVHD. Major aspects of tear physiology were severely impaired in cGVHD-associated dry eye.

  17. Topical Tacrolimus and Periodontal Therapy in the Management of a Case of Oral Chronic GVHD Characterized by Specific Gingival Localization

    PubMed Central

    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. PMID:24639902

  18. 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.

  19. Chimerism studies in HLA-identical nonmyeloablative hematopoietic stem cell transplantation point to the donor CD8(+) T-cell count on day + 14 as a predictor of acute graft-versus-host disease.

    PubMed

    Petersen, Søren L; Madsen, Hans O; Ryder, Lars P; Svejgaard, A; Masmas, Tania N; Dickmeiss, Ebbe; Heilmann, Carsten; Vindeløv, Lars L

    2004-05-01

    Chimerism analysis of hematopoietic cells has emerged as an essential tool in nonmyeloablative hematopoietic stem cell transplantation. We have investigated the development of donor chimerism in granulocytes and CD4(+) and CD8(+) T cells in blood and bone marrow of 24 patients with hematologic malignancies who received HLA-identical sibling peripheral blood stem cell grafts after conditioning with fludarabine and 2 Gy of total body irradiation. The T-cell chimerism of blood and bone marrow was tightly correlated. Complete donor chimerism was reached earlier in the granulocytes than in the T cells. Mixed T-cell chimerism was common at the time of onset of acute graft-versus-host disease (aGVHD), and both CD4(+) and CD8(+) donor T-cell chimerism increased with the occurrence of aGVHD grades II to IV (P =.0002 and P =.019, respectively). The rate of disappearance of recipient CD8(+) T cells was faster in patients with aGVHD grades II to IV than in patients without clinically significant aGVHD (P =.016). This observation indicates a role of graft-versus-lymphohematopoietic tissue reactions in creating complete donor T-cell chimerism. A donor CD8(+) T-cell count above the median on day +14 increased the risk of subsequent development of aGVHD grades II to IV (P =.003).

  20. Factors affecting long-term outcome after allogeneic haematopoietic stem cell transplantation for acute myelogenous leukaemia: a retrospective study of 172 adult patients reported to the Austrian Stem Cell Transplantation Registry.

    PubMed

    Greinix, Hildegard T; Nachbaur, David; Krieger, Otto; Eibl, Margit; Knöbl, Paul; Kalhs, Peter; Lutz, Dieter; Linkesch, Werner; Niederwieser, Dietger; Hinterberger, Wolfgang; Lechner, Klaus; Rosenmayr, Agathe; Gritsch, Beate

    2002-06-01

    Between 1982 and 2000, 172 patients with acute myelogenous leukaemia (AML) received haematopoietic stem cell transplants (SCT) from related (n = 132) or unrelated (n = 40) donors at four Austrian transplant centres and their results were reported to the Austrian Stem Cell Transplantation Registry. Conditioning for SCT consisted of cyclophosphamide and total body irradiation in 156 (91%) patients. Graft-versus-host disease (GVHD) prophylaxis was with standard cyclosporine and methotrexate in 95 (55%) patients. Median post-transplant follow-up was 5.6 years (range, 0.2--16.7). Multivariate analysis of transplant-related mortality (TRM) identified four variables associated with a lower risk: disease status of first complete remission (CR) at SCT, patient age of 45 years and younger, transplant performed during or after 1995, and lack of acute GVHD. Variables associated with significantly improved leukaemia-free survival were: bone marrow as the stem cell source, disease status of first CR at SCT, and occurrence of chronic GVHD. In multivariate analysis, transplantation performed during or after 1995, first CR at SCT, occurrence of limited chronic GVHD and lack of acute GVHD grades III to IV were associated with increased overall survival. Based on these analyses, options for the improvement of results obtained with allogeneic SCT in patients with AML could be defined. PMID:12060131

  1. Antibody- and aptamer-strategies for GvHD prevention

    PubMed Central

    Oelkrug, Christopher; Sack, Ulrich; Boldt, Andreas; Nascimento, Isis C; Ulrich, Henning; Fricke, Stephan

    2015-01-01

    Prevention of Graft-versus-Host-Disease (GvHD) by preserved Graft-versus-Leukaemia (GvL) effect is one of the major obstacles following allogeneic haematopoietic stem cell transplantation. Currently used drugs are associated with side effects and were not able to separate GvHD from the GvL-effect because of general T-cell suppression. This review focuses on murine models for GvHD and currently available treatment options involving antibodies and applications for the therapeutic use of aptamers as well as strategies for targeting immune responses by allogenic antigens. PMID:25353670

  2. Higher Dose of Mycophenolate Mofetil Reduces Acute Graft-Versus-Host Disease in Reduced Intensity Conditioning Double Umbilical Cord Blood Transplantation

    PubMed Central

    Bejanyan, Nelli; Rogosheske, John; DeFor, Todd; Lazaryan, Aleksandr; Esbaum, Kelli; Holtan, Shernan; Arora, Mukta; MacMillan, Margaret L.; Weisdorf, Daniel; Jacobson, Pamala; Wagner, John; Brunstein, Claudio G.

    2016-01-01

    Mycophenolate mofetil (MMF) is frequently used in hematopoietic cell transplantation (HCT) for graft-versus-host disease (GVHD) prophylaxis and to facilitate engraftment. We previously reported that a higher level of mycophenolic acid can be achieved with an MMF dose of 3 g/day as compared to 2g/day. Here, we retrospectively compared clinical outcomes of reduced intensity conditioning (RIC) double umbilical cord blood (dUCB) HCT recipients receiving cyclosporine A with MMF 2g (n=93) vs. 3g (n=175) daily. Multiple regression analysis adjusted for ATG in the conditioning revealed that MMF 3g/day led to a 49% relative risk reduction in grade II–IV acute GVHD rate (RR=0.51, 95%CI 0.36–0.72; p<0.01). However, the higher MMF dose was not protective for chronic GVHD. Additionally, MMF dose was not an independent predictor of neutrophil engraftment, treatment-related mortality at 6 months, or 2-year post-transplant disease relapse, disease-free survival, or overall survival. Higher MMF dose did not increase risk of infectious complications and infection-related mortality was similar for both MMF doses. Our data indicate that MMF 3g/day reduces the risk of acute GVHD without affecting other clinical outcomes and should be used for GVHD prophylaxis after RIC dUCBT. PMID:25655791

  3. Substitution of methotrexate with corticosteroid for acute graft-versus-host disease prevention in transplanted patients who develop methotrexate toxicity.

    PubMed

    Kim, Sung-Yong; Kim, Ah Ran; Yoon, So Young; Cho, Yo-Han; Lee, Mark Hong

    2016-02-01

    Methotrexate (MTX) toxicity can hamper the administration of all planned doses in acute graft-versus-host disease (GVHD) prophylaxis following allogeneic hematopoietic stem cell transplantation. Reduction or omission of MTX doses results in an increased risk of acute GVHD. In this prospective observational study, we compared the incidence of GVHD and the transplant outcomes between patients who received the full treatment course of MTX (group 1), patients in whom MTX doses were omitted if MTX toxicity developed (group 2), and patients receiving corticosteroid instead of MTX if MTX toxicity developed (group 3). The cumulative incidence of grades II-IV acute GVHD at 100 days post-transplantation was 22.2 % in group 1, 43.6 % in group 2, and 25.0 % in group 3 (P = 0.132). The risk of grades II-IV acute GVHD in group 2 was higher than that in group 1 (hazard ratio (HR) 3.262, P = 0.016), but the risk in group 3 was similar to that in group 1 (HR 0.960, P = 0.890). Group 3 also showed a trend towards a lower risk of chronic GVHD compared to the other groups. The cumulative risk of chronic GVHD at 2 years was 73.9, 71.6, and 33.3 % in groups 1, 2, and 3, respectively (P = 0.084). However, a likely higher relapse incidence and infection-related mortality in group 3 produced a trend towards the lowest relapse-free survival (2-year RFS, 46.3, 49.3, and 25.0 % in groups 1, 2, and 3, respectively; P = 0.329) and overall survival (2-year OS, 45, 52.3, and 25 %, respectively; P = 0.322) in group 3. Although the substitution of MTX with corticosteroid ameliorates the increased risk of GVHD in patients in which it is imperative to omit its dose, its negative impact on relapse and infection risk does not result in favorable transplant outcomes.

  4. Cell-autonomous role of TGFβ and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD.

    PubMed

    Sawamukai, Norifumi; Satake, Atsushi; Schmidt, Amanda M; Lamborn, Ian T; Ojha, Priti; Tanaka, Yoshiya; Kambayashi, Taku

    2012-06-01

    FoxP3(+) regulatory T cells (Tregs) suppress GVHD while preserving graft-versus-tumor effects, making them an attractive target for GVHD therapy. The donor-derived Treg pool can potentially be derived from the expansion of preexisting natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor Tconvs in the transplantation recipient. Using an MHC-mismatched model of acute GVHD, in the present study we found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Experiments using various combinations of T cells from wild-type and FoxP3-deficient mice suggested that both preexisting donor nTregs and the generation of iTregs in the recipient mice contribute to protection against GVHD. Surprisingly, CD8(+)FoxP3(+) T cells represented approximately 70% of the iTreg pool. These CD8(+)FoxP3(+) T cells shared phenotypic markers with their CD4(+) counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4(+) and CD8(+) Tregs appeared to be protective against GVHD-induced lethality and required IL-2 and TGFβ receptor expression for their generation. These data illustrate the complex makeup of the donor-derived FoxP3(+) Treg pool in allogeneic recipients and their potential role in protection against GVHD.

  5. Cell-autonomous role of TGFβ and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD

    PubMed Central

    Sawamukai, Norifumi; Satake, Atsushi; Schmidt, Amanda M.; Lamborn, Ian T.; Ojha, Priti; Tanaka, Yoshiya

    2012-01-01

    FoxP3+ regulatory T cells (Tregs) suppress GVHD while preserving graft-versus-tumor effects, making them an attractive target for GVHD therapy. The donor-derived Treg pool can potentially be derived from the expansion of preexisting natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor Tconvs in the transplantation recipient. Using an MHC-mismatched model of acute GVHD, in the present study we found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Experiments using various combinations of T cells from wild-type and FoxP3-deficient mice suggested that both preexisting donor nTregs and the generation of iTregs in the recipient mice contribute to protection against GVHD. Surprisingly, CD8+FoxP3+ T cells represented approximately 70% of the iTreg pool. These CD8+FoxP3+ T cells shared phenotypic markers with their CD4+ counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4+ and CD8+ Tregs appeared to be protective against GVHD-induced lethality and required IL-2 and TGFβ receptor expression for their generation. These data illustrate the complex makeup of the donor-derived FoxP3+ Treg pool in allogeneic recipients and their potential role in protection against GVHD. PMID:22496155

  6. Whole-body UVB irradiation during allogeneic hematopoietic cell transplantation is safe and decreases acute graft-versus-host disease.

    PubMed

    Kreutz, Marina; Karrer, Sigrid; Hoffmann, Petra; Gottfried, Eva; Szeimies, Rolf-Markus; Hahn, Joachim; Edinger, Matthias; Landthaler, Michael; Andreesen, Reinhard; Merad, Miriam; Holler, Ernst

    2012-01-01

    Depletion of host Langerhans cells (LCs) prevents cutaneous graft-versus-host disease (GvHD) in mice. We analyzed whether UVB irradiation is tolerated during the course of human allogeneic hematopoietic cell transplantation and whether depletion of LCs by broadband UVB could improve GvHD outcome. A total of 17 patients received six whole-body UVB irradiations with 75% of the individually determined minimal erythemal dose after conditioning with a reduced intensity protocol. LCs, dermal dendritic cells (DCs), and macrophages were analyzed before and after UVB irradiation by immunohistochemical analysis. Circulating blood cells and serum factors were analyzed in parallel. In striking contrast to previous data, our irradiation protocol was well tolerated in all patients. UVB treatment decreased the number of LCs and also affected dermal DCs. UVB-treated patients also had significantly higher 25-hydroxyvitamin D3 serum levels and higher numbers of circulating CD4+ FoxP3+ regulatory T cells. Strikingly, nine out of nine patients with complete LC depletion (<1 LC per field) developed only grade I GvHD or no GvHD up to day 100. Our results strongly suggest that prophylactic UVB irradiation post transplant is safe and should be further explored as a clinical strategy to prevent acute (skin) GvHD.

  7. Methotrexate Reduces the Incidence of Severe Acute Graft-versus-Host Disease without Increasing the Risk of Relapse after Reduced-Intensity Allogeneic Stem Cell Transplantation from Unrelated Donors.

    PubMed

    Vigouroux, Stéphane; Tabrizi, Reza; Melot, Cyril; Coiffard, Joelle; Lafarge, Xavier; Marit, Gérald; Bouabdallah, Krimo; Pigneux, Arnaud; Leguay, Thibaut; Dilhuydy, Marie-Sarah; Schmitt, Anna; Boiron, Jean-Michel; Milpied, Noël

    2011-01-01

    Optimized prophylaxis against graft-versus-host disease (GVHD) after unrelated reduced-intensity allogeneic transplantation when preceded by a conditioning regimen utilizing antithymocyte globulin (ATG) is poorly defined. To investigate the effects of methotrexate (MTX) in this treatment setting, we conducted a retrospective analysis. Sixty-three patients were selected based on the administration of a total dose of 5 mg/kg of ATG in the conditioning regimen and then separated into either group M+ (n = 39), which received MTX or group M- (n = 24), which did not. All patients received cyclosporine. In the M- and M+ groups, cumulative incidences (CI) of grade III-IV acute GVHD (aGVHD) were 43% and 10%, respectively (P = .002). Multivariate analysis indicated that grade III-IV aGVHD was favored by both the absence of MTX and the provision of a female donor for a male recipient. At 2 years, the M+ and M- groups exhibited, respectively: overall survival of 69% and 40% (P = .06), disease-free survival of 57% and 43% (P = .2), nonrelapse mortality of 20% and 44% (P = .1), and incidence of relapse of 27% and 35% (P = .6). These data suggest that MTX reduces the incidence of severe aGVHD without increasing the risk of relapse but with an accompanying trend toward improved survival after unrelated reduced-intensity transplantation with ATG in the conditioning regimen.

  8. Eculizumab Treatment in a Patient with Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy and Steroid-Refractory Acute Graft Versus Host Disease.

    PubMed

    Fernández, Cristina; Lario, Ana; Forés, Rafael; Cabrera, Rafael

    2015-11-23

    A 30-year-old man with acquired aplastic anemia underwent an HLA-identical bone marrow transplant. He developed a grade III acute graft versus host disease (GVHD) refractory to various lines of treatment. On post-transplant day 196, he was diagnosed with stem cell transplantation-associated thrombotic micro-angiopathy (HSCT-TMA) and he received treatment with eculizumab 900 mg iv weekly for 4 doses followed by a single dose of 1200 mg 2 weeks later. After the first dose of eculizumab, the patient ceased to require transfusions and a progressive improvement in analytical parameters for microangiopathy was observed until their complete normalization. Coinciding with the improved of HSCT-TMA, the patient presented a clear response to his acute GVHD with disappearance of the diarrhea and bilirubin normalization. He was discharged eight weeks after the start of treatment. Unfortunately, one month later, the patient was readmitted for a GVHD relapse and he died two weeks later by an acute respiratory distress syndrome. In our case, the rapid clinical and analytical response to early treatment with eculizumab supports the implication of the complement in HSCT-TMA and suggests that the drug has a beneficial effect when used as coadjuvant therapy in acute GVHD.

  9. Second allogeneic haematopoietic stem cell transplantation in relapsed acute and chronic leukaemias for patients who underwent a first allogeneic bone marrow transplantation: a survey of the Société Française de Greffe de moelle (SFGM).

    PubMed

    Michallet, M; Tanguy, M L; Socié, G; Thiébaut, A; Belhabri, A; Milpied, N; Reiffers, J; Kuentz, M; Cahn, J Y; Blaise, D; Demeocq, F; Jouet, J P; Michallet, A S; Ifrah, N; Vilmer, E; Molina, L; Michel, G; Lioure, B; Cavazzana-Calvo, M; Pico, J L; Sadoun, A; Guyotat, D; Attal, M; Curé, H; Bordigoni, P; Sutton, L; Buzyn-Veil, A; Tilly, M; Keoirruer, N; Feguex, N

    2000-02-01

    Although recurrent malignancy is the most frequent indication for second stem cell transplantation (2nd SCT), there are few reports that include sufficiently large numbers of patients to enable prognostic factor analysis. This retrospective study includes 150 patients who underwent a 2nd SCT for relapsed acute myeloblastic leukaemia (n = 61), acute lymphoblastic leukaemia (n = 47) or chronic myeloid leukaemia (n = 42) after a first allogeneic transplant (including 26 T-cell-depleted). The median interval between the first transplant and relapse, and between relapse and second transplant was 17 months and 5 months respectively. After the 2nd SCT, engraftment occurred in 93% of cases, 32% of patients developed acute graft-vs.-host disease (GVHD) >/= grade II and 38% chronic GVHD. The 5-year overall and disease-free survival were 32 +/- 8% and 30 +/- 8%, respectively, with a risk of relapse of 44 +/- 12% and a transplant-related mortality of 45 +/- 9%. In a multivariate analysis, five factors were associated with a better outcome after 2nd SCT: age < 16 years at second transplant; relapse occurring more than 12 months after the first transplant; transplantation from a female donor; absence of acute GVHD; and the occurrence of chronic GVHD. The best candidates for a second transplant are likely to be patients with acute leukaemia in remission before transplant, in whom the HLA-identical donor was female and who relapsed more than 1 year after the first transplant.

  10. Reduced-toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS).

    PubMed

    Kröger, N; Shimoni, A; Zabelina, T; Schieder, H; Panse, J; Ayuk, F; Wolschke, C; Renges, H; Dahlke, J; Atanackovic, D; Nagler, A; Zander, A

    2006-02-01

    We investigated a dose-reduced conditioning regimen consisting of treosulfan and fludarabine followed by allogeneic stem cell transplantation (SCT) in 26 patients with secondary AML or MDS. Twenty patients were transplanted from matched or mismatched unrelated donors and six from HLA-identical sibling donors. The median age of the patients was 60 years (range, 44-70). None of the patients was eligible for a standard myeloablative preparative regimen. No graft-failure was observed, and leukocyte and platelet engraftment were observed after a median of 16 and 17 days, respectively. Acute graft-versus-host disease (GvHD) grade II-IV was seen in 23% and severe grade III GvHD in 12% of the patients. No patients experienced grade IV acute GvHD. Chronic GvHD was noted in 36% of the patients, which was extensive disease in 18%. The 2-year cumulative incidence of relapse was 21%. The relapse rate was higher in patients beyond CR1 or with intermediate two or high risk MDS (P = 0.02). The treatment-related mortality at day 100 was 28%. The 2-year estimated overall and disease-free survival was 36-34%, respectively. No difference in survival was seen between unrelated and related SCT.

  11. 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

  12. 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

  13. 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

  14. 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

  15. Syk and tired of current chronic GVHD therapies.

    PubMed

    Fowler, Daniel H; Pavletic, Steven Z

    2015-06-25

    In this issue of Blood, Flynn et al1 provide key data that lend further support to the development of clinical trials of spleen tyrosine kinase (Syk) inhibition for more effective chronic graft-versus-host disease (cGVHD) treatment. PMID:26113534

  16. 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

  17. Assessing clinical outcomes of patients with acute calculous cholecystitis in addition to the Tokyo grading: a retrospective study.

    PubMed

    Cheng, Wei-Chun; Chiu, Yen-Cheng; Chuang, Chiao-Hsiung; Chen, Chiung-Yu

    2014-09-01

    The management of acute cholecystitis is still based on clinical expertise. This study aims to investigate whether the outcome of acute cholecystitis can be related to the severity criteria of the Tokyo guidelines and additional clinical comorbidities. A total of 103 patients with acute cholecystitis were retrospectively enrolled and their medical records were reviewed. They were all classified according to therapeutic modality, including early cholecystectomy and antibiotic treatment with or without percutaneous cholecystostomy. The impact of the Tokyo guidelines and the presence of comorbidities on clinical outcome were assessed by univariate and multivariate regression analyses. According to Tokyo severity grading, 48 patients were Grade I, 31 patients were Grade II, and 24 patients were Grade III. The Grade III patients had a longer hospital stay than Grade II and Grade I patients (15.2 days, 9.2 days, and 7.3 days, respectively, p < 0.05). According to multivariate analysis, patients with Grade III Tokyo severity, higher Charlson's Comorbidity Score, and encountering complications had a longer hospital stay. Based on treatment modality, surgeons selected the patients with less severity and fewer comorbidities for cholecystectomy, and these patients had a shorter hospital stay. In addition to the grading of the Tokyo guidelines, comorbidities had an additional impact on clinical outcomes and should be an important consideration when making therapeutic decisions.

  18. Acute graft-vs-host disease: pathobiology and management.

    PubMed

    Goker, H; Haznedaroglu, I C; Chao, N J

    2001-03-01

    Acute graft-vs-host disease (GVHD) is a major obstacle to safe allogeneic hematopoietic stem cell transplantation (HSCT), leading to a significant morbidity and mortality. GVHD occurs when transplanted donor T lymphocytes react to foreign host cells. It causes a wide variety of host tissue injuries. This review focuses on the pathobiological basis, clinical aspects, and current management strategies of acute GVHD. Afferent phase of acute GVHD starts with myeloablative conditioning, i.e., before the infusion of the graft. Total-body irradiation (TBI) or high-dose chemotherapy regimens cause extensive damage and activation in host tissues, which release inflammatory cytokines and enhance recipient major histocompatibility complex (MHC) antigens. Recognition of the foreign host antigens by donor T cells and activation, stimulation, and proliferation of T cells is crucial in the afferent phase. Effector phase of acute GVHD results in direct and indirect damage to host cells. The skin, gastrointestinal tract, and liver are major target organs of acute GVHD. Combination drug prophylaxis in GVHD is essential in all patients undergoing allogeneic HSCT. Steroids have remained the standard for the treatment of acute GVHD. Several clinical trials have evaluated monoclonal antibodies or receptor antagonist therapy for steroid-resistant acute GVHD, with different successes in a variety of settings. There are some newer promising agents like mycophenolate mofetil, glutamic acid-lysine-alanine-tyrosine (GLAT), rapamycin, and trimetrexate currently entering in the clinical studies, and other agents are in development. Future experimental and clinical studies on GVHD will shed further light on the better understanding of the disease pathobiology and generate the tools to treat malignant disorders with allogeneic HSCT with specific graft-vs-tumor effects devoid of GVHD. PMID:11274753

  19. Changes in nerve function and nerve fibre structure induced by acute, graded compression.

    PubMed Central

    Rydevik, B; Nordborg, C

    1980-01-01

    Rabbit tibial nerves were subjected to direct, acute graded compression by means of an inflatable compression chamber. The acute and long term effects of 50, 200 and 400 mmHg applied for two hours on nerve function and nerve fibre structure were investigated. A pressure of 50 mmHg applied for two hours induced only minimal or no acute deterioration of maximal conduction velocity and nerve fibre structure. Conduction velocity was gradually reduced during compression at 200-400 mmHg pressure for two hours and in those cases the recovery of nerve conduction after pressure release was incomplete. Ultrastructural analysis revealed pronounced, early nerve fibre damage in these nerves. Three weeks after compression, nerves compressed at 50 mmHg for two hours had normal afferent and motor conduction velocity, although there were morphological signs of slight nerve fibre damage. Nerves compressed at 200 mmHg for two hours exhibited reduction of conduction velocity only at the level of compression, in contrast to the nerves compressed at 400 mmHg for two hours in which conduction velocity was reduced both at the level of compression and distal to the compressed segment. Morphologically, the nerves compressed at 200-400 mmHg for two hours showed varying degrees of demyelination and axonal degeneration three weeks after compression. Images PMID:7217952

  20. Ex Vivo T Cell Depleted versus Unmodified Allografts in Patients with Acute Myeloid Leukemia in First Complete Remission

    PubMed Central

    Bayraktar, Ulas D.; de Lima, Marcos; Saliba, Rima M.; Maloy, Molly; Castro-Malaspina, Hugo R.; Chen, Julianne; Rondon, Gabriela; Chiattone, Alexander; Jakubowski, Ann A.; Boulad, Farid; Kernan, Nancy A.; O'Reilly, Richard J.; Champlin, Richard E.; Giralt, Sergio; Andersson, Borje S.; Papadopoulos, Esperanza B.

    2014-01-01

    Purpose To retrospectively compare the clinical outcomes after transplantation of T cell depleted (TCD) and unmodified allografts in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Patients and methods Patients received TCD grafts at Memorial Sloan-Kettering Cancer Center (MSKCC, N=115) between 2001 and 2010 using the following preparative regimens: Hyperfractionated total body irradiation (HFTBI) /thiotepa /fludarabine; HFTBI /thiotepa /cyclophosphamide; i.v. busulfan/melphalan/fludarabine. T cell depletion was performed by one of two immunomagnetic CD34+ cell selection methods for peripheral blood grafts or by soybean lectin agglutination followed by sRBC-rosette depletion for bone marrow grafts. No additional graft-versus-host disease (GVHD) prophylaxis was administered. Patients received unmodified grafts at MD Anderson Cancer Center (MDACC, N=181) after conditioning with busulfan /fludarabine and GVHD prophylaxis with tacrolimus /mini-methotrexate. Patients with unrelated or HLA-mismatched donors received anti-thymocyte globulin (ATG) at both centers with some recipients of matched related donor TCD transplants also receiving ATG depending upon the preparative regimen. Results TCD graft recipients were more likely to be older, receive a mismatched transplant, and have peripheral blood used as the graft source. The incidences of grade 2-4 acute GVHD and chronic GVHD were significantly lower in the TCD graft group (5% vs. 18% and 13% vs. 53%). Three-year relapse-free (RFS) and overall survival (OS) rates were 58% and 57% in recipients of TCD grafts, and 60% and 66% in recipients of unmodified grafts (P=NS). Conclusion Survival and RFS are similar after TCD and conventional transplants from related/unrelated donors in patients with AML in CR1 but TCD significantly reduces GVHD. PMID:23467126

  1. Role of acute graft-versus-host disease in the risk of bacteremia and invasive fungal disease after allogeneic hemopoietic stem cell transplantation in children. Results from a single-center observational study.

    PubMed

    Castagnola, Elio; Bagnasco, Francesca; Bandettini, Roberto; Caviglia, Ilaria; Morreale, Giuseppe; Lanino, Edoardo; Giardino, Stefano; Moroni, Cristina; Haupt, Riccardo; Faraci, Maura

    2014-07-01

    Data on epidemiology of severe infectious complications, ie, bacteremia or invasive fungal disease (IFD), in children with acute graft-versus-host disease (aGVHD) after allogeneic hemopoietic stem cell transplantation (HSCT) are scarce. In a retrospective, single-center study, we analyzed the risk (hazard ratio [HR]) and the rate (episodes/1000 patients days at risk) of bacteremias and IFD in children receiving allogeneic HSCT, according to the type of donor (matched related [MRD] or alternative [AD]) and presence and grade of aGVHD. From 2000 to 2009, 198 children receiving 217 allogeneic HSCT developed 134 severe infectious episodes (103 bacteremias and 31 IFD). The type of donor (AD versus MRD) was the most important risk factor for the severe infections (P = .0052). In separate multivariable analysis for bacteremia and IFD, children receiving an AD HSCT had increased HR and rate of bacteremia compared with those receiving a MRD transplantation (P = .0171 and P = .0001, respectively), whereas the HR and the rate of IFD were significantly influenced by the grade of aGVHD (P = .0002 and P < .0001, respectively). Finally, infectious episodes occurred late after HSCT, especially in presence of severe aGVHD, and bacteremias were 3 to 6 times more frequent than IFD. These data may be important to design management strategies of infections in pediatric allogeneic HSCT.

  2. Effect of adopting a new histological grading system of acute rejection after heart transplantation

    PubMed Central

    Balk, A.; Zondervan, P.; van der Meer, P.; van Gelder, T.; Mochtar, B.; Simoons, M.; Weimar, W.

    1997-01-01

    Background—Treatment policy of acute rejection after heart transplantation has been changed after adopting the ISHLT endomyocardial biopsy grading system in 1991.
Objective—To determine the effect of this policy change on clinical outcome after transplantation.
Methods—The outcome of 147 patients who had a transplant before (early group, median follow up 96 months) and 114 patients who had a transplant after (late group, median follow up 41 months) the introduction of the ISHLT biopsy grading system was studied retrospectively. Initially "moderate rejection" according to Billingham's conventional criteria was treated. From January 1991 grade 3A and higher was considered to require intensification of immunosuppression.
Results—There were some differences between the two groups: recipients (50 v 44 years) as well as donors (28 v 24 years) were older in the "late group" and more patients of this group received early anti-T cell prophylaxis (92% v 56%). Despite more extensive use of early prophylaxis more rejection episodes were diagnosed (2.4 v 1.4) and considerably more courses of rejection treatment were instituted in the late compared with the early group (3.2 v 1.5). There were no deaths because of rejection in the late group, however, more infections occurred within the first year (mean 1.8 v 1.4) and more non-skin malignancies within the first 41 months were diagnosed (8 of 57 v 6 of 147, 95% CIs of difference includes 0). The incidence of graft vascular disease in the late group has been comparable to the early group until now. 
Conclusion—The interpretation of the ISHLT grading system resulted in lowering of the threshold for the diagnosis of rejection thereby increasing the number of rejections and subsequently the immunosuppressive load and its complications.

 Keywords: transplantation;  biopsy grading system;  rejection PMID:9470880

  3. Increased BCR responsiveness in B cells from patients with chronic GVHD

    PubMed Central

    Allen, Jessica L.; Tata, Prasanthi V.; Fore, Matthew S.; Wooten, Jenna; Rudra, Sharmistha; Deal, Allison M.; Sharf, Andrew; Hoffert, Todd; Roehrs, Philip A.; Shea, Thomas C.; Serody, Jonathan S.; Richards, Kristy L.; Jagasia, Madan; Lee, Stephanie J.; Rizzieri, David; Horwitz, Mitchell E.; Chao, Nelson J.

    2014-01-01

    Although B cells have emerged as important contributors to chronic graft-versus-host-disease (cGVHD) pathogenesis, the mechanisms responsible for their sustained activation remain unknown. We previously showed that patients with cGVHD have significantly increased B cell–activating factor (BAFF) levels and that their B cells are activated and resistant to apoptosis. Exogenous BAFF confers a state of immediate responsiveness to antigen stimulation in normal murine B cells. To address this in cGVHD, we studied B-cell receptor (BCR) responsiveness in 48 patients who were >1 year out from allogeneic hematopoietic stem cell transplantation (HSCT). We found that B cells from cGVHD patients had significantly increased proliferative responses to BCR stimulation along with elevated basal levels of the proximal BCR signaling components B cell linker protein (BLNK) and Syk. After initiation of BCR signaling, cGVHD B cells exhibited increased BLNK and Syk phosphorylation compared with B cells from patients without cGVHD. Blocking Syk kinase activity prevented relative post-HSCT BCR hyper-responsiveness of cGVHD B cells. These data suggest that a lowered BCR signaling threshold in cGVHD associates with increased B-cell proliferation and activation in response to antigen. We reveal a mechanism underpinning aberrant B-cell activation in cGVHD and suggest that therapeutic inhibition of the involved kinases may benefit these patients. PMID:24532806

  4. Eosinophils in the blood of hematopoietic stem cell transplanted patients are activated and have different molecular marker profiles in acute and chronic graft-versus-host disease

    PubMed Central

    Cromvik, Julia; Johnsson, Marianne; Vaht, Krista; Johansson, Jan-Erik; Wennerås, Christine

    2014-01-01

    While increased numbers of eosinophils may be detected in patients with graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation, it is not known if eosinophils play a role in GVHD. The aims of this study were to determine: whether eosinophils are activated during GVHD; whether the patterns of activation are similar in acute and chronic GVHD; and the ways in which systemic corticosteroids affect eosinophils. Transplanted patients (n = 35) were investigated for eosinophil numbers and the expression levels of 16 eosinophilic cell surface markers using flow cytometry; all the eosinophil data were analyzed by the multivariate method OPLS-DA. Different patterns of molecule expression were observed on the eosinophils from patients with acute, chronic, and no GVHD, respectively. The molecules that provided the best discrimination between acute and chronic GVHD were: the activation marker CD9; adhesion molecules CD11c and CD18; chemokine receptor CCR3; and prostaglandin receptor CRTH2. Patients with acute or chronic GVHD who received systemic corticosteroid treatment showed down-regulation of the cell surface markers on their eosinophils, whereas corticosteroid treatment had no effect on the eosinophil phenotype in the patients without GVHD. In summary, eosinophils are activated in GVHD, display different activation profiles in acute and chronic GVHD, and are highly responsive to systemic corticosteroids. PMID:25400930

  5. 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

  6. 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

  7. 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

  8. 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.

  9. Successful Management of Intraoperative Acute Bilateral Pulmonary Embolism in a High Grade Astrocytoma Patient

    PubMed Central

    Khraise, Wail N.; Allouh, Mohammed Z.; Hiasat, Mohammad Y.; Said, Raed S.

    2016-01-01

    Patient: Female, 39 Final Diagnosis: Acute bilateral pulmonary embolism Symptoms: Headache • amnesia • seizure • urinary incontinence Medication: — Clinical Procedure: — Specialty: Anesthesiology Objective: Management of emergency care Background: Intraoperative pulmonary embolism (PE) is a rare life-threatening complication in patients undergoing surgical intervention. Generally, cancer patients have a higher risk for developing this complication. Unfortunately, there is no standard procedure for its management. Case Report: We report the case of a 39-year-old woman with high-grade glioma in the right frontal lobe who was admitted to the surgical theater for craniotomy and excision of the tumor. During the general anesthesia procedure and just before inserting the central venous line, her end-tidal CO2 and O2 saturation dropped sharply. The anesthesiologist quickly responded with an aggressive resuscitation procedure that included aspiration through the central venous line, 100% O2, and IV administration of ephedrine 6 mg, colloid 500 mL, normal saline 500 mL, and heparin 5000 IU. The patient was extubated and remained in the supine position until she regained consciousness and her vital signs returned to normal. Subsequent radiological examination revealed a massive bilateral PE. A retrievable inferior vena cava (IVC) filter was inserted, and enoxaparin anticoagulant therapy was prescribed to stabilize the patient’s condition. After 3 weeks, she underwent an uneventful craniotomy procedure and was discharged a week later under the enoxaparin therapy. Conclusions: The successful management of intraoperative PE requires a quick, accurate diagnosis accompanied with an aggressive, fast response. Anesthesiologists are usually the ones who are held accountable for the diagnosis and early management of this complication. They must be aware of the possibility of such a complication and be ready to react properly and decisively in the operation theater. PMID

  10. 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.

  11. 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.

  12. 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. PMID:25455279

  13. Cyclosporine Plus Methotrexate or Cyclosporine Plus Mycophenolate Mofetil as Graft Versus Host Disease Prophylaxis in Acute Leukemia Transplant: Comparison of Toxicity, Engraftment Kinetics and Transplant Outcome.

    PubMed

    Gupta, Alok; Punatar, Sachin; Mathew, Libin; Kannan, Sadhana; Khattry, Navin

    2016-09-01

    We sought to compare two graft-versus-host disease (GVHD) prophylaxis regimen, cyclosporine and methotrexate (CsA+MTX) with CsA+mycophenolate mofetil (MMF) in 77 acute leukemia patients who underwent hematopoietic stem cell transplant (HSCT) between January 2008 and March 2013. Fifty-three patients received CsA+MTX while 24 received CsA+MMF. The incidence of grade 3-4 mucositis and grade 3-4 diarrhea was 74 and 6 % with CsA+MTX compared to 33 % and 21 % with CsA+MMF (P = 0.001 and 0.09 respectively). Forty-two (79 %) patients in CsA+MTX group required total parenteral nutrition compared to 14 (58 %) in CsA+MMF group (P = 0.09). The incidence of engraftment fever was 17 % with CsA+MTX and 41 % with CsA+MMF (P = 0.02). The median time to neutrophil and platelet engraftment was 14 days and 13 days with CsA+MTX compared to 12 days and 10 days with CsA+MMF (P = 0.003 and 0.08 respectively). The incidence of any grade and grade II-IV acute GVHD was 45 and 13 % with CsA+MTX compared to 42 and 29 % with CsA+MMF (P = NS). Incidence of overall and extensive chronic GVHD was 57 and 38 % with CsA+MTX compared to 42 and 17 % with CsA+MMF (P = NS). Incidence of relapse was 38 % with CsA+MTX compared to 33 % with CsA+MMF (P = NS). TRM was 6 % with CsA+MTX and 21 % with CsA+MMF (P = NS). At 2 years, overall survival (OS) was 64 % in CsA+MTX group compared to 46 % in CsA+MMF group (P = NS). We conclude that CsA+MMF is associated with lesser toxicity, faster myeloid engraftment and similar rates of acute and chronic GVHD, TRM, relapse and OS compared to CsA+MTX in acute leukemia transplant.

  14. Impact of cyclosporine levels on the development of acute graft versus host disease after reduced intensity conditioning allogeneic stem cell transplantation.

    PubMed

    García Cadenas, Irene; Valcarcel, David; Martino, Rodrigo; Piñana, J L; Barba, Pere; Novelli, Silvana; Esquirol, Albert; Garrido, Ana; Saavedra, Silvana; Granell, Miquel; Moreno, Carol; Briones, Javier; Brunet, Salut; Sierra, Jorge

    2014-01-01

    We analyze the impact of cyclosporine (CsA) levels in the development of acute graft-versus-host disease (aGVHD) after reduced intensity conditioning allogeneic hematopoietic transplantation (allo-RIC). We retrospectively evaluated 156 consecutive patients who underwent HLA-identical sibling allo-RIC at our institution. CsA median blood levels in the 1st, 2nd, 3rd and 4th weeks after allo-RIC were 134 (range: 10-444), 219 (54-656), 253 (53-910) and 224 (30-699) ng/mL; 60%, 16%, 11% and 17% of the patients had median CsA blood levels below 150 ng/mL during these weeks. 53 patients developed grade 2-4 aGVHD for a cumulative incidence of 45% (95% CI 34-50%) at a median of 42 days. Low CsA levels on the 3rd week and sex-mismatch were associated with the development of GVHD. Risk factors for 1-year NRM and OS were advanced disease status (HR: 2.2, P = 0.02) and development of grade 2-4 aGVHD (HR: 2.5, P < 0.01), while there was a trend for higher NRM in patients with a low median CsA concentration on the 3rd week (P = 0.06). These results emphasize the relevance of sustaining adequate levels of blood CsA by close monitoring and dose adjustments, particularly when engraftment becomes evident. CsA adequate management will impact on long-term outcomes in the allo-RIC setting.

  15. Uptake and use of recommendations for the diagnosis, severity scoring and management of chronic GVHD: an international survey of the EBMT-NCI Chronic GVHD Task Force.

    PubMed

    Duarte, R F; Greinix, H; Rabin, B; Mitchell, S A; Basak, G; Wolff, D; Madrigal, J A; Pavletic, S Z; Lee, S J

    2014-01-01

    In 2005, the National Institutes of Health (NIH) consensus conference published a series of papers recommending methods to improve the conduct of clinical trials in chronic GVHD. Although the NIH recommendations were primarily aimed at strengthening research, several papers addressed issues relevant for clinical practice, particularly diagnosis, severity scoring, and ancillary and supportive care practices. We conducted an international survey to assess the uptake of these recommendations, identify barriers to greater use and document the use and perceived effectiveness of available treatments. The response rate for the American survey of 1387 practitioners was 21.8%, and it was 24.6% for 407 centers surveyed in Europe, Asia, Australia and Africa. Most respondents were familiar with the NIH consensus recommendations (94-96%) and used them in practice. Multiple barriers to greater use were reported. Besides lack of time (55-62%), unfamiliarity with the recommendations, scarcity of evidence supporting the impact of recommendations on outcomes, insufficient training/experience in chronic GVHD management and inaccessibility of subspecialists were also endorsed. Systemic corticosteroids were reported to be the most effective treatment for chronic GVHD, but many others were perceived to have moderate or great success. Therapeutic management of steroid-refractory chronic GVHD was identified as the highest priority for research.

  16. 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

  17. 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

  18. Development, preliminary usability and accuracy testing of the EBMT 'eGVHD App' to support GvHD assessment according to NIH criteria-a proof of concept.

    PubMed

    Schoemans, H; Goris, K; Durm, R V; Vanhoof, J; Wolff, D; Greinix, H; Pavletic, S; Lee, S J; Maertens, J; Geest, S D; Dobbels, F; Duarte, R F

    2016-08-01

    The EBMT Complications and Quality of Life Working Party has developed a computer-based algorithm, the 'eGVHD App', using a user-centered design process. Accuracy was tested using a quasi-experimental crossover design with four expert-reviewed case vignettes in a convenience sample of 28 clinical professionals. Perceived usefulness was evaluated by the technology acceptance model (TAM) and User satisfaction by the Post-Study System Usability Questionnaire (PSSUQ). User experience was positive, with a median of 6 TAM points (interquartile range: 1) and beneficial median total, and subscale PSSUQ scores. The initial standard practice assessment of the vignettes yielded 65% correct results for diagnosis and 45% for scoring. The 'eGVHD App' significantly increased diagnostic and scoring accuracy to 93% (+28%) and 88% (+43%), respectively (both P<0.05). The same trend was observed in the repeated analysis of case 2: accuracy improved by using the App (+31% for diagnosis and +39% for scoring), whereas performance tended to decrease once the App was taken away. The 'eGVHD App' could dramatically improve the quality of care and research as it increased the performance of the whole user group by about 30% at the first assessment and showed a trend for improvement of individual performance on repeated case evaluation. PMID:27042834

  19. 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

  20. Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation in Patients With Acute Myeloid Leukemia

    PubMed Central

    Gyurkocza, Boglarka; Storb, Rainer; Storer, Barry E.; Chauncey, Thomas R.; Lange, Thoralf; Shizuru, Judith A.; Langston, Amelia A.; Pulsipher, Michael A.; Bredeson, Christopher N.; Maziarz, Richard T.; Bruno, Benedetto; Petersen, Finn B.; Maris, Michael B.; Agura, Edward; Yeager, Andrew; Bethge, Wolfgang; Sahebi, Firoozeh; Appelbaum, Frederick R.; Maloney, David G.; Sandmaier, Brenda M.

    2010-01-01

    Purpose Allogeneic hematopoietic cell transplantation (HCT) after high-dose conditioning regimens imposes prohibitively high risks of morbidity and mortality for patients with high-risk acute myeloid leukemia (AML) who are older or have comorbid conditions. Here, we examined outcomes after nonmyeloablative allogeneic HCT in such patients. Patients and Methods Two hundred seventy-four patients (median age, 60 years) with de novo or secondary AML underwent allogeneic HCT from related (n = 118) or unrelated donors (n = 156) after conditioning with 2 Gy of total-body irradiation (TBI) with or without fludarabine. A calcineurin inhibitor and mycophenolate mofetil were used for postgrafting immunosuppression. Results With a median follow-up of 38 months in surviving patients, the estimated overall survival at 5 years was 33%. The estimated 5-year relapse/progression and nonrelapse mortality rates were 42% and 26%, respectively. The cumulative incidences of grades 2, 3, and 4 acute graft-versus-host disease (GVHD) were 38%, 9%, and 5%, respectively. The cumulative incidence of chronic GVHD at 5 years was 44%. Patients in first and second complete remission had better survival rates than patients with more advanced disease (37% and 34% v 18%, respectively). Patients with HLA-matched related or unrelated donors had similar survivals. Unfavorable cytogenetic risk status was associated with increased relapse and subsequent mortality. Chronic GVHD was associated with lower relapse risk. Conclusion Allogeneic HCT from related or unrelated donors after conditioning with low-dose TBI and fludarabine, relying almost exclusively on graft-versus-leukemia effects, can result in long-term remissions in older or medically infirm patients with AML. PMID:20439626

  1. B cells from patients with chronic GVHD are activated and primed for survival via BAFF-mediated pathways

    PubMed Central

    Allen, Jessica L.; Fore, Matthew S.; Wooten, Jenna; Roehrs, Philip A.; Bhuiya, Nazmim S.; Hoffert, Todd; Sharf, Andrew; Deal, Allison M.; Armistead, Paul; Coghill, James; Gabriel, Don A.; Irons, Robert; Essenmacher, Amber; Shea, Thomas C.; Richards, Kristy; Cutler, Corey; Ritz, Jerome; Serody, Jonathan; Baldwin, Albert S.

    2012-01-01

    Recent data reveal an important role for B cells in the pathogenesis of chronic GVHD (cGVHD). Patients with cGVHD have delayed B-cell reconstitution and elevated BAFF to B-cell ratios compared to patients without cGVHD. The mechanisms promoting and sustaining B-cell activation in this disease, however, remain unknown. As BAFF increases murine B-cell metabolism and survival and maintains autoreactive B-cell clones, we performed ex vivo analyses of peripheral B cells from 51 patients who either had or did not have active cGVHD and were greater than 1 year from the time of allogeneic hematopoietic stem cell transplantation. We found that B cells from patients with active cGVHD were in a heightened metabolic state and were resistant to apoptosis. Exogenous BAFF treatment amplified cell size and survival in B cells from these patients. We found significantly increased signaling through ERK and AKT that associated with decreased levels of proapoptotic Bim, suggesting a mechanistic link between elevated BAFF levels and aberrant B-cell survival. Thus, we identify a role for BAFF in the pathogenesis of cGVHD and define B-cell activation and survival pathways suitable for novel therapeutic development in cGVHD. PMID:22896003

  2. Experimental production of clinical-grade dendritic cell vaccine for acute myeloid leukemia.

    PubMed

    Tan, Yuen-Fen; Sim, Geok-Choo; Habsah, Aziz; Leong, Chooi-Fun; Cheong, Soon-Keng

    2008-12-01

    Dendritic cells (DC) are professional antigen presenting cells of the immune system. Through the use of DC vaccines (DC after exposure to tumour antigens), cryopreserved in single-use aliquots, an attractive and novel immunotherapeutic strategy is available as an option for treatment. In this paper we describe an in vitro attempt to scale-up production of clinical-grade DC vaccines from leukemic cells. Blast cells of two relapsed AML patients were harvested for DC generation in serum-free culture medium containing clinical-grade cytokines GM-CSF, IL-4 and TNF-alpha. Cells from patient 1 were cultured in a bag and those from patient 2 were cultured in a flask. The numbers of seeding cells were 2.24 x 10(8) and 0.8 x 10(8), respectively. DC yields were 10 x 10(6) and 29.8 x 10(6) cells, giving a conversion rate of 4.7% and 37%, respectively. These DC vaccines were then cryopreserved in approximately one million cells per vial with 20% fresh frozen group AB plasma and 10% DMSO. At 12 months and 21 months post cryopreservation, these DC vaccines were thawed, and their sterility, viability, phenotype and functionality were studied. DC vaccines remained sterile up to 21 months of storage. Viability of the cryopreserved DC in the culture bag and flask was found to be 50% and 70% at 12 months post cryopreservation respectively; and 48% and 67% at 21 months post cryopreservation respectively. These DC vaccines exhibited mature DC surface phenotypic markers of CD83, CD86 and HLA-DR, and negative for haemopoietic markers. Mixed lymphocyte reaction (MLR) study showed functional DC vaccines. These experiments demonstrated that it is possible to produce clinical-grade DC vaccines in vitro from blast cells of leukemic patients, which could be cryopreserved up to 21 months for use if repeated vaccinations are required in the course of therapy. PMID:19291915

  3. Traditional Chinese Patent Medicine for Acute Ischemic Stroke: An Overview of Systematic Reviews Based on the GRADE Approach.

    PubMed

    Zhang, Xin; Liu, Xue-Ting; Kang, De-Ying

    2016-03-01

    The aim of the study is to conduct an overview of systematic reviews (SRs) to provide a contemporary review of the evidence for delivery of Traditional Chinese Patent Medicine (TCPMs) for patients with acute ischemic stroke.SRs were assessed for quality using the Assessment of Multiple Systematic Reviews (AMSTAR) tool and the Oxman-Guyatt Overview Quality Assessment Questionnaire (OQAQ). We assessed the quality of the evidence of high methodological quality (an AMSTAR score ≥9 or an OQAQ score ≥7) for reported outcomes using the GRADE (the Grading of Recommendations Assessment, Development and Evaluation) approach.(1) Dan Shen agents: tiny trends toward the improvement in different neurological outcomes (RR = 1.16, 1.10, 1.23, 1.08, 1.12); (2) Mailuoning: a tiny trend toward improvement in the neurological outcome (RR = 1.18); (3) Ginkgo biloba: tiny trends toward improvement in the neurological outcome (RR = 1.18, MD = 0.81); (4) Dengzhanhua: a tiny trend toward an improvement in neurological (RR = 1.23); (5) Acanthopanax: a small positive (RR = 1.17, 1.31) result on neurological improvement reported; (6) Chuanxiong-type preparations: neurological functional improved (MD = 2.90);(7) Puerarin: no better effect on the rate of death or disability (OR = 0.81, 95% CI 0.35-1.87); (8) Milk vetch: no better effect on the rate of death (OR = 0.66, 95% CI: 0.11-2.83);(9) Qingkailing: rate of death reduced (OR = 0.66, 95% CI: 0.11-2.83). Limitations in the methodological quality of the RCTs, inconsistency and imprecision led to downgrading of the quality of the evidence, which varied by review and by outcome. Consequently, there are currently only weak evidences to support those TCPMs.The 9 TCPMs may be effective in the treatment of acute ischemic stroke, as the GRADE approach indicated a weak recommendation for those TCPMs' usage.

  4. Traditional Chinese Patent Medicine for Acute Ischemic Stroke: An Overview of Systematic Reviews Based on the GRADE Approach.

    PubMed

    Zhang, Xin; Liu, Xue-Ting; Kang, De-Ying

    2016-03-01

    The aim of the study is to conduct an overview of systematic reviews (SRs) to provide a contemporary review of the evidence for delivery of Traditional Chinese Patent Medicine (TCPMs) for patients with acute ischemic stroke.SRs were assessed for quality using the Assessment of Multiple Systematic Reviews (AMSTAR) tool and the Oxman-Guyatt Overview Quality Assessment Questionnaire (OQAQ). We assessed the quality of the evidence of high methodological quality (an AMSTAR score ≥9 or an OQAQ score ≥7) for reported outcomes using the GRADE (the Grading of Recommendations Assessment, Development and Evaluation) approach.(1) Dan Shen agents: tiny trends toward the improvement in different neurological outcomes (RR = 1.16, 1.10, 1.23, 1.08, 1.12); (2) Mailuoning: a tiny trend toward improvement in the neurological outcome (RR = 1.18); (3) Ginkgo biloba: tiny trends toward improvement in the neurological outcome (RR = 1.18, MD = 0.81); (4) Dengzhanhua: a tiny trend toward an improvement in neurological (RR = 1.23); (5) Acanthopanax: a small positive (RR = 1.17, 1.31) result on neurological improvement reported; (6) Chuanxiong-type preparations: neurological functional improved (MD = 2.90);(7) Puerarin: no better effect on the rate of death or disability (OR = 0.81, 95% CI 0.35-1.87); (8) Milk vetch: no better effect on the rate of death (OR = 0.66, 95% CI: 0.11-2.83);(9) Qingkailing: rate of death reduced (OR = 0.66, 95% CI: 0.11-2.83). Limitations in the methodological quality of the RCTs, inconsistency and imprecision led to downgrading of the quality of the evidence, which varied by review and by outcome. Consequently, there are currently only weak evidences to support those TCPMs.The 9 TCPMs may be effective in the treatment of acute ischemic stroke, as the GRADE approach indicated a weak recommendation for those TCPMs' usage. PMID:27015174

  5. 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.

  6. Moderate hyperprolactinemia is associated with survival in patients with acute graft-versus-host disease after allogeneic stem cell transplantation.

    PubMed

    Parra, Adalberto; Ramírez-Peredo, Jorge; Reyes, Enrique; Hidalgo, Rocío; Macías-Gallardo, Julio; Lutz-Presno, Julia; Ruiz-Argüelles, Alejandro; Garza, Eduardo; Infante, Eduardo; Gutiérrez-Aguirre, César H; Salazar-Riojas, Rosario; Villarreal, Jesús Z; Gómez-Almaguer, David; Ruiz-Argüelles, Guillermo J

    2012-03-01

    Fasting serum prolactin (PRL) levels in response to metoclopramide (MCP) and lymphocyte cytokine profiles was studied in patients given allografts and their donors. Thirty normoprolactinemic volunteers (12-59 years) were studied: group 1, 10 healthy men; group 2, 8 males and 2 females with various hematologic diseases; and group 3, 3 males and 7 females HLA-identical sibling donors: PRL and cytokines were measured. Four surviving recipients developed acute graft-versus-host disease (GVHD) (+), and six did not. Before transplant Fasting PRL concentrations were higher in 'future' GVHD(+) recipients than in their donors (P < 0.001). The opposite was seen in response to MCP (P = 0.01). Donors had a predominant T-helper type 1 (Th1) cytokine profile compared with recipients (P ≤ 0.02), and GVHD(+) recipients had a greater tumor necrosis factor (TNF) value than GVHD(-) (P = 0.05). After transplant On days +30 and +100, a mild sustained rise in fasting PRL levels occurred only in GVHD(+) recipients (P ≤ 0.05) simultaneously with a transient rise in Th1 cytokines. GVHD(-) recipients had no changes. Donors with a Th1 cytokine profile might be more prone to induce GVHD in their recipients, and a mild sustained rise in PRL concentrations after transplantation in recipients GVHD(+) might participate in the amelioration of the severity of GVHD.

  7. 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. PMID:27551984

  8. [Effects of myeloid antigen expression on hematopoietic reconstitution and disease prognosis in acute lymphocytic leukemia patients after allogeneic stem cell transplantation].

    PubMed

    Wang, Xiao-Ning; Liu, Hua-Sheng; Zhang, Mei

    2014-08-01

    This study was aimed to investigate the effects of myeloid antigen expression on hematopoietic reconstitution and disease prognosis in acute lymphocytic leukemia patients post-allogeneic stem cell transplantation (allo-HSCT). Clinical data of 20 patients with acute lymphocytic leukemia in Department of Hematology of the First Affiliated Hospital of Xi'an Jiaotong University from 2008 January to 2014 April were retrospectively analyzed, in which 5 cases were with myeloid antigen (My(+) ALL), while 15 patients were without myeloid antigen expression (My(-) ALL). Differences in prognosis and hematopoietic reconstitution post-allo-HSCT were observed in My(+) ALL and My(-) ALL patients. The results showed that the poor platelet engraftment in patients with My(+) ALL was found more than that in My(-)ALL patients. Three My(+) ALL patients experienced skin chronic graft versus host disease (cGVHD) including local in 2 cases and extensive in one case, and 3 My(-) ALL patients developed grade I-II acute GVHD, while five patients of My(-) ALL experienced cGVHD including local in 3 cases, extensive in 2 cases. One and two year overall survival rate of My(+) ALL and My(-) ALL patients was 80% and 85.7%, 53% and 69.8% respectively, one and two year progress-free survival rate was 53.3% and 54.7%, 26% and 27.4%, respectively. And there was no significant statistical difference between two groups (P > 0.05). It is concluded that the myeloid antigen expression may impact the platelet engraftment post-transplantation. There is no significant difference between one and two year overall survival rate and progress-free survival rate of My(+) ALL and My(-) ALL patients after allogeneic stem cell transplantation.

  9. Successful Management of Intraoperative Acute Bilateral Pulmonary Embolism in a High Grade Astrocytoma Patient.

    PubMed

    Khraise, Wail N; Allouh, Mohammed Z; Hiasat, Mohammad Y; Said, Raed S

    2016-01-01

    BACKGROUND Intraoperative pulmonary embolism (PE) is a rare life-threatening complication in patients undergoing surgical intervention. Generally, cancer patients have a higher risk for developing this complication. Unfortunately, there is no standard procedure for its management. CASE REPORT We report the case of a 39-year-old woman with high-grade glioma in the right frontal lobe who was admitted to the surgical theater for craniotomy and excision of the tumor. During the general anesthesia procedure and just before inserting the central venous line, her end-tidal CO2 and O2 saturation dropped sharply. The anesthesiologist quickly responded with an aggressive resuscitation procedure that included aspiration through the central venous line, 100% O2, and IV administration of ephedrine 6 mg, colloid 500 mL, normal saline 500 mL, and heparin 5000 IU. The patient was extubated and remained in the supine position until she regained consciousness and her vital signs returned to normal. Subsequent radiological examination revealed a massive bilateral PE. A retrievable inferior vena cava (IVC) filter was inserted, and enoxaparin anticoagulant therapy was prescribed to stabilize the patient's condition. After 3 weeks, she underwent an uneventful craniotomy procedure and was discharged a week later under the enoxaparin therapy. CONCLUSIONS The successful management of intraoperative PE requires a quick, accurate diagnosis accompanied with an aggressive, fast response. Anesthesiologists are usually the ones who are held accountable for the diagnosis and early management of this complication. They must be aware of the possibility of such a complication and be ready to react properly and decisively in the operation theater. PMID:27578311

  10. Oral chronic graft-versus-host disease: report from the International Consensus Conference on clinical practice in cGVHD.

    PubMed

    Meier, Johannes K-H; Wolff, Daniel; Pavletic, Steve; Greinix, Hildegard; Gosau, Martin; Bertz, Hartmut; Lee, Stefanie J; Lawitschka, Anita; Elad, Sharon

    2011-04-01

    Chronic graft-versus-host disease (cGVHD) is a multi-organ disease that occurs post-hematopoietic stem cell transplantation, with the mouth being one of the most frequently affected organs. In 2009, the German-Austrian-Swiss working party on bone marrow and blood stem cell transplantation held a consensus conference to define clinical management of cGVHD. The consensus conference aimed to summarize the literature on diagnosis and topical treatment options for oral cGVHD and to provide recommendations for clinical practice, including routine dental and oral care as well as monitoring for secondary malignancies and bisphophonate-induced osteonecrosis of the jaw.

  11. Bone Marrow Mesenchymal Stromal Cells from Patients with Acute and Chronic Graft-versus-Host Disease Deploy Normal Phenotype, Differentiation Plasticity, and Immune-Suppressive Activity.

    PubMed

    Copland, Ian B; Qayed, Muna; Garcia, Marco A; Galipeau, Jacques; Waller, Edmund K

    2015-05-01

    The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often limited by the development of acute and/or chronic graft-versus-host disease (GVHD). The lack of effective therapies to treat steroid-refractory GVHD patients has bolstered clinical evaluation of mesenchymal stromal cell (MSC) therapy for GVHD. Currently, testing of MSCs for the treatment of GVHD has exclusively used allogeneic MSCs despite emerging evidence that MSCs lose their immunoprivileged status in vivo. We hypothesized that autologous MSCs could be a viable alternative MSC source for treating active GVHD. MSCs were isolated and successfully expanded from the bone marrow of 12 volunteers (ages 2 to 55 years) who had allo-HSCT transplants and subsequently developed GVHD. MSCs from subjects with GVHD demonstrated an initial lag in growth compared with healthy control subjects; however, this lag disappeared with continued ex vivo expansion. Immunophenotype and mesodermal differentiation capacity of MSCs from GVHD patients were indistinguishable from that of healthy control MSCs. In vitro immunomodulatory functional analyses also demonstrated that GVHD MSCs were equivalent to healthy control MSCs with regards to dose dependently suppressing T cell proliferation and up-regulating indoleamine 2,3-dioxygenase expression when primed with IFN-γ. Single tandem repeat chimerism analyses further demonstrated that MSCs expanded from GVHD patients were exclusively recipient derived. Based on these data, we conclude that recipient-derived MSCs from patients with GVHD are analogous to MSCs from healthy volunteers and represent a viable option for clinical testing as an immunomodulatory option for symptomatic GVHD.

  12. Bone Marrow GvHD after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Szyska, Martin; Na, Il-Kang

    2016-01-01

    The bone marrow is the origin of all hematopoietic lineages and an important homing site for memory cells of the adaptive immune system. It has recently emerged as a graft-versus-host disease (GvHD) target organ after allogeneic stem cell transplantation (alloHSCT), marked by depletion of both hematopoietic progenitors and niche-forming cells. Serious effects on the restoration of hematopoietic function and immunological memory are common, especially in patients after myeloablative conditioning therapy. Cytopenia and durable immunodeficiency caused by the depletion of hematopoietic progenitors and destruction of bone marrow niches negatively influence the outcome of alloHSCT. The complex balance between immunosuppressive and cell-depleting treatments, GvHD and immune reconstitution, as well as the desirable graft-versus-tumor (GvT) effect remains a great challenge for clinicians. PMID:27066008

  13. Dynamics of early histopathological changes in GVHD after busulphan/cyclophosphamide conditioning regimen.

    PubMed

    Al-Hashmi, Sulaiman; Hassan, Zuzana; Sadeghi, Behnam; Rozell, Björn; Hassan, Moustapha

    2011-08-15

    Hematopoietic stem cell transplantation (HSCT) is a curative treatment for otherwise incurable diseases. Conditioning regimen is an important part of HSCT and consists of chemotherapy with or without irradiation. Conditioning exerts myelosuppressive, immunosuppressive and antitumor effects, but also contributes to HSCT-related complications including graft-versus-host disease (GVHD). Since almost 50% of the transplanted patients are conditioned with cytostatics without irradiation, we developed and characterized a GVHD mouse model following conditioning with busulphan and cyclophosphamide. Recipient Balb/c female mice were treated with busulphan (20 mg/kg/day for 4 days) and cyclophosphamide (100 mg/kg/day for two days). After one day of rest, recipient mice were transplanted with 2×10(7) bone marrow and 3×10(7) spleen cells from male C57BL/6 (allogeneic group) or female Balb/c (syngeneic/control group) mice. The allogeneic, but not syngeneic transplanted mice developed GVHD. Histopathology of the major internal organs (liver, pancreas, spleen, lungs, heart and kidney) was examined before conditioning start, after conditioning's end and 5, 7 and 21 days after transplantation using hematoxylin-eosin staining. Decreased spleen cellularity and diminished glycogen content in the liver were observed after conditioning regimen. Histopathological changes such as vasculitis, inflammation and apoptotic cell forms in liver, spleen, pancreas, lungs and heart were observed in allogeneic transplanted mice, however, only hypocellular spleen and extramedullar hematopoiesis were detected in syngeneic transplanted animals. No morphological changes were observed in kidney in either HSCT setting. This is the first study describing early histopathological changes after conditioning regimen with busulphan/cyclophosphamide and dynamics of GVHD development in several major internal organs.

  14. Third-party CD4+ invariant natural killer T cells protect from murine GVHD lethality.

    PubMed

    Schneidawind, Dominik; Baker, Jeanette; Pierini, Antonio; Buechele, Corina; Luong, Richard H; Meyer, Everett H; Negrin, Robert S

    2015-05-28

    Graft-versus-host disease (GVHD) is driven by extensive activation and proliferation of alloreactive donor T cells causing significant morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Invariant natural killer T (iNKT) cells are a potent immunoregulatory T-cell subset in both humans and mice. Here, we explored the role of adoptively transferred third-party CD4(+) iNKT cells for protection from lethal GVHD in a murine model of allogeneic HCT across major histocompatibility barriers. We found that low numbers of CD4(+) iNKT cells from third-party mice resulted in a significant survival benefit with retained graft-versus-tumor effects. In vivo expansion of alloreactive T cells was diminished while displaying a T helper cell 2-biased phenotype. Notably, CD4(+) iNKT cells from third-party mice were as protective as CD4(+) iNKT cells from donor mice although third-party CD4(+) iNKT cells were rejected early after allogeneic HCT. Adoptive transfer of third-party CD4(+) iNKT cells resulted in a robust expansion of donor CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) that were required for protection from lethal GVHD. However, in vivo depletion of myeloid-derived suppressor cells abrogated both Treg expansion and protection from lethal GVHD. Despite the fact that iNKT cells are a rare cell population, the almost unlimited third-party availability and feasibility of in vitro expansion provide the basis for clinical translation.

  15. Impact of performance grading on annual numbers of acute myocardial infarction-associated emergency department visits in Taiwan

    PubMed Central

    Tzeng, I-Shiang; Liu, Su-Hsun; Chen, Kuan-Fu; Wu, Chin-Chieh; Chen, Jih-Chang

    2016-01-01

    Abstract To reduce patient boarding time at the emergency department (ED) and to improve the overall quality of the emergent care system in Taiwan, the Minister of Health and Welfare of Taiwan (MOHW) piloted the Grading Responsible Hospitals for Acute Care (GRHAC) audit program in 2007–2009. The aim of the study was to evaluate the impact of the GRHAC audit program on the identification and management of acute myocardial infarction (AMI)-associated ED visits by describing and comparing the incidence of AMI-associated ED visits before (2003–2007), during (2007–2009), and after (2009–2012) the initial audit program implementation. Using aggregated data from the MOHW of Taiwan, we estimated the annual incidence of AMI-associated ED visits by Poisson regression models. We used segmented regression techniques to evaluate differences in the annual rates and in the year-to-year changes in AMI-associated ED visits between 2003 and 2012. Medical comorbidities such as diabetes mellitus, hyperlipidemia, and hypertensive disease were considered as potential confounders. Overall, the number of AMI-associated patient visits increased from 8130 visits in 2003 to 12,695 visits in 2012 (P-value for trend < 0.001), corresponding to an average annual growth rate of 5.3% (95%confidence interval [CI]: 0.5–10%). Although age was a major risk factor for AMI-associated ED visits, the statistical association was observed in middle-to-old (aged 40–64; P-value < 0.001) and older aged individuals (aged ≥65; P-value <0.001). As compared to 2003–2007, AMI-associated ED visits increased slightly during the intervention roll-in period (2007–2009, slope = 394.5, P-value = 0.117) followed by a dramatic uptake in the early post-intervention period (2010–2012, slope = 1037, P-value = 0.083). There was evidence suggesting for a significant intervention effect of the GRHAC program on identifying critically ill patients with AMI-associated diagnosis at the ED

  16. Comparative Proteomic Analysis of Serum from Patients with Systemic Sclerosis and Sclerodermatous GVHD. Evidence of Defective Function of Factor H

    PubMed Central

    Scambi, Cinzia; La Verde, Valentina; De Franceschi, Lucia; Barausse, Giovanni; Poli, Fabio; Benedetti, Fabio; Sorio, Marco; Deriu, Francesca; Roncada, Paola; Bortolami, Oscar; Turrini, Francesco; Caramaschi, Paola; Stranieri, Chiara; Bambara, Lisa M.; Biasi, Domenico

    2010-01-01

    Background Systemic sclerosis (SSc) is an autoimmune disease characterized by immunological and vascular abnormalities. Until now, the cause of SSc remains unclear. Sclerodermatous graft-versus-host disease (ScGVHD) is one of the most severe complications following bone marrow transplantation (BMT) for haematological disorders. Since the first cases, the similarity of ScGVHD to SSc has been reported. However, both diseases could have different etiopathogeneses. The objective of this study was to identify new serum biomarkers involved in SSc and ScGVHD. Methodology Serum was obtained from patients with SSc and ScGVHD, patients without ScGVHD who received BMT for haematological disorders and healthy controls. Bi-dimensional electrophoresis (2D) was carried out to generate maps of serum proteins from patients and controls. The 2D maps underwent image analysis and differently expressed proteins were identified. Immuno-blot analysis and ELISA assay were used to validate the proteomic data. Hemolytic assay with sheep erythrocytes was performed to evaluate the capacity of Factor H (FH) to control complement activation on the cellular surface. FH binding to endothelial cells (ECs) was also analysed in order to assess possible dysfunctions of this protein. Principal Findings Fourteen differentially expressed proteins were identified. We detected pneumococcal antibody cross-reacting with double stranded DNA in serum of all bone marrow transplanted patients with ScGVHD. We documented higher levels of FH in serum of SSc and ScGVHD patients compared healthy controls and increased sheep erythrocytes lysis after incubation with serum of diffuse SSc patients. In addition, we observed that FH binding to ECs was reduced when we used serum from these patients. Conclusions The comparative proteomic analysis of serum from SSc and ScGVHD patients highlighted proteins involved in either promoting or maintaining an inflammatory state. We also found a defective function of Factor H

  17. 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.

  18. Early-phase GVHD gene expression profile in target versus non-target tissues: kidney, a possible target?

    PubMed

    Sadeghi, B; Al-Chaqmaqchi, H; Al-Hashmi, S; Brodin, D; Hassan, Z; Abedi-Valugerdi, M; Moshfegh, A; Hassan, M

    2013-02-01

    GVHD is a major complication after allo-SCT. In GVHD, some tissues like liver, intestine and skin are infiltrated by donor T cells while others like muscle are not. The mechanism underlying targeted tropism of donor T cells is not fully understood. In the present study, we aim to explore differences in gene expression profile among target versus non-target tissues in a mouse model of GVHD based on chemotherapy conditioning. Expression levels of JAK-signal transducers and activators of transcription (STAT), CXCL1, ICAM1 and STAT3 were increased in the liver and remained unchanged (or decreased) in the muscle and kidney after conditioning. At the start of GVHD the expression levels of CXCL9, ITGb2, SAA3, MARCO, TLR and VCAM1 were significantly higher in the liver or kidney compared with the muscle of GVHD animals. Moreover, biological processes of inflammatory reactions, leukocyte migration, response to bacterium and chemotaxis followed the same pattern. Our data show that both chemotherapy and allogenicity exclusively induce expression of inflammatory genes in target tissues. Moreover, gene expression profile and histopathological findings in the kidney are similar to those observed in the liver of GVHD mice.

  19. 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.

  20. Conjunctival polyploid cells and donor-derived myofibroblasts in ocular GvHD.

    PubMed

    Hallberg, D; Stenberg, K; Hanson, C; Stenevi, U; Brune, M

    2016-05-01

    After allogeneic hematopoietic stem cell transplantation (allo-SCT), ocular GvHD is a common complication, typical symptoms being dry eye syndrome with features of fibrosis. In this study, we have identified and quantified two cell types-myofibroblasts (MFB) and polyploid (PP) cells-in the conjunctival surface of allo-SCT patients (pts) and have explored their kinetics and association with local and systemic GvHD. Results are compared with control groups of (a) pretransplant samples from allo-SCT patients, (b) recipients of autologous transplantation (auto-SCT) and (c) healthy controls. Imprint cytologies were obtained by pressing the conjunctival surface with a sterile, non-abrasive cellulose acetate filter (Millipore). After retraction, typically a monolayer of the outermost cells of the epithelium were retrieved. MFB were identified by immunofluorescent (IF) staining for alpha-smooth muscle protein. PP cells were detected by aberrant chromosome content analyzed via X/Y-FISH (X/Y fluorescence in situ hybridization). In female pts with a male donor (MF group), donor genotype were identified by sex chromosome detection using FISH methodology. IF and FISH methods were applied in situ on the same filter, and amounts of MFB and PP cells are expressed as the percentage of all cells on the filter. In all, 70 samples from 46 pts were obtained 1-122 months after allo-SCT. The total MFB density (MFB(TOT)) was higher in allo-SCT pts compared with healthy individuals and auto-SCT pts and increased by time after transplantation (P<0.001). In MF recipients, this increase proved to be due to a significant (P<0.001) and gradual elevation of donor-derived MFB (MFB(XY)), whereas recipient-derived MFB (MFB(XX)) did not vary over time. Clinical ocular GvHD correlated with MFB(XY)/MFB(TOT) ratio (P=0.034), whereas no association between MFB(TOT) or MFB(XY) systemic GvHD was observed. In the MF group (n=25), both MFB(XY) and MFB(XX) were detected on 28 of the 37 imprints (76

  1. Grade III ischemia on presentation with acute myocardial infarction predicts rapid progression of necrosis and less myocardial salvage with thrombolysis.

    PubMed

    Birnbaum, Yochai; Mahaffey, Kenneth W; Criger, Douglas A; Gates, Kathy B; Barbash, Gabriel I; Barbagelata, Alejandro; Clemmensen, Peter; Sgarbossa, Elena B; Gibbons, Raymond J; Rahman, M Atiar; Califf, Robert M; Granger, Chistopher B; Wagner, Galen S

    2002-01-01

    We assessed the relation between baseline electrocardiographic ischemia grades and initial myocardial area at risk (AR) and final infarct size (IS) in 49 patients who had undergone (99m)Tc sestamibi single-photon emission computed tomography before and 6 +/- 1 days after thrombolysis. Patients were classed as having grade III ischemia (ST segment elevation with terminal QRS distortion, n = 19) or grade II ischemia (ST elevation but no terminal QRS distortion, n = 30). We compared AR and IS by baseline ischemia grade and treatment (adenosine vs. placebo) and assessed relations of infarction index (IS/AR ratio x100) to time to thrombolysis, baseline ischemia grade, and adenosine therapy. Time to thrombolysis was similar for grade II and grade III. For placebo- treated patients, the median AR did not differ significantly between grade II (38%) and grade III patients (46%, p = 0.47), nor did median IS (16 vs. 40%, p = 0.096), but the median infarction index was 66 vs. 90% (p = 0.006). For adenosine-treated patients, median AR (21 vs. 26%, p = 0.44), median IS (5 vs. 17%, p = 0.15), and their ratio (31 vs. 67%, p = 0.23) did not differ significantly between grade II and grade III patients. The infarction index independently related to grade III ischemia (p = 0.0121) and adenosine therapy (p = 0.045). Infarct size related to baseline ischemia grade and was reduced by adenosine treatment. Necrosis progressed slowlier with baseline grade II versus III ischemia, which could offer more time for myocardial salvage with reperfusion. PMID:12077570

  2. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation.

    PubMed

    Hill, G R; Ferrara, J L

    2000-05-01

    Acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT), limits the application of this curative but toxic therapy. Studies of inflammatory pathways involved in GVHD in animals have shown that the gastrointestinal (GI) tract plays a major role in the amplification of systemic disease. Damage to the GI tract increases the translocation of inflammatory stimuli such as endotoxin, which promotes further inflammation and additional GI tract damage. The GI tract is therefore critical to the propagation of the "cytokine storm" characteristic of acute GVHD. Experimental approaches to the prevention of GVHD include reducing the damage to the GI tract by fortification of the GI mucosal barrier through novel "cytokine shields" such as IL-11 or keratinocyte growth factor. Such strategies have reduced GVHD while preserving a graft-versus-leukemia effect in animal models, and they now deserve formal testing in carefully designed clinical trials. (Blood. 2000;95:2754-2759)

  3. 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.

  4. Follow-up of Large Aneurysms Treated with Coil Embolization at an Acute Stage in Patients with Poor-Grade Subarachnoid Hemorrhage

    PubMed Central

    Hagiwara, S.; Tanaka, N.; Tani, S.; Nakamura, S.; Ohbuchi, H.; Hirota, K.; Iwabuchi, S.; Kasuya, H.

    2009-01-01

    Summary This study evaluated the clinical and angiographic outcome of large aneurysms treated with coil embolization at an acute stage in patients with poor-grade subarachnoid hemorrhage (SAH). Between July 1, 2001 and June 30, 2004, eight consecutive WFNS grade 5 patients with large aneurysms (15~23mm) were treated with endovascular coil embolization within two days and followed for at least 30 months. There were three middle cerebral and five internal carotid artery aneurysms. No patients were treated by craniotomy and none survived without treatment. Two patients died of primary brain damage or cerebral vasospasm within one month. One patient died of pneumonia at 24 months. Four patients were alive with good recovery or moderate disability at the time of final follow-up (30~66 months). Angiography immediately after the procedure showed complete occlusion in three, neck remnant in four, and body filling in one patient. No complication was seen related to the procedure. Three aneurysms that were initially neck remnant developed body filling due to coil compaction. Two were re-treated with coils at six and 12 months and resulted in neck remnant. One patient refused re-treatment and died of re-bleeding. Endovascular coil embolization can be selected at an acute stage for the treatment of aneurysms in patients with poor-grade SAH without intraparenchymal hematoma even if the aneurysm is large. Serial follow up by MRA/angiography is necessary for at least 12 months. PMID:20465928

  5. Absence of STAT1 in donor-derived plasmacytoid dendritic cells results in increased STAT3 and attenuates murine GVHD

    PubMed Central

    Nasholm, Nicole M.; Chien, Christopher D.; Larabee, Shannon M.; Qin, Haiying; Song, Young K.; Klover, Peter J.; Hennighausen, Lothar; Khan, Javed; Fry, Terry J.

    2014-01-01

    Selective targeting of non-T cells, including antigen-presenting cells (APCs), is a potential strategy to prevent graft-versus-host-disease (GVHD) but to maintain graft-versus-tumor (GVT) effects. Because type I and II interferons signal through signal transducer and activator of transcription-1 (STAT1), and contribute to activation of APCs after allogeneic bone marrow transplant (alloBMT), we examined whether the absence of STAT1 in donor APCs could prevent GVHD while preserving immune competence. Transplantation of STAT1−/− bone marrow (BM) prevented GVHD induced by STAT1+/+ T cells, leading to expansion of B220+ cells and regulatory T cells. STAT1−/− BM also preserved GVT activity and enhanced overall survival of tumor-challenged mice in the setting of GVHD. Furthermore, recipients of allogeneic STAT1−/− BM demonstrated increased CD9−Siglec Hhi plasmacytoid dendritic cells (pDCs), and depletion of pDCs after STAT1−/− BM transplantation prevented GVHD resistance. STAT1−/− pDCs were found to produce decreased free radicals, IFNα, and interleukin (IL)-12, and increased IL-10. Additionally, STAT1−/− pDCs that were isolated after alloBMT showed increased gene expression of S100A8 and S100A9, and transplantation of S100A9−/− BM reduced GVHD-free survival. Finally, elevated STAT3 was found in STAT1−/− pDCs isolated after alloBMT. We conclude that interfering with interferon signaling in APCs such as pDCs provides a novel approach to regulate the GVHD/GVT axis. PMID:25079358

  6. Transplant-related toxicity and mortality: an AIEOP prospective study in 636 pediatric patients transplanted for acute leukemia.

    PubMed

    Balduzzi, A; Valsecchi, M G; Silvestri, D; Locatelli, F; Manfredini, L; Busca, A; Iori, A P; Messina, C; Prete, A; Andolina, M; Porta, F; Favre, C; Ceppi, S; Giorgiani, G; Lanino, E; Rovelli, A; Fagioli, F; De Fusco, C; Rondelli, R; Uderzo, C

    2002-01-01

    Hematopoietic stem cell transplantation can cure high-risk acute leukemia (AL), but the occurrence of non-leukemic death is still high. The AIEOP conducted a prospective study in order to assess incidence and relationships of early toxicity and transplant-related mortality (TRM) in a pediatric population. Between 1990 and 1997 toxicities reported in eight organs (central nervous system, heart, lungs, liver, gut, kidneys, bladder, mucosa) were classified into three grades (mild, moderate, severe) and prospectively registered for 636 consecutive children who underwent autologous (216) or allogeneic (420) transplantation, either from an HLA compatible related (294), or alternative (126) donor in 13 AIEOP transplant centers. Overall, 47% of the patients are alive in CR (3-year EFS: 45.2%, s.e.: 2.1), 19% died in CR at a median of 60 days (90-day TRM: 14.3%, s.e.: 1.4), 34% relapsed. Toxicity of any organ, but mucosa and gut, was positively correlated with early death; moderate and severe toxicity to heart, lungs, liver and kidneys significantly increased early TRM, with estimated relative risks of 9.1, 5.5, 2.7 and 2.8, respectively, as compared to absent or mild toxicity. Patients with grade III-IV aGVHD experienced more than double (56% vs. 19%) TRM than patients with grade 0-II aGVHD. A higher cumulative toxicity score, estimating the impact of toxicity on TRM, was significantly associated with transplantation from an alternative donor. Quantitative assessment allowed us to describe the extent to which 'grade' of toxicity and 'type' of involved organs were related to mortality and pre-transplant characteristics and yielded a prognostic score potentially useful to compare different conditioning regimens and predict probability of early death.

  7. 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

  8. 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.

  9. The accuracy of MRI in predicting recovery and recurrence of acute grade one hamstring muscle strains within the same season in Australian Rules football players.

    PubMed

    Gibbs, N J; Cross, T M; Cameron, M; Houang, M T

    2004-06-01

    The purpose of this study was to use MRI to classify acute grade one hamstring muscle strains in Australian Rules footballers to determine if it was accurate in predicting the recovery time for each injury and also able to predict those that would recur within the same season. A prospective study was performed over five years at a professional Australian Football League club. Thirty-one acute grade one hamstring injuries underwent MRI examination within 24-72 hours following the injury. Each injury underwent the same rehabilitation programme. The rehabilitation interval (RI) was the time in days for the player to resume full team training. Fourteen (45%) of the injuries were normal on MRI. Seventeen (55%) were abnormal with a hyperintense T2 lesion on the axial fat suppressed views. The MRI negative group had a significantly faster RI (6.6 days) compared with the MRI positive group (20.2 days). Both the length and cross sectional area (CSA) of the MRI positive lesions were measured. The length of the lesion had a stronger correlation coefficient with the RI (0.84) than did the CSA (0.76). Six of the 17 MRI positive strains recurred with no correlation found between the lesion's length or CSA, or the RI. None of the 14 MRI negative injuries recurred. The study confirms that MRI can aid in the investigation of acute grade one hamstring muscle strains in predicting recovery time. However the size of the initial strain or the RI do not seem to be reliable indicators in predicting those strains that might recur.

  10. 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.

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

    PubMed Central

    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. PMID:27031239

  12. 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. PMID:27625651

  13. 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.

  14. 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

  15. A modified inflammatory bowel disease questionnaire and the Vaizey Incontinence questionnaire are more sensitive measures of acute gastrointestinal toxicity during pelvic radiotherapy than RTOG grading

    SciTech Connect

    Khalid, Usman; McGough, Camilla; Hackett, Claire; Blake, Peter; Harrington, Kevin J.; Khoo, Vincent S.; Tait, Diana; Norman, Andrew R.; Andreyev, H. Jervoise N. . E-mail: j@andreyev.demon.co.uk

    2006-04-01

    Purpose: Simple scales with greater sensitivity than Radiation Therapy Oncology Group (RTOG) grading to detect acute gastrointestinal toxicity during pelvic radiotherapy, could be clinically useful. Methods and Materials: Do questionnaires used in benign gastrointestinal diseases detect toxicity in patients undergoing radiotherapy? The patient-completed Inflammatory Bowel Disease (IBDQ) and Vaizey Incontinence questionnaires were compared prospectively at baseline and at Week 5 to physician-completed RTOG grading. Results: A total of 107 patients, median age 63 years, were recruited. After 5 weeks of treatment, patients with gynecologic and gastrointestinal cancer were more symptomatic than urologic patients (p 0.012; p = 0.014). Overall, 94% had altered bowel habits, 80% loose stool, 74% frequency, 65% difficult gas, 60% pain, >48% distress, 44% tenesmus, >40% restrictions in daily activity, 39% urgency, 37% fecal incontinence, and 40% required antidiarrheal medication. The median RTOG score was 1 (range, 0-2), median IBDQ score 204.5 (range, 74-224), and median Vaizey score 5 (range, 0-20). Chemotherapy preceding radiotherapy increased fecal incontinence (p 0.002). RTOG scores stabilized after 3 weeks, IBDQ scores peaked at Week 4, and Vaizey scores worsened throughout treatment. IBDQ and Vaizey scores distinguished between groups with different RTOG scores. Conclusion: The IBDQ and Vaizey questionnaires are reliable and sensitive, offering greater insight into the severity and range of symptoms compared with RTOG grading.

  16. Reduced GVHD in C3-deficient mice is associated with the decrease of donor Th1/Th17 differentiation

    PubMed Central

    Ma, Qing; Li, Dan; Nurieva, Roza; Patenia, Rebecca; Bassett, Roland; Cao, Wei; Alekseev, Andrei M.; He, Hong; Molldrem, Jeffrey J.; Kroll, Michael H.; Champlin, Richard E.; Sale, George E.; Afshar-Kharghan, Vahid

    2012-01-01

    Graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is mediated by the activation of recipient dendritic cells (DCs) and subsequent proliferation of donor T cells. Recently complement system has been shown to modulate adaptive immunity through the interaction between the complement system and lymphocytes. Complement proteins participate in the activation of DCs, antigen presentation to T cells, and proliferation of T cells. Our studies with a murine model of bone marrow transplantation (BMT) demonstrate that complement system regulates alloimmune responses in GVHD. Mice deficient in the central component of the complement system (C3−/−) had significantly lower GVHD-related mortality and morbidity compared to the wild type (WT) recipient mice. The number of donor-derived T cells including IFNγ+, IL17+ and IL17+IFNγ+ subsets was decreased in secondary lymphoid organs of C3−/− recipients. Furthermore, there was a reduction of recipient CD8α+CD11c+ in lymphoid organs. We conclude C3 regulates Th1/17 differentiation in BMT, and define a novel function of the complement system in GVHD. PMID:22664751

  17. 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

  18. A Grading System To Evaluate Objectively the Strength of Pre-Clinical Data of Acute Neuroprotective Therapies for Clinical Translation in Spinal Cord Injury

    PubMed Central

    Okon, Elena B.; Tsai, Eve; Beattie, Michael S.; Bresnahan, Jacqueline C.; Magnuson, David K.; Reier, Paul J.; McTigue, Dana M.; Popovich, Phillip G.; Blight, Andrew R.; Oudega, Martin; Guest, James D.; Weaver, Lynne C.; Fehlings, Michael G.; Tetzlaff, Wolfram

    2011-01-01

    Abstract The past three decades have seen an explosion of research interest in spinal cord injury (SCI) and the development of hundreds of potential therapies that have demonstrated some promise in pre-clinical experimental animal models. A growing number of these treatments are seeking to be translated into human clinical trials. Conducting such a clinical trial, however, is extremely costly, not only for the time and money required to execute it, but also for the limited resources that will then no longer be available to evaluate other promising therapies. The decision about what therapies have sufficient pre-clinical evidence of efficacy to justify testing in humans is therefore of utmost importance. Here, we have developed a scoring system for objectively grading the body of pre-clinical literature on neuroprotective treatments for acute SCI. The components of the system include an evaluation of a number of factors that are thought to be important in considering the “robustness” of a therapy's efficacy, including the animal species and injury models that have been used to test it, the time window of efficacy, the types of functional improvements effected by it, and whether efficacy has been independently replicated. The selection of these factors was based on the results of a questionnaire that was performed within the SCI research community. A modified Delphi consensus-building exercise was then conducted with experts in pre-clinical SCI research to refine the criteria and decide upon how to score them. Finally, the grading system was applied to a series of potential neuroprotective treatments for acute SCI. This represents a systematic approach to developing an objective method of evaluating the extent to which the pre-clinical literature supports the translation of a particular experimental treatment into human trials. PMID:20507235

  19. 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

  20. IL-35 inhibits acute graft-versus-host disease in a mouse model.

    PubMed

    Zhang, Xiao-Hui; Zhou, Yi; Zhang, Jia-Min; Zhou, Shi-Yuan; Wang, Min; Feng, Ru; Feng, Fer-Er; Wang, Qian-Ming; Zhu, Xiao-Lu; Zhao, Xiao-Su; Lv, Meng; Kong, Yuan; Chang, Ying-Jun; Huang, Xiao-Jun

    2015-12-01

    Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous study found that the novel anti-inflammatory cytokine IL-35 could suppress aGVHD in patients after allo-HSCT. In this study, we used C57BL/6 (B6, H-2b) mice as donors and (B6×DBA/2) F1 (BDF1, H-2b×d) mice as recipients to create a model of aGVHD and explore the relationship between IL-35 and aGVHD. The mice receiving IL-35 survived longer than did the control mice. We observed that treatment with IL-35 and RAPA could reduce the incidence of aGVHD. Additionally, this treatment inhibited intestinal and thymic epithelial cell apoptosis and liver infiltration by the donor T-cells, thereby ameliorating the enteropathy and liver injury caused by aGVHD. We found that IL-35 and RAPA also markedly suppressed TNF-α and IL-17A expression and enhanced IFN-γ expression in the intestine and liver. We measured Tregs in spleen and found that IL-35 and RAPA treatment expanded the number of Tregs in spleen. We found that the phosphorylation of STAT1 and STAT4 were inhibited in mice with aGVHD. In contrast, STAT1 and STAT4 were phosphorylated when the mice were treated with IL-35. IL-35 may have therapeutic potential in the treatment of aGVHD after allo-HSCT. PMID:26507167

  1. Acute lethal graft-versus-host disease stimulates cellular proliferation in the adult rat liver.

    PubMed

    Klein, R M; Clancy, J; Stuart, S

    1982-11-01

    The present investigation was designed to analyse the effects of acute lethal graft-versus-host disease (GVHD) in adult (DA x LEW)F1 rats on cellular proliferation within the liver. The influence of the host thymus on GVHD-induced proliferation was also assessed. From 1-28 days after initiation of GVHD [3H]thymidine ([3H]-TdR) was injected i.v. and rats were killed one hour later. Percentage labelled cells (LI) of periportal infiltrating cells (PIC), hepatocytes (H), and sinusoidal lining cells (SC) were counted. Mean values for control rats were 0.3 +/- 0.1% (H), 0.4 +/- 0.1% (SC) and 0.2 +/- 0.1% (PIC). GVHD rats demonstrated a significant increase in LI of PIC (days 1-21), SC (days 2-17) and H (days 2-17). Most labelled cells in PIC were large lymphocytes. Peak LI values were 7.0 +/- 1.0% PIC (day 17), 6.8 +/- 0.9% SC (day 17), and 5.2 +/- 0.9% H (day 7), with all cellular compartments returning to near normal LI values by day 28. Stimulation of cellular proliferation occurred in all three liver cell compartments in neonatally thymectomized (TXM) rats. The intensity of GVHD-induced cell proliferation was significantly decreased at day 7 in all compartments and PIC was dramatically decreased at day 21 in TXM-GVHD rats as compared to non-TXM-GVHD rats. It is hypothesized that the general stimulation of hepatocyte cell proliferation in GVHD is related to the secretion of lymphokines by primarily donor and secondarily host T cells in the periportal infiltrate. PMID:7172201

  2. IL-35 inhibits acute graft-versus-host disease in a mouse model.

    PubMed

    Zhang, Xiao-Hui; Zhou, Yi; Zhang, Jia-Min; Zhou, Shi-Yuan; Wang, Min; Feng, Ru; Feng, Fer-Er; Wang, Qian-Ming; Zhu, Xiao-Lu; Zhao, Xiao-Su; Lv, Meng; Kong, Yuan; Chang, Ying-Jun; Huang, Xiao-Jun

    2015-12-01

    Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous study found that the novel anti-inflammatory cytokine IL-35 could suppress aGVHD in patients after allo-HSCT. In this study, we used C57BL/6 (B6, H-2b) mice as donors and (B6×DBA/2) F1 (BDF1, H-2b×d) mice as recipients to create a model of aGVHD and explore the relationship between IL-35 and aGVHD. The mice receiving IL-35 survived longer than did the control mice. We observed that treatment with IL-35 and RAPA could reduce the incidence of aGVHD. Additionally, this treatment inhibited intestinal and thymic epithelial cell apoptosis and liver infiltration by the donor T-cells, thereby ameliorating the enteropathy and liver injury caused by aGVHD. We found that IL-35 and RAPA also markedly suppressed TNF-α and IL-17A expression and enhanced IFN-γ expression in the intestine and liver. We measured Tregs in spleen and found that IL-35 and RAPA treatment expanded the number of Tregs in spleen. We found that the phosphorylation of STAT1 and STAT4 were inhibited in mice with aGVHD. In contrast, STAT1 and STAT4 were phosphorylated when the mice were treated with IL-35. IL-35 may have therapeutic potential in the treatment of aGVHD after allo-HSCT.

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

    PubMed Central

    Richards, Jennifer C.; Crecelius, Anne R.; Larson, Dennis G.

    2015-01-01

    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. PMID:25980023

  4. Modified Extracorporeal Photopheresis with Cells from a Healthy Donor for Acute Graft-versus-Host Disease in a Mouse Model

    PubMed Central

    Budde, Holger; Kolb, Susanne; Salinas Tejedor, Laura; Wulf, Gerald; Reichardt, Holger M.; Riggert, Joachim; Legler, Tobias J.

    2014-01-01

    Background Graft-versus-host disease (GvHD) is a major challenge after hematopoietic stem cell transplantation but treatment options for patients are still limited. In many cases first-line treatment with glucocorticoids is not successful. Among second-line therapies the extracorporeal photopheresis (ECP) is frequently performed, due to induction of selective tolerance instead of general immunosuppression. However, for some patients with severe acute GvHD the leukapheresis step of the ECP procedure is physically exhausting and limits the number of ECP cycles. Methods We hypothesized that leukocytes from healthy cell donors could be used as a replacement for ECP leukocytes gained from the GvHD patient. For this purpose we used a well established mouse model of acute GvHD. The ECP therapy was based on cells with the genetic background of the initial donor of the stem cell transplantation. As a precondition we developed a protocol representing conventional ECP in mice equivalent to clinical used ECP setup. Results We could demonstrate that conventional, clinically derived ECP setup is able to alleviate acute GvHD. By using leukocytes obtained from healthy mice with the bone marrow donor’s genetic background we could not observe a statistically significant therapeutic effect. Conclusions Conventional human ECP setup is effective in the mouse model of severe acute GvHD. In addition we could not prove that ECP cells from healthy mice with bone marrow donor’s genetic background are as effective as ECP cells derived from GvHD mice. Based on our findings, new questions arise for further studies, in which the cellular characteristics for ECP mediated immune tolerance are a matter of investigation. PMID:25148404

  5. Antilymphocytic antibodies and marrow transplantation. VIII. Recipient conditioning with Clq-affine monoclonal anti-pan T antibodies prevents GVHD in homozygous fully mismatched mice

    SciTech Connect

    Thierfelder, S.; Kummer, U.; Schuh, R.; Mysliwietz, J.

    1986-10-01

    An approach to suppressing secondary disease with antibodies was studied that differed from conventional antibody treatment of donor marrow in vitro. It consisted of the selection of anti-Thy-1 antibodies with high affinity for Clq, the first subunit of the complement cascade, and a single injection of such antibodies into prospective irradiated marrow recipients. Monoclonal mouse IgM and rat IgG 2c antibodies of high titers in complement-dependent test systems but with low affinity for Clq caused little immunosuppression. Monoclonal rat IgG2b or mouse IgG2a anti-Thy-1 antibodies with high affinity for Clq prevented acute and chronic mortality of graft-v-host disease (GVHD), however, when injected in irradiated CBA or AKR mice prior to C57BL/6 spleen and/or bone marrow cell transfusion. This treatment simultaneously suppressed residual host-v-graft reactivity of the irradiated mice, so that permanent hematopoietic engraftment ensued even at 5 or 6 Gy. Full chimerism and specific tolerance were obtained. Primary immune response to SRBC was clearly depressed in the chimeras; secondary immune response was not. Clearance of T cell antibody activity (greater than 6 days), timing, and dose of injected antibody, as well as other modalities of the conditioning treatment that may have contributed to the remarkable immunosuppression, are discussed.

  6. miR-146b antagomir-treated human Tregs acquire increased GVHD inhibitory potency.

    PubMed

    Lu, Yunjie; Hippen, Keli L; Lemire, Amanda L; Gu, Jian; Wang, Weizhi; Ni, Xuhao; Ranganathan, Parvathi; Levine, Bruce L; Riley, James L; June, Carl H; Turka, Laurence A; Munn, David H; Garzon, Ramiro; Lu, Ling; Blazar, Bruce R

    2016-09-01

    CD4(+)CD25(+)FoxP3(+) thymic-derived regulatory T cells (tTregs) are indispensable for maintaining immune system equilibrium. Adoptive transfer of tTregs is an effective means of suppressing graft-versus-host disease (GVHD) in murine models and in early human clinical trials. Tumor necrosis factor receptor-associated factor 6 (TRAF6), an ubiquitin-conjugating enzyme that mediates nuclear factor κB (NF-κB) activation, plays an essential role in modulating regulatory T cell survival and function. MicroRNAs (miRNAs) are noncoding RNAs, which mediate RNA silencing and posttranscriptional gene repression. By performing comprehensive TaqMan Low Density Array miRNA assays, we identified 10 miRNAs differentially regulated in human tTreg compared with control T cells. One candidate, miR-146b, is preferentially and highly expressed in human naive tTregs compared with naive CD4 T cells. miRNA prediction software revealed that TRAF6 was the one of the top 10 scored mRNAs involved tTreg function with the highest probability as a potential miR-146b target. Antagomir-mediated knockdown of miRNA-146b, but not another miRNA-146 family member (miRNA-146a), enhanced TRAF6 expression. TRAF6, in turn, increases NF-κB activation, which is essential for tTreg function as well as Foxp3 protein and antiapoptotic gene expression, and downregulates proapoptotic gene expression. miR-146b knockdown increased the nuclear localization and expression of genes regulated by NF-κB, which was associated with enhanced tTreg survival, proliferation, and suppressive function measured in vitro and in vivo. TRAF6 inhibition had the opposite effects. We conclude that an miR-146b-TRAF6-NF-κB-FoxP3 signaling pathway restrains regulatory T cell survival, proliferation, and suppressor function. In vitro exposure of human tTregs to miR-146b antagomirs can be exploited to improve the clinical efficacy of human adoptive tTreg transfer in a GVHD setting. PMID:27485827

  7. 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.

  8. Modulation of Immunoregulatory Properties of Mesenchymal Stromal Cells by Toll-Like Receptors: Potential Applications on GVHD

    PubMed Central

    2016-01-01

    In the last decade, the immunomodulatory properties of mesenchymal stromal cells (MSCs) have attracted a lot of attention, due to their potential applicability in the treatment of graft-versus-host disease (GVHD), a condition frequently associated with opportunistic infections. The present review addresses how Pathogen-Associated Molecular Patterns (PAMPS) modulate the immunosuppressive phenotype of human MSCs by signaling through Toll-like receptors (TLRs). Overall, we observed that regardless of the source tissue, human MSCs express TLR2, TLR3, TLR4, and TLR9. Stimulation of distinct TLRs on MSCs elicits distinct inflammatory signaling pathways, differentially influencing the expression of inflammatory factors and the ability of MSCs to suppress the proliferation of immune system cells. The capacity to enhance the immunosuppressive phenotype of MSCs through TLRs stimulation might be properly elucidated in order to improve the MSC-based immunotherapy against GVHD. PMID:27738438

  9. UVB pretreatment of rat bone marrow allografts. Prevention of GVHD and induction of allochimerism and donor-specific unresponsiveness

    SciTech Connect

    Chabot, J.A.; Pepino, P.; Wasfie, T.; Stegall, M.D.; Marboe, C.; Hardy, M.A. )

    1990-05-01

    Ultraviolet B irradiation has been used to pretreat blood and islets to prevent subsequent graft rejection. In this study the optimal dose of UVB irradiation of bone marrow was determined in syngeneic recipients and was subsequently applied to in-vitro treatment of bone marrow allografts. UVB pretreatment of donor bone marrow inoculum led to complete prevention of GVHD in allogeneic rat recipients without major marrow or other toxicity. Long-standing recipients of allogeneic UVB-BM became stable adult chimeras. The recipients of allogeneic BM were populated by donor-type peripheral blood lymphocytes and did not reject host or donor-type heart grafts. The BM allograft recipients were immunocompetent as measured by their ability to normally reject third-party cardiac allografts. We suggest that the prevention of GVHD and induction of stable chimerism in adult recipients of allogeneic UVB-BM may be mediated by suppressor mechanisms.

  10. Endothelial microparticles carrying hedgehog-interacting protein induce continuous endothelial damage in the pathogenesis of acute graft-versus-host disease.

    PubMed

    Nie, Di-Min; Wu, Qiu-Ling; Zheng, Peng; Chen, Ping; Zhang, Ran; Li, Bei-Bei; Fang, Jun; Xia, Ling-Hui; Hong, Mei

    2016-05-15

    Accumulating evidence suggests that endothelial microparticles (EMPs), a marker of endothelial damage, are elevated in acute graft-versus-host disease (aGVHD), and that endothelial damage is implicated in the pathogenesis of aGVHD, but the mechanisms remain elusive. In this study, we detected the plasma EMP levels and endothelial damage in patients and mice with aGVHD in vivo and then examined the effects of EMPs derived from injured endothelial cells (ECs) on endothelial damage and the role of hedgehog-interacting protein (HHIP) carried by EMPs in these effects in vitro. Our results showed that EMPs were persistently increased in the early posttransplantation phase in patients and mice with aGVHD. Meanwhile, endothelial damage was continuous in aGVHD mice, but was temporary in non-aGVHD mice after transplantation. In vitro, EMPs induced endothelial damage, including increased EC apoptosis, enhanced reactive oxygen species, decreased nitric oxide production and impaired angiogenic activity. Enhanced expression of HHIP, an antagonist for the Sonic hedgehog (SHH) signaling pathway, was observed in patients and mice with aGVHD and EMPs from injured ECs. The endothelial damage induced by EMPs was reversed when the HHIP incorporated into EMPs was silenced with an HHIP small interfering RNA or inhibited with the SHH pathway agonist, Smoothened agonist. This work supports a feasible vicious cycle in which EMPs generated during endothelial injury, in turn, aggravate endothelial damage by carrying HHIP into target ECs, contributing to the continuously deteriorating endothelial damage in the development of aGVHD. EMPs harboring HHIP would represent a potential therapeutic target for aGVHD. PMID:27009877

  11. Graft monocytic myeloid-derived suppressor cell content predicts the risk of acute graft-versus-host disease after allogeneic transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells.

    PubMed

    Vendramin, Antonio; Gimondi, Silvia; Bermema, Anisa; Longoni, Paolo; Rizzitano, Sara; Corradini, Paolo; Carniti, Cristiana

    2014-12-01

    Myeloid-derived suppressor cells (MDSCs) are powerful immunomodulatory cells that in mice play a role in infectious and inflammatory disorders, including acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Their relevance in clinical acute GVHD is poorly known. We analyzed whether granulocyte colony-stimulating factor (G-CSF) administration, used to mobilize hematopoietic stem cells, affected the frequency of MDSCs in the peripheral blood stem cell grafts of 60 unrelated donors. In addition, we evaluated whether the MDSC content in the peripheral blood stem cell grafts affected the occurrence of acute GVHD in patients undergoing unrelated donor allogeneic stem cell transplantation. Systemic treatment with G-CSF induces an expansion of myeloid cells displaying the phenotype of monocytic MDSCs (Lin(low/neg)HLA-DR(-)CD11b(+)CD33(+)CD14(+)) with the ability to suppress alloreactive T cells in vitro, therefore meeting the definition of MDSCs. Monocytic MDSC dose was the only graft parameter to predict acute GVHD. The cumulative incidence of acute GVHD at 180 days after transplantation for recipients receiving monocytic MDSC doses below and above the median was 63% and 22%, respectively (P = .02). The number of monocytic MDSCs infused did not impact the relapse rate or the transplant-related mortality rate (P > .05). Although further prospective studies involving larger sample size are needed to validate the exact monocytic MDSC graft dose that protects from acute GVHD, our results strongly suggest the modulation of G-CSF might be used to affect monocytic MDSCs graft cell doses for prevention of acute GVHD.

  12. 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.

  13. 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

  14. Use of noninvasive ventilation at the pulmonary infection control window for acute respiratory failure in AECOPD patients: A systematic review and meta-analysis based on GRADE approach.

    PubMed

    Peng, Le; Ren, Peng-Wei; Liu, Xue-Ting; Zhang, Chao; Zuo, Hong-Xia; Kang, De-Ying; Niu, Yu-Ming

    2016-06-01

    The aim of the study was to comprehensively examine the efficacy and safety of noninvasive ventilation used at the pulmonary infection control (PIC) window for acute respiratory failure (ARF) in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD).Seven electronic databases and relevant resources were searched to identify randomized controlled trials (RCTs) comparing patients using noninvasive ventilation at PIC window with those continuing receiving invasive ventilation. Retrieved citations were screened, risk of bias was assessed, and data were extracted by 2 independent review authors. Overall effect sizes were synthesized by using meta-analyses. Quality of evidence was rated by using Grading of Recommendations, Assessment, Development and Evaluation approach.A total of 17 trials involving 959 participants were included for this review. Compared with continuous invasive ventilation, noninvasive ventilation used at PIC window significantly reduced mortality, ventilator-associated pneumonia, weaning failures, reintubations, duration of invasive ventilation, total duration of mechanical ventilation, length of stay (LOS) in intensive care unit, and LOS in hospital as well as hospital costs. Of these, mortality significantly decreased (risk ratio = 0.27, 95% confidence interval: 0.17-0.42, P < 0.001) without significant heterogeneity (I = 0%, P = 0.99). Quality of evidence regarding the 9 outcomes across the included studies was rated from moderate to low.Use of noninvasive ventilation at PIC window showed beneficial effects across identified trials for ARF in AECOPD patients. Considering the absence of high quality of available evidence and the uncertainty of long-term effect of this intervention, a weak recommendation for clinical practice was generated, and further well-designed and adequately powered RCTs are required to validate this conclusion. PMID:27310978

  15. Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality.

    PubMed

    Jasperson, Lisa K; Bucher, Christoph; Panoskaltsis-Mortari, Angela; Mellor, Andrew L; Munn, David H; Blazar, Bruce R

    2009-12-01

    During graft-versus-host disease (GVHD), donor T cells become activated and migrate to tissue sites. Previously, we demonstrated a crucial role for the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) in GVHD regulation. Here, we show that upon arrival in the colon, activated donor T cells produced interferon-gamma that up-regulated IDO, causing T-cell anergy and apoptosis. IDO induces GCN2 kinase, up-regulating a T-cell stress response implicated in IDO immunosuppression. Donor T cells did not require GCN2 kinase to respond to IDO, suggesting toxic IDO metabolites, and not tryptophan depletion, were responsible for suppression. When exogenous metabolites were administered, GVHD lethality was reduced. To determine whether IDO could be induced before transplantation for enhanced GVHD suppression, we first determined whether antigen-presenting cells (APCs) or epithelial cells were primarily responsible for IDO expression and subsequent GVHD suppression. Recipients with wild-type versus IDO(-/-) APCs had increased survival, regardless of epithelial-cell expression of IDO, suggesting that APCs were suitable targets for inducing IDO. Administration of an agonist to toll-like receptor-7/8, a receptor expressed primarily on APCs, induced IDO and reduced injury in the colon and ameliorated lethality. We conclude that IDO up-regulation may have therapeutic potential for preventing GVHD in the clinic.

  16. 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.

  17. Angiogenic factors are associated with development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Nie, Di-min; Wu, Qiu-ling; Zhu, Xia-xia; Zhang, Ran; Zheng, Peng; Fang, Jun; You, Yong; Zhong, Zhao-dong; Xia, Ling-hui; Hong, Mei

    2015-10-01

    Acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the mechanisms of aGVHD are not well understood. We aim to investigate the roles of the three angiogenic factors: angiopoietin-1 (Ang-1), Ang-2 and vascular endothelial growth factor (VEGF) in the development of aGVHD. Twenty-one patients who underwent allo-HSCT were included in our study. The dynamic changes of Ang-1, Ang-2 and VEGF were monitored in patients before and after allo-HSCT. In vitro, endothelial cells (ECs) were treated with TNF-β in the presence or absence of Ang-1, and then the Ang-2 level in the cell culture medium and the tubule formation by ECs were evaluated. After allo-HSCT, Ang-1, Ang-2 and VEGF all exhibited significant variation, suggesting these factors might be involved in the endothelial damage in transplantation. Patients with aGVHD had lower Ang-1 level at day 7 but higher Ang-2 level at day 21 than those without aGVHD, implying that Ang-1 may play a protective role in early phase yet Ang-2 is a promotion factor to aGVHD. In vitro, TNF-β promoted the release of Ang-2 by ECs and impaired tubule formation of ECs, which were both weakened by Ang-1, suggesting that Ang-1 may play a protective role in aGVHD by influencing the secretion of Ang-2, consistent with our in vivo tests. It is concluded that monitoring changes of these factors following allo-HSCT might help to identify patients at a high risk for aGVHD. PMID:26489624

  18. Preventive azithromycin treatment reduces noninfectious lung injury and acute graft-versus-host disease in a murine model of allogeneic hematopoietic cell transplantation.

    PubMed

    Radhakrishnan, Sabarinath Venniyil; Palaniyandi, Senthilnathan; Mueller, Gunnar; Miklos, Sandra; Hager, Max; Spacenko, Elena; Karlsson, Fridrik J; Huber, Elisabeth; Kittan, Nicolai A; Hildebrandt, Gerhard C

    2015-01-01

    Noninfectious lung injury and acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) are associated with significant morbidity and mortality. Azithromycin is widely used in allogeneic HCT recipients for pulmonary chronic GVHD, although current data appear controversial. We induced GVHD and noninfectious lung injury in lethally irradiated B6D2F1 mice by transplanting bone marrow and splenic T cells from allogeneic C57BL/6 mice. Experimental groups were treated with oral azithromycin starting on day 14 until the end of week 6 or week 14 after transplantation. Azithromycin treatment resulted in improved survival and decreased lung injury; the latter characterized by improved pulmonary function, reduced peribronchial and perivascular inflammatory cell infiltrates along with diminished collagen deposition, and a decrease in lung cytokine and chemokine expression. Azithromycin also improved intestinal GVHD but did not affect liver GVHD at week 6 early after transplantation. At week 14, azithromycin decreased liver GVHD but had no effect on intestinal GVHD. In vitro, allogeneic antigen-presenting cell (APC)- dependent T cell proliferation and cytokine production were suppressed by azithromycin and inversely correlated with relative regulatory T cell (Treg) expansion, whereas no effect was seen when T cell proliferation occurred APC independently through CD3/CD28-stimulation. Further, azithromycin reduced alloreactive T cell expansion but increased Treg expansion in vivo with corresponding downregulation of MHC II on CD11c(+) dendritic cells. These results demonstrate that preventive administration of azithromycin can reduce the severity of acute GVHD and noninfectious lung injury after allo-HCT, supporting further investigation in clinical trials.

  19. 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.

  20. Sirolimus and Mycophenolate Mofetil in Preventing GVHD in Patients With Hematologic Malignancies Undergoing HSCT

    ClinicalTrials.gov

    2016-06-14

    Adult Hodgkin Lymphoma; Adult Myelodysplastic Syndrome; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Hodgkin Lymphoma; Childhood Myelodysplastic Syndrome; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Myelofibrosis; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Non-Hodgkin Lymphoma

  1. Differential effects of the absence of interferon-gamma and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice.

    PubMed Central

    Murphy, W J; Welniak, L A; Taub, D D; Wiltrout, R H; Taylor, P A; Vallera, D A; Kopf, M; Young, H; Longo, D L; Blazar, B R

    1998-01-01

    Graft-versus-host disease (GVHD), in which immunocompetent donor cells attack the host, remains a major cause of morbidity after allogeneic bone marrow transplantation (BMT). To understand the role of cytokines in the pathobiology of GVHD, we used cytokine knockout (KO) mice as a source of donor T cells. Two different MHC-disparate strain combinations were examined: BALB/c (H2(d)) donors into lethally irradiated C57BL/6 (H2(b)) recipients or C57BL/6 (H2(b)) donors into B10.BR (H2(k)) recipients. Donor cells were from mice in which either the interferon-gamma (IFN-gamma) or the IL-4 gene was selectively disrupted to understand the role of these cytokines in acute GVHD. In both strain combinations the same pattern was noted with regard to GVHD onset and morbidity. All mice exhibited the classic signs of acute GVHD: weight loss with skin, gut, and liver pathology resulting in morbidity and mortality. Surprisingly, donor cells obtained from mice lacking IFN-gamma gave rise to accelerated morbidity from GVHD when compared with cells from wild-type control donors. Similar results were obtained using normal donors when neutralizing antibodies to IFN-gamma were administered immediately after the BMT. These results suggest that IFN-gamma plays a role in protection from acute GVHD. In marked contrast, cells obtained from IL-4 KO mice resulted in protection from GVHD compared with control donors. Splenocytes from IFN KO mice stimulated with a mitogen proliferated to a significantly greater extent and produced more IL-2 compared with splenocytes obtained from IL-4 KO or control mice. Additionally, there was increased IL-2 production in the spleens of mice undergoing GVHD using IFN-gamma KO donors. These results therefore indicate, with regard to the TH1/ TH2 cytokine paradigm, the absence of a TH1-type cytokine can be deleterious in acute GVHD, whereas absence of a TH2 cytokine can be protective. PMID:9802888

  2. Oral glutamine supplementation improves intestinal permeability dysfunction in a murine acute graft-vs.-host disease model.

    PubMed

    Noth, Rainer; Häsler, Robert; Stüber, Eckhard; Ellrichmann, Mark; Schäfer, Heiner; Geismann, Claudia; Hampe, Jochen; Bewig, Burkhard; Wedel, Thilo; Böttner, Martina; Schreiber, Stefan; Rosenstiel, Philip; Arlt, Alexander

    2013-04-01

    Although a profound barrier dysfunction has been reported, little is known about the pathophysiological mechanism evoking gastrointestinal graft-vs.-host disease (GI-GvHD) and apparent therapeutic options. The aim of this study was to evaluate the influence of oral glutamine on the course of GI-GvHD in an acute semiallogenic graft-vs.-host disease (GvHD) in irradiated B6D2F1 mice. An acute semiallogenic GvHD was induced by intraperitoneal injection of lymphocytes from C57BL/6 mice to irradiated B6D2F1 mice. Half of the GvHD animals received oral glutamine supplementation for 6 days started at the time of lymphocyte transfer. Six days after induction of the semiallogenic GvHD, jejunum specimens were prepared. The expression of the proinflammatory cytokine TNF-α and the tight junction protein occludin was investigated by PCR. Histological changes along with the apoptotic response were evaluated and intestinal permeability was assessed. Animals with GvHD showed a strong increase in paracellular permeability as a sign of the disturbed barrier function. TNF-α expression was significantly increased and the expression of the tight junction protein occludin decreased. GvHD led to mucosal atrophy, crypt hyperplasia, crypt apoptosis, and a disintegration of the tight junctions. Glutamine-treated mice showed reduced expression of TNF-α, increased occludin expression, fewer histological changes in the jejunum, smaller number of apoptotic cells in the crypt, and reduced gastrointestinal permeability. In conclusion, oral glutamine seems to have beneficial effects on the severity of inflammatory changes in the course of GvHD and might be a therapeutic option.

  3. Patient Specific Characteristics Are an Important Factor That Determines the Risk of Acute Grade ≥ 2 Rectal Toxicity in Patients Treated for Prostate Cancer with IMRT and Daily Image Guidance Based on Implanted Gold Markers

    PubMed Central

    Liu, Xiaonan; Li, Jing; Wu, Teresa; Schild, Steven E; Schild, Michael H; Wong, William; Vora, Sujay; Fatyga, Mirek

    2016-01-01

    Aim To model acute rectal toxicity in Intensity Modulated Radiation Therapy (IMRT) for prostate cancer using dosimetry and patient specific characteristics. Methods A database of 79 prostate cancer patients treated with image guided IMRT was used to fit parameters of Lyman-Kutcher-Burman (LKB) and logistic regression Normal Tissue Complications Probability (NTCP) models to acute grade ≥ 2 rectal toxicities. We used a univariate regression model to find the dosimetric index which was most correlated with toxicity and a multivariate logistic regression model with machine learning algorithm to integrate dosimetry with patient specific characteristics. We used Receiver Operating Characteristics (ROC) analysis and the area under the ROC curve (AUC) to quantify the predictive power of models. Results Sixteen patients (20.3%) developed acute grade≥2 rectal toxicity. Our best estimate (95% confidence interval) of LKB model parameters for acute rectal toxicity are exponent n=0.13 (0.1–0.16), slope m=0.09 (0.08–0.11), and threshold dose TD50=56.8 (53.7–59.9) Gy. The best dosimetric indices in the univariate logistic regression NTCP model were D25% and V50Gy. The best AUC of dosimetry only modeling was 0.67 (0.54, 0.8). In the multivariate logistic regression two patient specific variables were particularly strongly correlated with acute rectal toxicity, the use of statin drugs and PSA level prior to IMRT, while two additional variables, age and diabetes were weakly correlated. The AUC of the logistic regression NTCP model improved to 0.88 (0.8, 0.96) when patient specific characteristics were included. In a group of 79 patients, 40 took Statins and 39 did not. Among patients who took statins, (4/40)=10% developed acute grade ≥2 rectal toxicity, compared to (12/39)=30.8% who did not take statins (p=0.03). The average and standard deviation of PSA distribution for patients with acute rectal toxicity was PSAtox = 5.77 ± 2.27 and it was PSAnotox = 9.5 ± 7.8 for the

  4. The Prognostic Value of a Four-Dimensional CT Angiography-Based Collateral Grading Scale for Reperfusion Therapy in Acute Ischemic Stroke Patients

    PubMed Central

    Zhang, Sheng; Chen, Weili; Tang, Huan; Han, Quan; Yan, Shenqiang; Zhang, Xiaocheng; Chen, Qingmeng; Parsons, Mark; Wang, Shaoshi; Lou, Min

    2016-01-01

    Objective Leptomeningeal collaterals, which affects tissue fate, are still challenging to assess. Four-dimensional CT angiography (4D CTA) originated from CT perfusion (CTP) provides the possibility of non-invasive and time-resolved assessment of leptomeningeal collateral flow. We sought to develop a comprehensive rating system to integrate the speed and extent of collateral flow on 4D CTA, and investigate its prognostic value for reperfusion therapy in acute ischemic stroke (AIS) patients. Methods We retrospectively studied 80 patients with M1 ± internal carotid artery (ICA) occlusion who had baseline CTP before intravenous thrombolysis. The velocity and extent of collaterals were evaluated by regional leptomeningeal collateral score on peak phase (rLMC-P) and temporally fused intensity projections (tMIP) (rLMC-M) on 4D CTA, respectively. The cutoffs of rLMC-P and rLMC-M score for predicting good outcome (mRS score ≤ 2) were integrated to develop the collateral grading scale (CGS) (rating from 0–2). Results The CGS score was correlated with 3-months mRS score (non-recanalizers: ρ = -0.495, p = 0.01; recanalizers: ρ = -0.671, p < 0.001). Patients with intermediate or good collaterals (CGS score of 1 and 2) who recanalized were more likely to have good outcome than those without recanalization (p = 0.038, p = 0.018), while there was no significant difference in outcome in patients with poor collaterals (CGS score of 0) stratified by recanalization (p = 0.227). Conclusions Identification of collaterals based on CGS may help to select good responders to reperfusion therapy in patients with large artery occlusion. PMID:27505435

  5. 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 "Grade Span and…

  6. Acute graft-versus-host disease: a bench-to-bedside update.

    PubMed

    Holtan, Shernan G; Pasquini, Marcelo; Weisdorf, Daniel J

    2014-07-17

    Over the past 5 years, many novel approaches to early diagnosis, prevention, and treatment of acute graft-versus-host disease (aGVHD) have been translated from the bench to the bedside. In this review, we highlight recent discoveries in the context of current aGVHD care. The most significant innovations that have already reached the clinic are prophylaxis strategies based upon a refinement of our understanding of key sensors, effectors, suppressors of the immune alloreactive response, and the resultant tissue damage from the aGVHD inflammatory cascade. In the near future, aGVHD prevention and treatment will likely involve multiple modalities, including small molecules regulating immunologic checkpoints, enhancement of suppressor cytokines and cellular subsets, modulation of the microbiota, graft manipulation, and other donor-based prophylaxis strategies. Despite long-term efforts, major challenges in treatment of established aGVHD still remain. Resolution of inflammation and facilitation of rapid immune reconstitution in those with only a limited response to corticosteroids is a research arena that remains rife with opportunity and urgent clinical need. PMID:24914140

  7. 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

  8. Small Bowel Dose Parameters Predicting Grade ≥3 Acute Toxicity in Rectal Cancer Patients Treated With Neoadjuvant Chemoradiation: An Independent Validation Study Comparing Peritoneal Space Versus Small Bowel Loop Contouring Techniques

    SciTech Connect

    Banerjee, Robyn; Chakraborty, Santam; Nygren, Ian; Sinha, Richie

    2013-04-01

    Purpose: To determine whether volumes based on contours of the peritoneal space can be used instead of individual small bowel loops to predict for grade ≥3 acute small bowel toxicity in patients with rectal cancer treated with neoadjuvant chemoradiation therapy. Methods and Materials: A standardized contouring method was developed for the peritoneal space and retrospectively applied to the radiation treatment plans of 67 patients treated with neoadjuvant chemoradiation therapy for rectal cancer. Dose-volume histogram (DVH) data were extracted and analyzed against patient toxicity. Receiver operating characteristic analysis and logistic regression were carried out for both contouring methods. Results: Grade ≥3 small bowel toxicity occurred in 16% (11/67) of patients in the study. A highly significant dose-volume relationship between small bowel irradiation and acute small bowel toxicity was supported by the use of both small bowel loop and peritoneal space contouring techniques. Receiver operating characteristic analysis demonstrated that, for both contouring methods, the greatest sensitivity for predicting toxicity was associated with the volume receiving between 15 and 25 Gy. Conclusion: DVH analysis of peritoneal space volumes accurately predicts grade ≥3 small bowel toxicity in patients with rectal cancer receiving neoadjuvant chemoradiation therapy, suggesting that the contours of the peritoneal space provide a reasonable surrogate for the contours of individual small bowel loops. The study finds that a small bowel V15 less than 275 cc and a peritoneal space V15 less than 830 cc are associated with a less than 10% risk of grade ≥3 acute toxicity.

  9. 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.

  10. 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. PMID:24816030

  11. 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.

  12. Topical Tacrolimus with Custom Trays in the Treatment of Severe Oral cGVHD Refractory to a Potent Topical Steroid Therapy: A Case Report

    PubMed Central

    Brown, Ronald S.; Edwards, Dean; Walsh-Chocolaad, Tracey; Childs, Richard W.

    2012-01-01

    Background The authors present a case demonstrating the success of topical tacrolimus (TAC) therapy with custom trays in the treatment of oral chronic graft versus host disease (cGVHD). The 41 year-old male patient initially responded to topical steroid therapy (clobetasol propionate 0.05% ointment) applied both topically and with flexible carrier trays, but later became refractory to this potent topical agent. Topical TAC therapy with flexible carrier trays and systemic prednisone therapy was initiated. Results The patient responded favorably with the change to topical TAC therapy with custom trays (and oral prednisone). His oral cGVHD lesions resolved within a period of four weeks. The improvement has remained stable at 14 month follow-up. Clinical Implications This is the first case reported with regard to the successful resolution of steroid recalcitrant cGVHD successfully treated with topical TAC with custom trays. PMID:23102802

  13. CD4+ invariant natural killer T cells protect from murine GVHD lethality through expansion of donor CD4+CD25+FoxP3+ regulatory T cells.

    PubMed

    Schneidawind, Dominik; Pierini, Antonio; Alvarez, Maite; Pan, Yuqiong; Baker, Jeanette; Buechele, Corina; Luong, Richard H; Meyer, Everett H; Negrin, Robert S

    2014-11-20

    Dysregulated donor T cells lead to destruction of host tissues resulting in graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We investigated the impact of highly purified (>95%) donor CD4(+) invariant natural killer T (iNKT) cells on GVHD in a murine model of allogeneic HCT. We found that low doses of adoptively transferred donor CD4(+) iNKT cells protect from GVHD morbidity and mortality through an expansion of donor CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs). These Tregs express high levels of the Ikaros transcription factor Helios and expand from the Treg pool of the donor graft. Furthermore, CD4(+) iNKT cells preserve T-cell-mediated graft-versus-tumor effects. Our studies reveal new aspects of the cellular interplay between iNKT cells and Tregs in the context of tolerance induction after allogeneic HCT and set the stage for clinical translation. PMID:25293774

  14. Genital chronic GVHD in men after hematopoietic stem cell transplantation: a single-center cross-sectional analysis of 155 patients.

    PubMed

    Mueller, Simon M; Haeusermann, Peter; Rovó, Alicia; Halter, Joerg P; Passweg, Jakob; Itin, Peter; Tichelli, André

    2013-11-01

    We assessed the prevalence and clinical features of genital skin changes in men after allogeneic hematopoietic stem cell transplantation (HSCT) and evaluated the correlation between genital chronic graft-versus-host disease (cGVHD) and other manifestations of cGVHD as well as sexual issues. In a cross-sectional cohort study, 155 male recipients alive 1 year or more after HSCT were assessed during their annual follow-up evaluation. Correlation between genital skin changes and other cGVHD manifestations was evaluated, and post-transplantation sexual contentment and sexual functioning were assessed by 2 self-assessment questionnaires, including the 5-item version of the International Index of Erectile Function (IIEF-5) and the modified Brief Sexual Symptom Checklist (mBSSC). Median time between HSCT and genital examination was 5.9 years (range, 1 to 30.3 years). Thirty-one of 155 patients (20%) presented with genital skin changes. Twenty-one of those (13%) presented clinically inflammatory genital skin changes considered as genital cGVHD: 12 had inflammatory (noninfectious) balanoposthitis, 6 had lichen sclerosis-like lesions, 5 had phimosis, and 2 patients had more than 1 feature. Patients with inflammatory genital skin changes had a significantly higher coincidence of oral (P < .0001), ocular (P < .002), and/or cutaneous cGVHD (P < .026) when compared with patients without genital lesions. The rate of IIEF-5 questionnaire response was 59% (91 of 155). Among them, 67% reported erectile dysfunction. Erectile dysfunction was significantly more frequent in patients with genital cGVHD (P = .0075). Seventy-five of 155 patients (48%) answered the mBSSC questionnaire. Only 40% of them reported sexual contentment. Genital skin changes in male recipients after allogeneic HSCT are frequent and seem to be an under-reported relevant late effect. Inflammatory genital skin changes can be considered as a form of genital cGVHD often associated with manifestations of extragenital

  15. 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

  16. miR-146a and miR-155 Expression Levels in Acute Graft-Versus-Host Disease Incidence

    PubMed Central

    Atarod, Sadaf; Ahmed, Mohammed Mahid; Lendrem, Clare; Pearce, Kim Frances; Cope, Wei; Norden, Jean; Wang, Xiao-Nong; Collin, Matthew; Dickinson, Anne Mary

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for numerous hematological malignancies. However, acute graft-versus-host disease (aGVHD) is still the major complication causing mortality. MicroRNAs (miRNAs) play a significant role in inflammation and have potential as prognostic and diagnostic biomarkers. This study investigated the role of two immune-specific miRNAs (miR-146a and miR-155) as biomarkers for aGVHD incidence in the peripheral blood of allo-HSCT patients prior to disease onset. The study showed that miR-146a and its statistical interaction with miR-155 at day +28 were predictive of aGVHD incidence. Interestingly, the expression levels of miR-146a and miR-155 negatively correlated with the transcription factor, SPI1 (PU.1gene) mRNA expression. PMID:27014257

  17. Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD.

    PubMed

    MacDonald, Kelli P A; Kuns, Rachel D; Rowe, Vanessa; Morris, Edward S; Banovic, Tatjana; Bofinger, Helen; O'Sullivan, Brendan; Markey, Kate A; Don, Alistair L; Thomas, Ranjeny; Hill, Geoffrey R

    2007-06-01

    Antigen-presenting cells (APCs) are critical for the initiation of graft-versus-host disease (GVHD), although the responsible APC subset and molecular mechanisms remain unclear. Because dendritic cells (DCs) are the most potent APCs and the NF-kB/Rel family member RelB is associated with DC maturation and potent APC function, we examined their role in GVHD. Within 4 hours of total body irradiation, RelB nuclear translocation was increased and restricted to CD11c(hi) DCs within the host APC compartment. Furthermore, the transient depletion of CD11c(hi) donor DCs that reconstitute in the second week after transplantation resulted in a transient decrease in GVHD severity. By using RelB(-/-) bone marrow chimeras as transplant recipients or RelB(-/-) donor bone marrow, we demonstrate that the induction and maintenance of GVHD is critically dependent on this transcription factor within both host and donor APCs. Critically, RelB within APCs was required for the expansion of donor helper T cell type 1 (Th1) effectors and subsequent alloreactivity, but not the peripheral expansion or function of donor FoxP3(+) regulatory T cells. These data suggest that the targeted inhibition of nuclear RelB translocation within APCs represents an attractive therapeutic strategy to dissociate effector and regulatory T-cell function in settings of Th1-mediated tissue injury.

  18. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD

    PubMed Central

    Alho, Ana C.; Kim, Haesook T.; Chammas, Marie J.; Reynolds, Carol G.; Matos, Tiago R.; Forcade, Edouard; Whangbo, Jennifer; Nikiforow, Sarah; Cutler, Corey S.; Koreth, John; Ho, Vincent T.; Armand, Philippe; Antin, Joseph H.; Alyea, Edwin P.; Lacerda, Joao F.; Soiffer, Robert J.

    2016-01-01

    The development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells. To characterize the complex mechanisms that lead to unbalanced recovery of these distinct T-cell populations, we studied 107 adult patients who received T-replete stem cell grafts after reduced-intensity conditioning. Immune reconstitution of CD4Treg, CD4Tcon, and CD8 T cells was monitored for a 2-year period. CD3 T-cell counts gradually recovered to normal levels during this period but CD8 T cells recovered more rapidly than either CD4Tregs or CD4Tcons. Reconstituting CD4Tregs and CD4Tcons were predominantly central memory (CM) and effector memory (EM) cells and CD8 T cells were predominantly terminal EM cells. Thymic generation of naive CD4Tcon and CD8 T cells was maintained but thymic production of CD4Tregs was markedly decreased with little recovery during the 2-year study. T-cell proliferation was skewed in favor of CM and EM CD4Tcon and CD8 T cells, especially 6 to 12 months after HSCT. Intracellular expression of BCL2 was increased in CD4Tcon and CD8 T cells in the first 3 to 6 months after HSCT. Early recovery of naive and CM fractions within each T-cell population 3 months after transplant was also strongly correlated with the subsequent development of chronic graft-versus-host disease (GVHD). These dynamic imbalances favor the production, expansion, and persistence of effector T cells over CD4Tregs and were associated with the development of chronic GVHD. PMID:26670634

  19. The triterpenoid CDDO-Me delays murine acute graft-versus-host disease with the preservation of graft-versus-tumor effects after allogeneic bone marrow transplantation

    PubMed Central

    Li, Minghui; Sun, Kai; Redelman, Doug; Welniak, Lisbeth A.; Murphy, William J.

    2010-01-01

    The occurrence of acute graft-versus-host disease (GVHD) and tumor relapse represent the two major obstacles impeding the efficacy of allogeneic bone marrow transplantation (BMT) in cancer. We have previously shown that the synthetic triterpenoid CDDO can inhibit murine early acute GVHD but anti-tumor effects were not assessed. In the current study, we found that a new derivative of CDDO, CDDO-Me, had an increased ability to inhibit allogeneic T cell responses and induce cell death of alloreactive T cells in vitro. Administration of CDDO-Me to mice following allogeneic BMT resulted in significant and increased protection from acute lethal GVHD compared to CDDO. This correlated with reduced TNF-α production, reduced donor T cell proliferation and decreased adhesion molecule (α4β7 integrin) expression on the donor T cells. CDDO-Me was also superior to CDDO in inhibiting leukemia growth in vitro. When CDDO-Me was administered following an allogeneic BMT to leukemia-bearing mice, significant increases in survival were observed. These findings suggest that CDDO-Me is superior to CDDO in delaying acute GVHD while preserving or possibly even augmenting GVT effects. PMID:20338256

  20. Long-Term Effects of Intravitreal Injection of GMP-Grade Bone-Marrow–Derived CD34+ Cells in NOD-SCID Mice with Acute Ischemia-Reperfusion Injury

    PubMed Central

    Caballero, Sergio; Bauer, Gerhard; Shibata, Bradley; Roth, Alan; Fitzgerald, Paul G.; Forward, Krisztina I.; Zhou, Ping; McGee, Jeannine; Telander, David G.; Grant, Maria B.; Nolta, Jan A.

    2012-01-01

    Purpose. To determine long-term safety of intravitreal administration of good manufacturing practice (GMP)–grade human bone-marrow–derived CD34+ cells in NOD-SCID (nonobese diabetic–severe combined immunodeficiency) mice with acute retinal ischemia-reperfusion injury, a model for retinal vasculopathy. Method. Acute ischemia-reperfusion injury was induced in the right eye of adult NOD-SCID mice (n = 23) by transient elevation of intraocular pressure. Seven days later, 12 injured eyes and 5 normal contralateral eyes were injected each intravitreally with 5 × 104 CD34+ cells isolated under GMP conditions from a healthy human donor bone marrow using an immunomagnetic cell isolation system. The remaining 11 injured eyes were not treated and served as controls. Mice were euthanized 1 day, 4 months, and 8 months later. Both eyes were enucleated and examined by immunohistochemical analysis and hematoxylin and eosin staining. Among mice followed for 8 months, electroretinography (ERG) was performed on both eyes before euthanization. All major organs were examined grossly and histologically after serial sectioning. Results. Immunohistochemical staining 4 months after injection showed detectable CD34+ cells in the retinal vasculature. ERG at 8 months after CD34+ cell injection showed signals that were similar in untreated eyes. Histology of the enucleated eyes injected with CD34+ cells showed no intraocular tumor or abnormal tissue growth after 8 months. Histologic analysis of all major organs showed no abnormal proliferation of human cells. Conclusions. Intravitreal administration of GMP-grade human bone-marrow–derived CD34+ cells appears to be well tolerated long-term in eyes with acute retinal ischemic injury. A clinical trial will start to further explore this therapy. PMID:22247454

  1. Risk Factors for Steroid-Refractory Acute Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation from Matched Related or Unrelated Donors.

    PubMed

    Calmettes, Claire; Vigouroux, Stéphane; Labopin, Myriam; Tabrizi, Reza; Turlure, Pascal; Lafarge, Xavier; Marit, Gérald; Pigneux, Arnaud; Leguay, Thibaut; Bouabdallah, Krimo; Dilhuydy, Marie-Sarah; Duclos, Cédric; Mohr, Catherine; Lascaux, Axelle; Dumas, Pierre-Yves; Dimicoli-Salazar, Sophie; Saint-Lézer, Arnaud; Milpied, Noël

    2015-05-01

    We performed a retrospective study to identify pretransplantation risk factors for steroid-refractory (SR) acute graft-versus host disease (aGVHD) after allogeneic stem cell transplantation from matched donors in 630 adult patients who underwent transplantation at our center between 2000 and 2012. The cumulative incidence (CI) of SR aGVHD was 11.3% ± 2.3%. The identified independent risk factors were matched unrelated donor (hazard ratio [HR], 2.52; P = .001), female donor for male recipient (HR, 1.84; P = .023) and absence of antithymocyte globulin (HR, 2.02; P = .005). Three risk groups were defined according to the presence of these risk factors. In the whole cohort, the CI of SR aGVHD was 3.5% ± 1.7% in the low-risk group (0 risk factor, n = 115), 9.3% ± 1.6% in the intermediate-risk group (1 risk factor, n = 323), and 19.3% ± 2.9% in the high-risk group (2 or 3 risk factors, n = 192). Our study suggests that pretransplantation characteristics might help identify patients at high risk for SR aGVHD. A risk adapted first-line treatment of aGVHD could be evaluated in those patients.

  2. MC1288, a vitamin D analog, prevents acute graft-versus-host disease in rat bone marrow transplantation.

    PubMed

    Pakkala, I; Taskinen, E; Pakkala, S; Räisänen-Sokolowski, A

    2001-04-01

    The major obstacle to successful bone marrow transplantation (BMT) is graft-versus-host disease (GVHD). Vitamin D analogs have shown their efficacy in solid organ transplantation. The purpose of this study was to investigate the suitability of a novel vitamin D analog, MC1288, in the prevention of acute GVHD in a rat BMT model. Allogeneic BMT were performed from Lewis to BN rats (n = 18). The animals were divided into four groups: an untreated control group, MC1288, cyclosporin A (CsA), and MC1288 + CsA-treated groups. Rats were harvested for histology and immunohistochemistry on day 20 after BMT. Histological changes for GVHD in liver, skin, and spleen were scored. Positivity in immunostaining was quantified as the number of positive cells/high power field. Treatment with MC1288 decreased clinical signs of GVHD compared with untreated or CsA-treated rats. Histological manifestations of GVHD, expressed as mean total increment, were significantly lower (1.4 +/- 0.5) in MC1288 than in untreated (5.0 +/- 1.6) or CsA (3.5 +/- 1.0) groups. Combining MC1288 and CsA further improved histology (1.1 +/- 0.6). The expression of CD4, CD8, MHC class II, interleukin-2 receptor, nitric oxide 2, and NKR-P1A (NK cells) positivity was significantly decreased in the liver and skin of BMT rats by MC1288. MC1288 was effective in preventing clinical and histological signs and symptoms of GVHD. This novel vitamin D analog could be used as an immunomodulating agent in BMT.

  3. Grade Configuration

    ERIC Educational Resources Information Center

    Williamson, Ronald

    2012-01-01

    Where to locate the 7th and 8th grade is a perennial question. While there are many variations, three approaches are most often used---include them in a 7-12 secondary campus, maintain a separate middle grades campus, or include them as part of a K-8 program. Research says that grade configuration is inconclusive at best and there is no research…

  4. Allogeneic stem-cell transplantation in patients with refractory acute leukemia: a long-term follow-up.

    PubMed

    Oyekunle, A A; Kröger, N; Zabelina, T; Ayuk, F; Schieder, H; Renges, H; Fehse, N; Waschke, O; Fehse, B; Kabisch, H; Zander, A R

    2006-01-01

    We examined retrospectively 44 patients with refractory acute leukemia (acute myeloid leukemia (AML)/acute lymphoblastic leukemia=25/19) who underwent allogeneic transplantation at our center between 11/1990 and 04/2004. The median leukemic blasts was 25% and age 28 years (range, 3-56). Twenty-one patients had untreated relapse, 13 failed reinduction, eight in partial remission and two aplastic. Conditioning was myeloablative using cyclophosphamide, busulfan, total-body irradiation and etoposide (Bu/Cy/VP, n=22; TBI/Cy/VP, n=17; others, n=5) followed by marrow or peripheral blood transplant (n=23/21) from unrelated or related donors (n=28/16). All patients had graft-versus-host disease (GVHD) prophylaxis with cyclosporin and methotrexate. One patient experienced late graft failure. Severe acute-GVHD and chronic-GVHD appeared in eight and 14 patients, respectively. Thirteen patients (30%) remain alive after a median of 25.3 months (range, 2.4-134.1); with 31 deaths, mostly from relapse (n=15) and infections (n=12). Overall survival (OS) and progression-free survival (PFS) at 5 years was 28 and 26%, respectively. OS and PFS were significantly better with blasts < or =20% and time to transplant < or =1 year while transplant-related mortality was less with the use of TBI. We conclude that patients with refractory leukemia can benefit from allogeneic BMT, especially with < or =20% marrow blast.

  5. [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. PMID:1488582

  6. [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.

  7. Impacts of graft-versus-host disease on outcomes after allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia: A nationwide retrospective study.

    PubMed

    Itonaga, Hidehiro; Iwanaga, Masako; Aoki, Kazunari; Aoki, Jun; Ishiyama, Ken; Ishikawa, Takayuki; Sakura, Toru; Fukuda, Takahiro; Najima, Yuho; Yujiri, Toshiaki; Mori, Takehiko; Kurokawa, Mineo; Nawa, Yuichiro; Uchida, Naoyuki; Morishita, Yoshihisa; Hashimoto, Hisako; Eto, Tetsuya; Hirokawa, Makoto; Morishima, Yasuo; Nagamura-Inoue, Tokiko; Atsuta, Yoshiko; Miyazaki, Yasushi

    2016-02-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a therapeutic option that may lead to improved outcomes in patients with chronic myelomonocytic leukemia (CMML). However, few studies have examined the impact of the grade of graft-versus-host disease (GVHD) on post-transplant outcomes for CMML. We retrospectively analyzed the outcomes of 141 patients with CMML who underwent allo-HSCT between 1987 and 2010, and achieved neutrophil engraftment. The effects of acute GVHD (aGVHD) or chronic GVHD (cGVHD) on overall survival (OS), leukemia-associated mortality (LAM), and transplant-related mortality were evaluated by hazards regression models, in which the onset date of aGVHD or cGVHD was treated as a time-dependent covariate. Grade I aGVHD was associated with better OS and lower LAM (P=0.042, P=0.033, respectively) than no GVHD in univariate analyses, but not in the multivariate analyses. The multivariate analyses demonstrated that extensive cGVHD significantly associated with better OS (Hazard Ratio [HR] 0.35 [95% confidence intervals (CI), 0.16-0.74]; P=0.007) and lower LAM (HR 0.36 [95% CI, 0.14-0.92]; P=0.033) in patients who were not in complete remission at transplantation. In conclusion, the occurrence of cGVHD may be an important factor affecting the outcomes of CMML patients who received transplantation. PMID:26754557

  8. 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.

  9. 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

    2016-10-31

    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; RAEB-1; RAEB-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; Refractory Anemia With Excess Blasts

  10. T-bet Promotes Acute Graft-versus-Host Disease by Regulating Recipient Hematopoietic Cells in Mice.

    PubMed

    Fu, Jianing; Wu, Yongxia; Nguyen, Hung; Heinrichs, Jessica; Schutt, Steven; Liu, Yuejun; Liu, Chen; Jin, Junfei; Anasetti, Claudio; Yu, Xue-Zhong

    2016-04-01

    Beyond its critical role in T cells, T-bet regulates the functions of APCs including dendritic cells and B cells, as well as NK cells. Given that recipient APCs are essential for priming allogeneic T cells and recipient NK or T cells are able to reject allogeneic donor cells, we evaluated the role of T-bet on the host in acute graft-versus-host disease (GVHD) using murine models of allogeneic bone marrow transplantation. T-bet(-/-) recipients developed significantly milder GVHD than their wild type counterparts in MHC-mismatched or CD4-dependent minor histocompatibility Ag-mismatched models. Allogeneic donor T cells, in particular, CD4 subset, significantly reduced IFN-γ production, proliferation and migration, and caused less injury in liver and gut of T-bet(-/-) recipients. We further observed that T-bet on recipient hematopoietic cells was primarily responsible for the donor T cell response and pathogenicity in GVHD. T-bet(-/-) dendritic cells expressed higher levels of Trail, whereas they produced lower levels of IFN-γ and IL-12/23 p40, as well as chemokine CXCL9, resulting in significantly higher levels of apoptosis, less priming, and infiltration of donor T cells. Meanwhile, NK cells in T-bet(-/-) hosts partially contribute to the decreased donor T cell proliferation. Furthermore, although T-bet on hematopoietic cells was required for GVHD development, it was largely dispensable for the graft-versus-leukemia effect. Taken together with our previous findings, we propose that T-bet is a potential therapeutic target for the control of GVHD through regulating donor T cells and recipient hematopoietic cells. PMID:26903480

  11. Effect of major histocompatibility complex haplotype matching by C4 and MICA genotyping on acute graft versus host disease in unrelated hematopoietic stem cell transplantation.

    PubMed

    Park, Yongjung; Cheong, June-Won; Park, Myoung Hee; Kim, Myoung Soo; Kim, Jong Sun; Kim, Hyon-Suk

    2016-02-01

    We explored whether matching of human leukocyte antigen (HLA) haplotypes between the recipient and donor of hematopoietic stem cell transplantation (HSCT) predicted by C4 and MICA typing is associated with the incidence of acute graft versus host disease (aGVHD). DNA preparations collected from a total of 81 recipient and donor pairs were used for PCR-based C4 subtyping and/or MICA sequence-based typing. Incidences of aGVHD were compared according to C4 and MICA matching. The six most common MICA alleles were MICA*008:01, *010:01, *002:01, *004, *009:01/049, and *012:01. Among the 59 unrelated pairs, HLA alleles were matched in 34 (57.6%). C4 subtypes were identical between the recipient and donor in 28 (82.4%) HLA-matched unrelated pairs, while MICA genotypes were matched in all HLA-matched unrelated pairs. In the 22 HLA-matched related pairs, all recipients showed identical C4 subtypes with their respective donors. In multivariate analysis, C4 mismatch was a significant risk factor associated with the development of aGVHD in unrelated HSCT (hazard ratio=3.24, P=0.006). PCR-based C4 subtyping is a simple method for assessing the genetic identity of the HLA region between a recipient and unrelated donor. This test would be also useful for prediction of aGVHD in HSCT.

  12. Safety and Tolerability Trial of Abatacept-based Immunosuppression for Prevention of Acute Graft Versus Host Disease (aGVHD) During Transplant

    ClinicalTrials.gov

    2009-11-12

    AML; ALL; Undifferentiated Leukemia; Biphenotypic Leukemia; Refractory Anemia; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ringed Sideroblasts; Refractory Anemia With Excess Blasts-1 (5-10% Blasts); Refractory Anemia With Excess Blasts-2 (10-20% Blasts); Myelodysplastic Syndrome, Unclassified; MDS Associated With Isolated Del (5q)

  13. [Nutritional support to establish refeeding in a patient with acute gastrointestinal graft-versus-host disease - a case report].

    PubMed

    Matsuoka, Mio; Iijima, Shohei

    2014-12-01

    A patient with acute myeloid leukemia having acute gastrointestinal graft-versus-host disease(aGVHD)was provided nutritional support. Oral intake was not permitted owing to the gastrointestinal injury induced by aGVHD. Our goal was to achieve oral feeding by the time of discharge. The initial aim in reinitiating eating was to stimulate intestinal adaptation to the mucosal injury. Via total parenteral nutrition(TPN), the patient was provided food in the form of a semisolid jelly, which passed through the intestinal tract slowly. After interviewing the patient and ascertaining that no complications had arisen owing to eating, a regular diet was initiated. Considering the unstable nature of the gastrointestinal condition and the associated long-term hospitalization, it is important to ensure that the meal contents comply with the patient's taste, while considering the patients'uneasiness and fear of progress to oral intake. It is difficult to predict improvement of aGVHD. Therefore, it is essential that patients are offered meals via TPN, suitable to their intestinal condition and mental status.

  14. 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

  15. GVHD after haploidentical transplantation: a novel, MHC-defined rhesus macaque model identifies CD28− CD8+ T cells as a reservoir of breakthrough T-cell proliferation during costimulation blockade and sirolimus-based immunosuppression

    PubMed Central

    Miller, Weston P.; Srinivasan, Swetha; Panoskaltsis-Mortari, Angela; Singh, Karnail; Sen, Sharon; Hamby, Kelly; Deane, Taylor; Stempora, Linda; Beus, Jonathan; Turner, Alexa; Wheeler, Caleb; Anderson, Daniel C.; Sharma, Prachi; Garcia, Anapatricia; Strobert, Elizabeth; Elder, Eric; Crocker, Ian; Crenshaw, Timothy; Penedo, M. Cecilia T.; Ward, Thea; Song, Mingqing; Horan, John; Larsen, Christian P.; Blazar, Bruce R.

    2010-01-01

    We have developed a major histocompatibility complex–defined primate model of graft-versus-host disease (GVHD) and have determined the effect that CD28/CD40-directed costimulation blockade and sirolimus have on this disease. Severe GVHD developed after haploidentical transplantation without prophylaxis, characterized by rapid clinical decline and widespread T-cell infiltration and organ damage. Mechanistic analysis showed activation and possible counter-regulation, with rapid T-cell expansion and accumulation of CD8+ and CD4+ granzyme B+ effector cells and FoxP3pos/CD27high/CD25pos/CD127low CD4+ T cells. CD8+ cells down-regulated CD127 and BCl-2 and up-regulated Ki-67, consistent with a highly activated, proliferative profile. A cytokine storm also occurred, with GVHD-specific secretion of interleukin-1 receptor antagonist (IL-1Ra), IL-18, and CCL4. Costimulation Blockade and Sirolimus (CoBS) resulted in striking protection against GVHD. At the 30-day primary endpoint, CoBS-treated recipients showed 100% survival compared with no survival in untreated recipients. CoBS treatment resulted in survival, increasing from 11.6 to 62 days (P < .01) with blunting of T-cell expansion and activation. Some CoBS-treated animals did eventually develop GVHD, with both clinical and histopathologic evidence of smoldering disease. The reservoir of CoBS-resistant breakthrough immune activation included secretion of interferon-γ, IL-2, monocyte chemotactic protein-1, and IL-12/IL-23 and proliferation of cytotoxic T-lymphocyte–associated antigen 4 immunoglobulin-resistant CD28− CD8+ T cells, suggesting adjuvant treatments targeting this subpopulation will be needed for full disease control. PMID:20833977

  16. Infusion-related febrile reaction after haploidentical stem cell transplantation in children is associated with higher rates of engraftment syndrome and acute graft-versus-host disease.

    PubMed

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

    2015-12-01

    The clinical significance and prognostic impact of IRFR in pediatric recipients of haploidentical SCT are not clearly understood. Therefore, we attempted to determine how IRFR affects clinical outcomes in children. Clinical data from 100 consecutive pediatric patients (60 boys and 40 girls; median age, 12 yr [range, 2-18 yr] after haploidentical SCT between January 2010 and December 2012 were collected retrospectively. IRFR was described as unexplained fever (>38 °C) within 24 h after the infusion of haploidentical PBSCs. Thirty-eight (38.0%) cases met the criteria for IRFR. ES was found in 24 (63.2%) of the 38 children with IRFR, with the median time of developing ES of +9 (7-16) days, while only 15 (25.4%) of the 59 children without IRFR were found with ES (p < 0.001). Similarly, the cumulative incidence rates of grade II-IV aGVHD were 50.0% in the IRFR group and 29.3% (p = 0.012) in the non-febrile group. Multivariate analysis identified IRFR as the risk factor for ES and aGVHD. In the haploidentical setting, IRFR is associated with the development of ES and aGVHD. We attempted to determine how IRFR affects clinical outcomes in children after haploidentical SCT. Thirty-eight children comprised the IRFR group, and 59 were in the control (non-IRFR) group. High incidence of ES was observed in children with the occurrence of IRFR. Similarly, the incidence of stage I-IV and II-IV aGVHD was significantly higher in the febrile group. Multivariate analysis showed IRFR to be the risk factor for ES and aGVHD.

  17. [Effect of decitabine on immune regulation in patients with acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation].

    PubMed

    Wang, Jing; Zhou, Jin; Zheng, Hui-Fei; Fu, Zheng-Zheng

    2014-10-01

    Based on the representative articles in recent years, the different mechanisms of decitabine on immune regulation in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) are summarized. Decitabine improves the expression of WT1 gene to stimulate specific cytotoxic T cells which can enhance graft versus leukemia effect (GVL) and improve the expression of FOXP3 gene to stimulate regulatory T cells so as to inhibit the acute graft versus host disease (GVHD). Through the above-mentimed mechanisms, decitabine can improve both therapeutic effect and quality of life in the patients with AML after allogeneic HSCT.

  18. Cystitis - acute

    MedlinePlus

    Uncomplicated urinary tract infection; UTI - acute; Acute bladder infection; Acute bacterial cystitis ... International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 ...

  19. Improving Grading Consistency through Grade Lift Reporting

    ERIC Educational Resources Information Center

    Millet, Ido

    2010-01-01

    We define Grade Lift as the difference between average class grade and average cumulative class GPA. This metric provides an assessment of how lenient the grading was for a given course. In 2006, we started providing faculty members individualized Grade Lift reports reflecting their position relative to an anonymously plotted school-wide…

  20. Radiation appendicitis: demonstration with graded compression US

    SciTech Connect

    Puylaert, J.B.; Hoekstra, F.; de Vries, B.C.; Rutgers, P.H.; Lalisang, R.I.; Ooms, E.C.

    1987-08-01

    In a patient who had received presurgical radiation therapy for extensive rectal carcinoma, ultrasonography with graded compression disclosed an inflamed appendix. The patient had no clinical signs of acute appendicitis. At laparotomy for resection of the rectal carcinoma, the appendix appeared grossly abnormal and was removed. Pathologic examination showed severe radiation enteritis of the appendix. The sonographic appearance of radiation appendicitis closely resembled that of acute appendicitis.

  1. Association between acute and chronic graft-versus-host disease and bronchiolitis obliterans organizing pneumonia in recipients of hematopoietic stem cell transplants.

    PubMed

    Freudenberger, Todd D; Madtes, David K; Curtis, J Randall; Cummings, Peter; Storer, Barry E; Hackman, Robert C

    2003-11-15

    Bronchiolitis obliterans organizing pneumonia (BOOP) has been reported following hematopoietic stem cell (HSC) transplantation, but the clinical features and risk factors for this disorder have not been well characterized. This case-control study of 49 patients with histologic BOOP and 161 control subjects matched by age and year of transplantation describes the clinical features and analyzes the risk factors for BOOP following HSC transplantation. Data on clinical features and outcome were collected by chart review. Odds ratios, estimating the relative risk of BOOP in allogeneic HSC recipients, were calculated by conditional logistic regression with adjustment for potential confounding factors. Clinical features of BOOP in this population were similar to idiopathic BOOP and BOOP occurring in other disease settings. There was an association between acute and chronic graft-versus-host disease (GVHD) and the subsequent development of BOOP (odds ratios, 3.8 [95% CI, 1.2 to 12.3] and 3.1 [95% CI, 1.1 to 9.2], respectively). Patients with BOOP were more likely to have acute GVHD involving the skin (odds ratio, 4.6; P =.005) and chronic GVHD involving the gut (odds ratio, 6.6; P =.018) and oral cavity (odds ratio, 5.9; P =.026). This study shows that histologic BOOP following HSC transplantation has clinical features that resemble idiopathic BOOP and is strongly associated with prior acute and chronic GVHD. These results have important implications for the care of patients who develop respiratory symptoms after HSC transplantation and may help elucidate the pathogenesis of idiopathic BOOP.

  2. Phase II Trial of Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide after Reduced-Intensity Busulfan/Fludarabine Conditioning for Hematological Malignancies.

    PubMed

    Alousi, Amin M; Brammer, Jonathan E; Saliba, Rima M; Andersson, Borje; Popat, Uday; Hosing, Chitra; Jones, Roy; Shpall, Elizabeth J; Khouri, Issa; Qazilbash, Muzaffar; Nieto, Yago; Shah, Nina; Ahmed, Sairah; Oran, Betul; Al Atrash, Gheath; Ciurea, Stefan; Kebriaei, Partow; Chen, Julianne; Rondon, Gabriela; Champlin, Richard E

    2015-05-01

    Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (CY) after ablative HLA-matched bone marrow (BM) transplantation has been reported to have comparable rates of acute GVHD with an apparent reduction in chronic GVHD and infections when compared to historical prophylaxis with a calcineurin-inhibitor (CNI) and methotrexate (MTX). We conducted a phase II trial of post-transplantation CY (post-CY) after reduced-intensity conditioning (RIC) using intravenous busulfan (area under the curve of 4000 micromolar minute), fludarabine (40 mg/m(2)) for 4 days, and CY 50 mg/kg on days +3 and +4 after BM or peripheral blood (PB) transplantations from matched related (MRD) or unrelated donors (MUD). MUD recipients received antithymocyte globulin (ATG); however, a later amendment removed ATG. Forty-nine patients were treated (acute myeloid leukemia/myelodysplastic syndrome, 82%). Median age was 62 years (range, 39 to 72). Fifteen patients received an MRD (9 PB/6 BM); 34 had a MUD (2 PB/32 BM). The cumulative incidence of grade II to IV acute GVHD, III to IV acute GVHD, and chronic GVHD was 58%, 22%, and 18%, respectively. A matched cohort analysis compared outcomes to tacrolimus/methotrexate GVHD prophylaxis and indicated higher rates of acute GVHD grade II to IV (46% versus 19%; hazard ratio [HR], 2.8; P = .02) and treatment-related mortality (HR, 3.3; P = .035) and worse overall survival (HR, 1.9; P = .04) with post-CY. The incidence of chronic GVHD and CMV reactivation did not differ. This study suggests that post-CY should not be used as sole GVHD prophylaxis after a RIC transplantation from HLA-matched donors. PMID:25667989

  3. T lymphocytes expressing HECA-452 epitope are present in cutaneous acute graft-versus-host disease and erythema multiforme, but not in acute graft-versus-host disease in gut organs.

    PubMed Central

    Davis, R. E.; Smoller, B. R.

    1992-01-01

    Lymphocytes in formalin-fixed skin biopsies from patients with cutaneous acute graft-versus-host disease (aGVHD) were studied with HECA-452 (an antibody recognizing lymphocytes with skin-homing properties) and a panel of antibodies recognizing pan-B (L26 [CD20]), pan-T (L60 [CD43] and A6 [CD45RA]), and T-helper subset (OPD4) antigens in paraffin sections. Biopsies from patients with erythema multiforme (EM) were similarly studied for comparison. In both conditions, T lymphocytes stained by OPD4 were predominantly confined to the dermis, whereas those stained by HECA-452 were concentrated in the epidermis; however, there was considerable variation between cases, and overlap between findings in the dermis and epidermis. Lymphocytes similarly studied in paraffin sections of liver, salivary gland, and gut affected by aGVHD were essentially unreactive with HECA-452, although they were largely stained by pan-T markers and showed some comparable reactivity with OPD4. The findings suggest that aGVHD of the skin is mediated by a different set of lymphocytes than in gut organs, and may have a similar immunologic mechanism to EM. Images Figure 1 Figure 2 PMID:1381561

  4. Acute Bronchitis

    MedlinePlus

    ... tightness. There are two main types of bronchitis: acute and chronic. Most cases of acute bronchitis get better within several days. But your ... that cause colds and the flu often cause acute bronchitis. These viruses spread through the air when ...

  5. 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.

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

    PubMed

    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

    2015-07-01

    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 who received TBI (1200 to 1500 cGY) for acute leukemia from 2003 to 2010. The 2 cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Philadelphia chromosome-positive acute lymphoblastic leukemia, HLA-matched siblings, stem cell source, antithymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect transplantation-related mortality (24% versus 23% at 3 years, P = .67; relative risk, 1.01; P = .91), leukemia relapse (27% versus 29% at 3 years, P = .34; relative risk, .89, P = .18), leukemia-free survival (49% versus 48% at 3 years, P = .27; relative risk, .93; P = .29), chronic GVHD (45% versus 47% at 1 year, P = .39; relative risk, .9; P = .11), or overall survival (53% versus 52% at 3 years, P = .62; relative risk, .96; P = .57) for CyTBI and TBICy, respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (P = .08), respectively. This study demonstrates that the sequence of Cy and TBI does not impact transplantation outcomes and complications in patients with acute leukemia undergoing hematopoietic cell transplantation with myeloablative conditioning.

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

    PubMed

    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

    2015-07-01

    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 who received TBI (1200 to 1500 cGY) for acute leukemia from 2003 to 2010. The 2 cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Philadelphia chromosome-positive acute lymphoblastic leukemia, HLA-matched siblings, stem cell source, antithymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect transplantation-related mortality (24% versus 23% at 3 years, P = .67; relative risk, 1.01; P = .91), leukemia relapse (27% versus 29% at 3 years, P = .34; relative risk, .89, P = .18), leukemia-free survival (49% versus 48% at 3 years, P = .27; relative risk, .93; P = .29), chronic GVHD (45% versus 47% at 1 year, P = .39; relative risk, .9; P = .11), or overall survival (53% versus 52% at 3 years, P = .62; relative risk, .96; P = .57) for CyTBI and TBICy, respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (P = .08), respectively. This study demonstrates that the sequence of Cy and TBI does not impact transplantation outcomes and complications in patients with acute leukemia undergoing hematopoietic cell transplantation with myeloablative conditioning. PMID:25840335

  8. Gleason grading system

    MedlinePlus

    ... medlineplus.gov/ency/patientinstructions/000920.htm Gleason grading system To use the sharing features on this page, ... score of between 5 and 7. Gleason Grading System Sometimes, it can be hard to predict how ...

  9. The Case against Grades

    ERIC Educational Resources Information Center

    Kohn, Alfie

    2011-01-01

    Decades of research shows that grades diminish students' interest in whatever they're learning, discourage students from taking academic risks, and reduce the quality of students' thinking, writes Kohn. Contrary to what many people assume, grades are not necessary to promote achievement. Attempts to "improve" grading--such as standards-based…

  10. Differential Grading Standards Revisited.

    ERIC Educational Resources Information Center

    Strenta, A. Christopher; Elliott, Rogers

    1987-01-01

    Differential grading standards were examined in a sample of 1,029 Dartmouth College graduates. Fields of study that attracted students (as majors) who scored higher on the Scholastic Aptitude Test (SAT) employed stricter grading standards. These differential standards attenuated the substantial correlation between SAT scores and grades.…

  11. [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. PMID:27393141

  12. Bias in Grading

    ERIC Educational Resources Information Center

    Malouff, John

    2008-01-01

    Bias in grading can be conscious or unconscious. The author describes different types of bias, such as those based on student attractiveness or performance in prior courses, and a variety of methods of reducing bias, including keeping students anonymous during grading and using detailed criteria for subjective grading.

  13. Redesigning Grading--Districtwide

    ERIC Educational Resources Information Center

    Townsley, Matt

    2014-01-01

    In the first years of his career as a high school math teacher, Matt Townsley was bothered by the fact that his grades penalized students for not learning content quickly. A student could master every standard, but low quiz grades and homework assignments they didn't complete because they didn't understand would lower their final grade,…

  14. Salvage chemotherapy followed by granulocyte colony-stimulating factor-primed donor leukocyte infusion with graft-vs.-host disease control for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation: prognostic factors and clinical outcomes.

    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

    2016-03-01

    This study investigated the prognostic factors and clinical outcomes of preemptive chemotherapy followed by granulocyte colony-stimulating factor-primed donor leukocyte infusion (Chemo-DLI) according to minimal residual disease (MRD) status in patients with acute leukemia and myelodysplastic syndromes who received allogeneic hematopoietic stem cell transplantation (HSCT) (n = 101). Patients received immunosuppressive drugs to prevent graft-vs.-host disease (GVHD) after Chemo-DLI. The 3-yr cumulative incidences of relapse, non-relapse mortality, and disease-free survival (DFS) after HSCT were 39.5%, 9.6%, and 51.7%, respectively. The cumulative incidences of relapse and DFS were significantly poorer in patients who exhibited early-onset MRD. Forty-four patients turned MRD negative 1 month after Chemo-DLI; their cumulative incidences of relapse and DFS were significantly better than those with persistent MRD 1 month after preemptive Chemo-DLI (relapse: 19.8% vs. 46.8%, P = 0.001; DFS: 69.6% vs. 46.4%, P = 0.004). The cumulative incidences of relapse and DFS after HSCT were significantly better in patients with chronic GVHD (cGVHD) than those without cGVHD (relapse: 19.6% vs. 63.7%, P < 0.001; DFS: 74.4% vs. 23.8%, P < 0.001). Early-onset MRD, persistent MRD after Chemo-DLI, and non-cGVHD after Chemo-DLI, which were associated with increased relapse and impaired DFS, suggest unsatisfactory response to preemptive Chemo-DLI.

  15. 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…

  16. Haploidentical hematopoietic stem cell transplantation for paediatric high-risk T-cell acute lymphoblastic leukaemia.

    PubMed

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

    2016-06-01

    Paediatric HR T-cell ALL demonstrates dismal prognosis with chemotherapy, and poor outcomes could be improved with allo-SCT. HID-SCT is an almost immediately available choice; however, few studies have focused on the outcomes of HID-SCT for paediatric HR T-ALL. Forty-eight consecutive HR T-ALL children who underwent HID-SCT were included. Survival outcomes and factors predictive of outcomes were retrospectively analysed. Of the 48 patients, 35 were in CR1, 10 in CR2, and three in relapse. The cumulative incidence of grade 3/4 aGVHD was 10.4% and that of extensive cGVHD was 28.4%. The CIR at three yr was 30.8% and that of NRM at three yr was 14.7%. At a median follow-up of 20.0 (range 2.5-124.2) months, the three-yr LFS was 54.4%. Children who received transplants during CR1 had a better LFS (65.7% vs. 26.0%, p = 0.008) and a lower relapse rate (19.8% vs. 56.7%, p = 0.014) compared to those during non-CR1. HID-SCT is feasible for HR T-ALL children, and survival outcomes are better when performed in CR1 compared to non-CR1. Prospective clinical trials would be needed to confirm that. PMID:26996140

  17. 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

  18. Bronchitis - acute

    MedlinePlus

    ... produces mucus -- the mucus may be clear or yellow-green Fatigue Fever -- usually low-grade Shortness of breath that gets ... fever or shaking chills Have a low-grade fever for 3 or more days Have thick, yellow-green mucus, especially if it has a bad ...

  19. Are Math Grades Cyclical?

    ERIC Educational Resources Information Center

    Adams, Gerald J.; Dial, Micah

    1998-01-01

    The cyclical nature of mathematics grades was studied for a cohort of elementary school students from a large metropolitan school district in Texas over six years (average cohort size of 8495). The study used an autoregressive integrated moving average (ARIMA) model. Results indicate that grades do exhibit a significant cyclical pattern. (SLD)

  20. The Grades Game

    ERIC Educational Resources Information Center

    Fleenor, Andy; Lamb, Sarah; Anton, Jennifer; Stinson, Todd; Donen, Tony

    2011-01-01

    It can be quite alarming (and eye-opening) to see exactly how many of the grades students receive are based on their behaviors rather than their learning. Students should be assessed on what they know and can use rather than on their behavior. The reality, unfortunately, is that the opposite is often the case. Grades for students who work hard are…

  1. 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…

  2. 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…

  3. 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…

  4. Grading to Communicate

    ERIC Educational Resources Information Center

    Winger, Tony

    2005-01-01

    High school teacher and instructional coach Tony Winger laments how traditional classroom grading practices lead to grades becoming a distraction from learning--a commodity students feel they work the system to attain--rather than a clear message to students and parents. Teachers' passion for their subjects is too often met with students'…

  5. Grading Exceptional Learners

    ERIC Educational Resources Information Center

    Jung, Lee Ann; Guskey, Thomas R.

    2010-01-01

    Teachers often grapple with the challenge of giving report card grades to students with learning disabilities and English language learners. The authors offer a five-step model that "offers a fair, accurate, and legal way to adapt the grading process for exceptional learners." The model begins with a high-quality reporting system for all students…

  6. [Grading of neuroendocrine tumors].

    PubMed

    Saeger, W; Schnabel, P A; Komminoth, P

    2016-07-01

    The current WHO classification of neuroendocrine tumors (NET) differentiates between typical carcinoids (low grade NET), atypical carcinoids (intermediate grade NET) and small cell and large cell carcinomas (high grade NET) according to the prognosis. Neuroendocrine neoplasms (NEN) of the gastrointestinal tract and the pancreas are graded in an identical way. Together with the TNM system this enables a preoperative estimation of the prognosis in biopsies and fine needle aspirates. Well-differentiated tumors are graded into G1 tumors by the number of mitoses, <2 per 10 high-power fields (HPF) and the Ki-67 (index <3 %) and G2 tumors (2-20 mitoses/10 HPF, Ki-67 3-20 %). Discrepancies between the number of mitoses and the Ki-67 index are not uncommon and in these cases the higher value of the two should be applied. The more differentiated tumors of the G3 type have to be differentiated from undifferentiated carcinomas of the small cell type and large cell type with a much poorer prognosis. Prognosis relevant grading of thyroid cancers is achieved by special subtyping so that the G1-G3 system is not applicable. The rare cancers of the parathyroid gland and of the pituitary gland are not graded. Adrenal tumors also have no grading system. The prognosis is dependent on the Ki-67 index and with some reservations on the established scoring systems. PMID:27379621

  7. 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.

  8. 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…

  9. 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…

  10. 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…

  11. Graft-versus-host disease biomarkers: omics and personalized medicine.

    PubMed

    Paczesny, Sophie; Raiker, Nisha; Brooks, Sam; Mumaw, Christy

    2013-09-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective form of tumor immunotherapy available to date and the frequency of transplants continues to increase worldwide. However, while allo-HSCT usually induces a beneficial graft-versus leukemia effect, a major source of morbidity and mortality following allo-HSCT is graft-versus-host disease (GVHD). Currently available diagnostic and staging tools frequently fail to identify those at higher risk for GVHD morbidity, treatment unresponsiveness, and death. Furthermore, there are shortcomings in the risk stratification of patients before GVHD clinical signs develop. In parallel, recent years have been characterized by an explosive evolution of omics technologies, largely due to technological advancements in chemistry, engineering, and bioinformatics. Building on these opportunities, plasma biomarkers have been identified and validated as promising diagnostic and prognostic tools for acute GVHD. This review summarizes current information on the types of GVHD biomarkers, the omics tools used to identify them, the biomarkers currently validated as acute GVHD markers, and future recommendations for incorporating biomarkers into new grading algorithms for risk-stratifying patients and creating more personalized treatment courses. Future directions will include randomized evaluations of these biomarkers in multicenter prospective studies while extending on the need for biomarkers of chronic GVHD.

  12. 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.

  13. [Grading of lung cancer].

    PubMed

    Bohle, R M; Schnabel, P A

    2016-07-01

    In comparison with other tumor entities there is no common generally accepted grading system for lung cancer with clearly defined criteria and clinical relevance. In the recent fourth edition of the World Health Organization (WHO) classification from 2015 of tumors of the lungs, pleura, thymus and heart, there is no generally applicable grading for pulmonary adenocarcinomas, squamous cell carcinomas or rarer forms of carcinoma. Since the new IASLC/ATS/ERS classification of adenocarcinomas published in 2011, 5 different subtypes with significantly different prognosis are proposed. This results in an architectural (histologic) grading, which is usually applied to resection specimens. For squamous cell carcinoma the number of different histological subtypes in the new WHO classification was reduced compared to earlier versions but without a common grading system. In recent publications nesting and budding were proposed as the main (histologic) criteria for a grading of squamous cell carcinomas. The grading of neuroendocrine tumors (NET) of the lungs in comparison with NET in other organs is presented in a separate article in this issue. Certain rare tumor types are high grade per definition: small cell, large cell and pleomorphic carcinomas, carcinosarcomas and pulmonary blastomas. In the future it is to be expected that these developments will be further refined, e. g. by adding further subtypes for adenocarcinomas and cytologic and/or nuclear criteria for adenocarcinoma and/or squamous cell carcinomas. PMID:27356985

  14. MRL/lpr-->severe combined immunodeficiency mouse allografts produce autoantibodies, acute graft-versus-host disease or a wasting syndrome depending on the source of cells.

    PubMed Central

    Ashany, D; Hines, J J; Gharavi, A E; Mouradian, J; Drappa, J; Elkon, K B

    1992-01-01

    MRL/lpr (lpr) mice spontaneously develop a lupus-like illness as well as massive lymphadenopathy. Attempts to transfer autoimmunity by adoptive transfer or radiation bone marrow chimeras have been unsuccessful. Since severe combined immunodeficiency (SCID) mice have been engrafted with human and rat xenografts without apparent graft-versus-host disease (GVHD), we subjected SCID mice to low-dose irradiation and reconstituted the mice with spleen cells from young or old lpr mice or with lpr bone marrow. Fourteen out of twenty (70%) of SCID mice engrafted with spleen cells from old lpr mice produced autoantibodies (anti-DNA and anti-Sm) without evidence of the severe lymphoid atrophy previously described for lpr spleen-->+/+ chimeras. SCID mice engrafted with spleen cells from young lpr mice developed acute GVHD and 5/6 (83%) died within 4 weeks post-transfer. Although 8/11 (73%) of lpr-->SCID bone marrow allografts survived for at least 4 months, these mice developed a wasting disease characterized by lymphoid atrophy and fibrosis without the production of autoantibodies. None of the lpr-->SCID grafts resulted in the transfer of double negative T cells or the lymphoproliferative syndrome characteristic of MRL/lpr mice. These findings indicate that SCID mice can be engrafted with splenocytes from old MRL/lpr mice and that B cells continue to secrete autoantibodies for several months in the SCID recipients. This study also demonstrates that, unlike i.p. transplant of xenogeneic cells, acute GVHD is a consistent feature of i.p. transplants of normal allogeneic mononuclear cells into SCID mice. Images Fig. 5 Fig. 7 Fig. 7 PMID:1458684

  15. 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.

  16. Acute gastroenteritis.

    PubMed

    Graves, Nancy S

    2013-09-01

    Acute gastroenteritis is a common infectious disease syndrome, causing a combination of nausea, vomiting, diarrhea, and abdominal pain. There are more than 350 million cases of acute gastroenteritis in the United States annually and 48 million of these cases are caused by foodborne bacteria. Traveler's diarrhea affects more than half of people traveling from developed countries to developing countries. In adult and pediatric patients, the prevalence of Clostridium difficile is increasing. Contact precautions, public health education, and prudent use of antibiotics are necessary goals in decreasing the prevalence of Clostridium difficle. Preventing dehydration or providing appropriate rehydration is the primary supportive treatment of acute gastroenteritis.

  17. 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

  18. Acute Bronchitis

    MedlinePlus

    ... bronchitis? Acute bronchitis is almost always caused by viruses that attack the lining of the bronchial tree ... infection. As your body fights back against these viruses, more swelling occurs and more mucus is produced. ...

  19. Acute Pericarditis

    MedlinePlus

    ... large pericardial effusions). Acute pericarditis usually responds to colchicine or NSAIDs (such as aspirin and ibuprofen ) taken ... reduce pain but relieves it by reducing inflammation. Colchicine also decreases the chance of pericarditis returning later. ...

  20. Students Make the Grade.

    ERIC Educational Resources Information Center

    Wyatt, Cherie J.; Willis, Courtney W.

    2000-01-01

    Highlights classroom techniques that educators can use to promote intelligent, probing discussions on topics such as technology, human society, group behavior, social change, social conflicts, and global interdependence. Describes the graded discussion method. (SAH)

  1. 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)

  2. Acute necrotising ulcerative gingivitis in an immunocompromised young adult.

    PubMed

    Hu, Jessie; Kent, Paul; Lennon, Joshua M; Logan, Latania K

    2015-01-01

    Acute necrotising ulcerative gingivitis is an acute onset disease characterised by ulceration, necrosis, pain and bleeding in gingival surfaces. It is predominantly seen in severely malnourished children and young adults with advanced HIV infection. We present a unique presentation in a young adult with high-grade osteogenic sarcoma.

  3. Improved Outcome of Refractory/Relapsed Acute Myeloid Leukemia after Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation with Myeloablative Conditioning and Early Prophylactic Granulocyte Colony-Stimulating Factor-Mobilized Donor Lymphocyte Infusions.

    PubMed

    Jaiswal, Sarita Rani; Zaman, Shamsuz; Chakrabarti, Aditi; Sen, Subrata; Mukherjee, Shashwata; Bhargava, Sneh; Ray, Kunal; O'Donnell, Paul V; Chakrabarti, Suparno

    2016-10-01

    We carried out post-transplantation cyclophosphamide (PTCy)-based haploidentical peripheral blood stem cell transplantation in 51 patients with refractory/relapsed acute myeloid leukemia not in remission. The first 10 patients received nonmyeloablative conditioning followed by planned granulocyte colony-stimulating factor (G-CSF)-mobilized donor lymphocyte infusions (DLIs) on days 35, 60, and 90. No patient developed graft-versus-host disease (GVHD), but 90% had disease progression between 3 and 6 months. A subsequent 41 patients received myeloablative conditioning (MAC); the first 20 patients did not receive DLIs (MAC group) and the next 21 patients received G-CSF-mobilized DLIs (G-DLI) on days 21, 35, and 60 (MAC-DLI group). The incidence of disease progression and progression-free survival at 18 months were 66% and 25% in the MAC group compared with 21.4% and 61.9% in the MAC-DLI group (P = .01). Chronic GVHD but not acute GVHD was increased in the MAC-DLI group (41.2% versus 11%, P = .05). Natural killer cell alloreactive donor was associated with lower incidence of disease progression in the MAC but not in MAC-DLI group. The only factor favorably influencing disease progression and progression-free survival was administration of G-DLI after myeloablative conditioning. Our study shows that early administration of G-DLI is feasible after PTCy-based haploidentical hematopoietic stem cell transplantation for refractory/relapsed acute myeloid leukemia and might be associated with improved survival after MAC. PMID:27470289

  4. Diarrhoea in adults (acute)

    PubMed Central

    2008-01-01

    Introduction An estimated 4000 million cases of diarrhoea occurred worldwide in 1996, resulting in 2.5 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 traveling 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 2007 (BMJ 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 71 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, and 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). PMID:19450323

  5. 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

  6. 7 CFR 810.105 - Grades and grade requirements.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD ADMINISTRATION (FEDERAL GRAIN INSPECTION SERVICE), DEPARTMENT OF AGRICULTURE OFFICIAL UNITED STATES STANDARDS FOR GRAIN General Provisions Grades, Grade Requirements, and Grade Designations § 810.105 Grades and...

  7. 7 CFR 810.105 - Grades and grade requirements.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD ADMINISTRATION (FEDERAL GRAIN INSPECTION SERVICE), DEPARTMENT OF AGRICULTURE OFFICIAL UNITED STATES STANDARDS FOR GRAIN General Provisions Grades, Grade Requirements, and Grade Designations § 810.105 Grades and...

  8. 7 CFR 810.105 - Grades and grade requirements.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD ADMINISTRATION (FEDERAL GRAIN INSPECTION SERVICE), DEPARTMENT OF AGRICULTURE OFFICIAL UNITED STATES STANDARDS FOR GRAIN General Provisions Grades, Grade Requirements, and Grade Designations § 810.105 Grades and...

  9. 7 CFR 810.105 - Grades and grade requirements.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD ADMINISTRATION (FEDERAL GRAIN INSPECTION SERVICE), DEPARTMENT OF AGRICULTURE OFFICIAL UNITED STATES STANDARDS FOR GRAIN General Provisions Grades, Grade Requirements, and Grade Designations § 810.105 Grades and...

  10. 7 CFR 810.105 - Grades and grade requirements.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD ADMINISTRATION (FEDERAL GRAIN INSPECTION SERVICE), DEPARTMENT OF AGRICULTURE OFFICIAL UNITED STATES STANDARDS FOR GRAIN General Provisions Grades, Grade Requirements, and Grade Designations § 810.105 Grades and...

  11. 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.…

  12. 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. PMID:24602828

  13. The Meaning of College Grades in Three Grading Systems.

    ERIC Educational Resources Information Center

    Eiszler, Charles F.

    1983-01-01

    To determine if college students (n=345) attribute different meanings to specific grades (depending on the nature of the grading system used), three grading systems were compared: competitive, mastery, and growth. In addition, students were asked to rate the meaning of a specific grade ("A,""B," or "C") in the context of one of the three grading…

  14. 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.

  15. Imaging of acute pancreatitis and its complications. Part 1: acute pancreatitis.

    PubMed

    Türkvatan, A; Erden, A; Türkoğlu, M A; Seçil, M; Yener, Ö

    2015-02-01

    Acute pancreatitis is an acute inflammatory disease of the pancreas that may also involve surrounding tissues or remote organs. The Atlanta classification of acute pancreatitis was introduced in 1992 and divides patients into mild and severe groups based on clinical and biochemical criteria. Recently, the terminology and classification scheme proposed at the initial Atlanta Symposium have been reviewed and a new consensus statement has been proposed by the Acute Pancreatitis Classification Working Group. Generally, imaging is recommended to confirm the clinical diagnosis, investigate the etiology, and grade the extend and severity of the acute pancreatitis. Ultrasound is the first-line imaging modality in most centers for the confirmation of the diagnosis of acute pancreatitis and the ruling out of other causes of acute abdomen, but it has limitations in the acute clinical setting. Computed tomography not only establishes the diagnosis of acute pancreatitis, but also enables to stage severity of the disease. Magnetic resonance imaging has earned an ever more important role in the diagnosis of acute pancreatitis. It is especially useful for imaging of patients with iodine allergies, characterizing collections and assessment of an abnormal or disconnected pancreatic duct. The purpose of this review article is to present an overview of the acute pancreatitis, clarify confusing terminology, underline the role of ultrasound, computed tomography and magnetic resonance imaging according to the proper clinical context and compare the advantages and limitations of each modality.

  16. Outcomes of hematopoietic cell transplantation in adult patients with acquired aplastic anemia using intermediate-dose alemtuzumab-based conditioning.

    PubMed

    Hamad, Nada; Del Bel, Ryan; Messner, Hans A; Kim, Dennis; Kuruvilla, John; Lipton, Jeffrey H; Uhm, Jieun; Seftel, Matthew; Alam, Naheed; Xu, Wei; Gupta, Vikas

    2014-11-01

    Graft-versus-host disease (GVHD) has no therapeutic benefit after hematopoietic cell transplantation (HCT) for patients with acquired aplastic anemia (AA), and its prevention is highly desirable. We designed a conditioning regimen using an intermediate dose of alemtuzumab (50 to 60 mg) and describe our institutional experience of 41 patients who underwent HCT for AA. The median age at HCT was 37 years (range, 17 to 59). The conditioning regimen was high-dose cyclophosphamide (n = 9) or fludarabine based (n = 32). Additional GVHD prophylaxis was with cyclosporine. With a median follow-up of 3.6 years, overall survival at 3 years was 85%. Survival in patients <40 years and ≥40 years was 96% and 67%, respectively (P = .04). Graft failure occurred in 4 (10%) patients; 2 primary and 2 secondary. The cumulative incidences of acute (grades 1 to 2) and chronic GVHD were 27% and 15%, respectively. No patients developed grade 3 to 4 acute GVHD or severe chronic GVHD. The following viral complications were frequent: cytomegalovirus reactivation (79%), herpes simplex (18%), varicella zoster (25%), and BK virus hemorrhagic cystitis (8%). The majority of patients had no significant long-term health issues. This intermediate-dose alemtuzumab-based conditioning regimen results in excellent survival with a favorable impact on GVHD and long-term health outcomes, but close monitoring for viral complications is important.

  17. The impact of pre-transplant minimal residual disease on outcome of intensified myeloablative cord blood transplant for acute myeloid leukemia in first or second complete remission.

    PubMed

    Zheng, Changcheng; Zhu, Xiaoyu; Tang, Baolin; Zhang, Lei; Geng, Liangquan; Liu, Huilan; Sun, Zimin

    2016-01-01

    The impact of pretransplant minimal residual disease (MRD) on outcome of myeloablative cord blood transplant (CBT) for acute myeloid leukemia (AML) in complete remission (CR) has not been reported. Seventy-two AML patients were assessed for MRD before CBT, and the majority (84.7%) of these patients received single-unit CBT. All patients received intensified myeloablative conditioning with BUCY2 or TBICY plus high-dose cytarabine, and graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. The cumulative incidences of neutrophil and platelet engraftment, acute or chronic GVHD were comparable between MRD-negative and MRD-positive groups. The cumulative incidence of transplant-related mortality (TRM) and relapse did not differ significantly between the two cohorts (25.6% vs. 32.5%, 16.1% vs. 19.2%; p = 0.52, 0.61). There were no apparent differences in 3-year overall survival (OS) (68.9% in MRD-negative group and 57.9% in MRD-positive group, p = 0.31) and 3-year leukemia-free survival (LFS) (62.5% in MRD-negative group and 52.7% in MRD-positive group, p = 0.42) between both groups. The current study suggests that AML patients in morphological CR1 or CR2 who have detectable MRD might benefit from unrelated CBT with intensified myeloablative conditioning. PMID:26690538

  18. The impact of pre-transplant minimal residual disease on outcome of intensified myeloablative cord blood transplant for acute myeloid leukemia in first or second complete remission.

    PubMed

    Zheng, Changcheng; Zhu, Xiaoyu; Tang, Baolin; Zhang, Lei; Geng, Liangquan; Liu, Huilan; Sun, Zimin

    2016-01-01

    The impact of pretransplant minimal residual disease (MRD) on outcome of myeloablative cord blood transplant (CBT) for acute myeloid leukemia (AML) in complete remission (CR) has not been reported. Seventy-two AML patients were assessed for MRD before CBT, and the majority (84.7%) of these patients received single-unit CBT. All patients received intensified myeloablative conditioning with BUCY2 or TBICY plus high-dose cytarabine, and graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. The cumulative incidences of neutrophil and platelet engraftment, acute or chronic GVHD were comparable between MRD-negative and MRD-positive groups. The cumulative incidence of transplant-related mortality (TRM) and relapse did not differ significantly between the two cohorts (25.6% vs. 32.5%, 16.1% vs. 19.2%; p = 0.52, 0.61). There were no apparent differences in 3-year overall survival (OS) (68.9% in MRD-negative group and 57.9% in MRD-positive group, p = 0.31) and 3-year leukemia-free survival (LFS) (62.5% in MRD-negative group and 52.7% in MRD-positive group, p = 0.42) between both groups. The current study suggests that AML patients in morphological CR1 or CR2 who have detectable MRD might benefit from unrelated CBT with intensified myeloablative conditioning.

  19. Incidence and prognostic value of eosinophilia in chronic graft-versus-host disease after nonmyeloablative hematopoietic cell transplantation.

    PubMed

    Ahmad, Imran; Labbé, Annie-Claude; Chagnon, Miguel; Busque, Lambert; Cohen, Sandra; Kiss, Thomas; Lachance, Silvy; Roy, Denis-Claude; Sauvageau, Guy; Roy, Jean

    2011-11-01

    Data from a number of cohorts indicate that eosinophilia (Eo) could be associated with better outcomes following allogeneic hematopoietic cell transplant (HCT). However, little is known about its significance and prognostic value in chronic graft-versus-host disease (cGVHD) after nonmyeloablative (NMA) transplantation. Data were collected from 170 patients who underwent HCT using the same preparative regimen and GVHD prophylaxis. Donors were 6/6 HLA-matched siblings and stem cell source was peripheral blood. An eosinophil count of ≥0.5 × 10(9)/L was defined as Eo. Patients were transplanted mainly for lymphoproliferative disorders. Median age and follow-up were 54 years and 58 months, respectively. Incidents of grade II-IV acute GVHD (aGVHD) and cGVHD were 8.2% and 81.2%. Median time from HCT to cGVHD diagnosis was 142 days. Organs involved were: mouth in 80% of patients, skin in 75%, liver in 57%, eyes in 37%, gut in 14%, lungs in 5%, others in 5%. Eo was found in 44% of patients at diagnosis of cGVHD (range: 0.5-4.4 × 10(9)/L). Median time between first appearance of Eo and diagnosis of cGVHD was 4.5 days. We found no correlation between organ involvement and Eo but a lower prevalence of Eo in cGVHD associated with thrombocytopenia (P = .023). Nevertheless, we observed no association among Eo and overall survival (OS), relapse incidence, or nonrelapse mortality (NRM) in the overall cohort, nor in subsets of patients with multiple myeloma and follicular non-Hodgkin lymphoma. Although Eo is observed frequently in cGVHD following NMA transplantation, we report no correlation beween Eo and outcome. PMID:21601640

  20. 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…

  1. 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…

  2. 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)…

  3. 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…

  4. Determinants of Elementary School Grading.

    ERIC Educational Resources Information Center

    Leiter, Jeffrey; Brown, James S.

    1985-01-01

    Grades given by primary school teachers were found to reflect classroom-specific achievement more than widely valued achievement measured by standardized test scores. The strongest determinant of grading, however, was found to be the effect that a grade in one subject has on the grade in a second subject. (Author/RM)

  5. 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)…

  6. 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)…

  7. 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)…

  8. 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…

  9. 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.

  10. Acute pancreatitis: prognostic value of CT

    SciTech Connect

    Balthazar, E.J.; Ranson, J.H.C.; Naidich, D.P.; Megibow, A.J.; Caccavale, R.; Cooper, M.M.

    1985-09-01

    In 83 patients with acute pancreatitis, the initial computed tomographic (CT) examinations were classified by degree of disease severity (grades A-E) and were correlated with the clinical follow-up, objective prognostic signs, and complications and death. The length of hospitalization correlated well with the severity of the initial CT findings. Abscesses occurred in 21.6% of the entire group, compared with 60.0% of grade E patients. Pleural effusions were also more common in grade E patients. Abscesses were seen in 80.0% of patients with six to eight prognostic signs, compared with 12.5% of those with zero to two. The use of prognostic signs with initial CT findings results in improved prognostic accuracy. Early CT examination of patients with acute pancreatitis is a useful prognostic indicator of morbidity and mortality.

  11. Reprint of: Acute Graft-versus-Host Disease: Novel Biological Insights.

    PubMed

    Teshima, Takanori; Reddy, Pavan; Zeiser, Robert

    2016-03-01

    Graft-versus-host disease (GVHD) continues to be a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Recent insights into intestinal homeostasis and uncovering of new pathways and targets have greatly reconciled our understanding of GVHD pathophysiology and will reshape contemporary GVHD prophylaxis and treatment. Gastrointestinal (GI) GVHD is the major cause of mortality. Emerging data indicate that intestinal stem cells (ISCs) and their niche Paneth cells are targeted, resulting in dysregulation of the intestinal homeostasis and microbial ecology. The microbiota and their metabolites shape the immune system and intestinal homeostasis, and they may alter host susceptibility to GVHD. Protection of the ISC niche system and modification of the intestinal microbiota and metabolome to restore intestinal homeostasis may, thus, represent a novel approach to modulate GVHD and infection. Damage to the intestine plays a central role in amplifying systemic GVHD by propagating a proinflammatory cytokine milieu. Molecular targeting to inhibit kinase signaling may be a promising approach to treat GVHD, ideally via targeting the redundant effect of multiple cytokines on immune cells and enterocytes. In this review, we discuss insights on the biology of GI GVHD, interaction of microflora and metabolome with the hosts, identification of potential new target organs, and identification and targeting of novel T cell-signaling pathways. Better understanding of GVHD biology will, thus, pave a way to develop novel treatment strategies with great clinical benefits. PMID:26899274

  12. 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). PMID:27000734

  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. Predictions in the face of clinical reality: HistoCheck versus high-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease.

    PubMed

    Askar, Medhat; Sobecks, Ronald; Morishima, Yasuo; Kawase, Takakazu; Nowacki, Amy; Makishima, Hideki; Maciejewski, Jaroslaw

    2011-09-01

    HLA polymorphism remains a major hurdle for hematopoietic stem cell transplantation (HSCT). In 2004, Elsner et al. proposed the HistoCheck Web-based tool to estimate the allogeneic potential between HLA-mismatched stem cell donor/recipient pairs expressed as a sequence similarity matching (SSM). SSM is based on the structure of HLA molecules and the functional similarity of amino acids. According to this algorithm, a high SSM score represents high dissimilarity between MHC molecules, resulting in a potentially more deleterious impact on stem cell transplant outcomes. We investigated the potential of SSM to predict high-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease (aGVHD grades III and IV) published by Kawase et al., by comparing SSM in low- and high-risk combinations. SSM was calculated for allele mismatch combinations using the HistoCheck tool available on the Web (www.histocheck.org). We compared ranges and means of SSM among high-risk (15 combinations observed in 722 donor/recipient pairs) versus low-risk allele combinations (94 combinations in 3490 pairs). Simulation scenarios were created where the recipient's HLA allele was involved in multiple allele mismatch combinations with at least 1 high-risk and 1 low-risk mismatch combination. SSM values were then compared. The mean SSM for high- versus low-risk combinations were 2.39 and 2.90 at A, 1.06 and 2.53 at B, 16.60 and 14.99 at C, 4.02 and 3.81 at DRB1, and 7.47 and 6.94 at DPB1 loci, respectively. In simulation scenarios, no predictable SSM association with high- or low-risk combinations could be distinguished. No DQB1 combinations met the statistical criteria for our study. In conclusion, our analysis demonstrates that mean SSM scores were not significantly different, and SSM distributions were overlapping among high- and low-risk allele combinations within loci HLA-A, B, C, DRB1, and DPB1. This analysis does not support selecting donors for HSCT recipients

  15. Graft-versus-host disease management.

    PubMed

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

    2016-01-01

    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).

  16. Graft-versus-host disease management.

    PubMed

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

    2016-01-01

    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). PMID:27546540

  17. 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

  18. Career Awareness: Grade 2.

    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 two, performance…

  19. 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…

  20. 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…

  1. First Grade Online.

    ERIC Educational Resources Information Center

    Oakes, Celeste

    1996-01-01

    A teacher describes how she integrated telecommunications and Internet technology into her first-grade language arts curriculum. The use of electronic mail to communicate with other student penpals generated student enthusiasm and motivation which improved reading and writing skills. Other projects included researching questions using Internet…

  2. 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,…

  3. 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…

  4. 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…

  5. Student Almanac. Grade Five.

    ERIC Educational Resources Information Center

    Minnesota Univ., Minneapolis. Project Social Studies Curriculum Center.

    This almanac is designed for use in the fifth grade course on regional studies which focuses on several case studies rather than on detailed study of each region. (The course is described in ED 062 226). For that reason the factual information is selected and includes figures relevant to the case studies in the regional areas of the Midwest, North…

  6. The Ninth Grade Experiment.

    ERIC Educational Resources Information Center

    Rourke, James R.

    2001-01-01

    Several districts have taken a radical approach to middle/high school transitions, removing ninth-graders from the mix to give them the attention needed to succeed in high school. Three ninth-grade-only schools with 720 to 750 students in Virginia, Texas, and Pennsylvania are profiled. Students experience less social pressure from upper-classmen.…

  7. 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,…

  8. Second-Grade "Professors"

    ERIC Educational Resources Information Center

    Wu, Zhonghe; An, Shuhua; King, Joyce; Ramirez, Melissa; Evans, Stacee

    2009-01-01

    Finding ways to help primary-grade students overcome difficulties in solving mathematical word problems can be a daunting task for teachers in a regular classroom setting. Student challenges may include: (1) difficulty with vocabulary; (2) lack of confidence when solving problems; (3) confusion on the proper operation to use when solving a…

  9. Graphing for Any Grade.

    ERIC Educational Resources Information Center

    Nibbelink, William

    1982-01-01

    An instructional sequence for teaching graphing that has been extensively field tested in kindergarten through grade six is detailed. The material begins with point graphs, employs a movable y-axis to begin with minimal clutter, and has graphs constructed before reading graphs is required. (MP)

  10. 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…

  11. Pay for Grades

    ERIC Educational Resources Information Center

    Johnston, Howard

    2008-01-01

    The practice of paying students to earn good grades either in class or on standardized achievement tests has touched off a storm of controversy. Praised by some educators as a way of linking economic rewards to school performance, it is being tested in a number of large cities, such as New York, Baltimore and Chicago, as well as some smaller…

  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. 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…

  14. 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…

  15. 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…

  16. 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…

  17. Grades as Information

    ERIC Educational Resources Information Center

    Grant, Darren

    2007-01-01

    We determine how much observed student performance in microeconomics principles can be attributed, inferentially, to three kinds of student academic "productivity," the instructor, demographics, and unmeasurables. The empirical approach utilizes an ordered probit model that relates student performance in micro to grades in prior coursework,…

  18. Suppression of acute graft-versus-host response by TCDD is independent of the CTLA-4-IFN-γ-IDO pathway.

    PubMed

    Rohlman, Diana; Punj, Sumit; Pennington, Jamie; Bradford, Sam; Kerkvliet, Nancy I

    2013-09-01

    Activation of the aryl hydrocarbon receptor (AhR) by its prototypic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces potent suppression of an acute graft-versus-host (GVH) response and prevents GVH disease (GVHD). Suppression is associated with development of a regulatory population of donor CD4(+) CD25(+)T-cells that express high levels of cytotoxic T-lymphocyte antigen 4 (CTLA-4). However, a direct link between these AhR-induced Tregs (AhR-Tregs) and suppression of GVHD remains to be shown. CTLA-4 is a negative regulator of T-cell responses and is associated with the induction of tolerogenic dendritic cells (DCs) that produce indoleamine 2,3-dioxygenase (IDO). We hypothesized that AhR-Tregs mediate suppression via their enhanced expression of CTLA-4, which, in turn, induces IFN-γ and IDO in host DCs. Subsequent depletion of tryptophan by IDO leads to termination of the donor T-cell response prior to development of effector CTL. Here, we show that despite increased expression of Ifng, Irf3, Irf7, Ido1, and Ido2 in the lymph nodes of TCDD-treated host mice, inhibition of IDO enzyme activity by 1-methyl-tryptophan was unable to relieve TCDD-mediated suppression of the GVH response. Furthermore, treatment with an anti-CTLA-4 antibody that blocks CTLA-4 signaling was also unable to alleviate TCDD-mediated suppression. Alternatively, we investigated the possibility that donor-derived AhR-Tregs produce IFN-γ to suppress effector CTL development. However, suppression of GVHD by TCDD was not affected by the use of Ifng-deficient donor cells. Together, these results indicate that neither overexpression of CTLA-4 nor production of IFN-γ by AhR-Tregs plays a major role in the manifestation of their immunosuppressive function in vivo.

  19. The Grades Transfer from One Grading Scale to Other Algorithmization

    ERIC Educational Resources Information Center

    Lieponiene, Jurgita; Kulvietiene, Regina

    2011-01-01

    The article presents the consideration of grading scales used for education outcomes in different countries, describes likeness and differences of applied grading scales. Application of the European Credit Transfer and Accumulation System (ECTS) grading scale is investigated according of the analysis of scientific literature as well as cases of…

  20. Graded Readers: How the Publishers Make the Grade

    ERIC Educational Resources Information Center

    Claridge, Gillian

    2012-01-01

    Publishing graded readers is big business, but there is evidence that the texts themselves are not being read in sufficient quantity to improve language proficiency. This article reports on a study of graded readers, focusing on interviews with some major publishers of graded readers, to investigate their production rationales. The findings…

  1. Write More, Grade Less: Five Practices for Effectively Grading Writing

    ERIC Educational Resources Information Center

    Lucas, Lisa

    2012-01-01

    One of the dilemmas that teachers frequently face is grading student papers. As a teacher, the author regularly reads research regarding instructional practices, grading, and assessment, but struggled to translate theory into practice in her own classroom. The intent of this article is to share one method of instructing and grading writing that…

  2. 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

  3. [Acute diarrhea].

    PubMed

    Burgmann, Konstantin; Schoepfer, Alain

    2014-09-01

    Diarrhea, defined as three or more loose or watery stools per day, represents a frequent problem in outpatients as well as inpatients. As most of the patients with acute diarrhea show a self-limiting disease course, the main challenge for the physician is to discriminate patients for whom symptomatic therapy is sufficient from those with severe disease course and threatening complications. This review aims to provide a practical guidance for such decisions.

  4. 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....

  5. 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....

  6. 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....

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. The Timing of Grade Skipping

    ERIC Educational Resources Information Center

    Kuo, Yi-Lung; Lohman, David F.

    2011-01-01

    The purposes of this study were to investigate the following: (a) the impact of sex, ethnicity, socioeconomic status, and family income on the likelihood of whole-grade skipping between kindergarten and Grade 7 and (b) the effects of grade skipping during elementary or middle school on students' academic achievement in high school. The authors…

  12. Four Steps in Grading Reform

    ERIC Educational Resources Information Center

    Guskey, Thomas R.; Jung, Lee Ann

    2012-01-01

    The field of education is moving rapidly toward a standards-based approach to grading. School leaders have become increasingly aware of the tremendous variation that exists in grading practices, even among teachers of the same courses in the same department in the same school. Consequently, students' grades often have little relation to their…

  13. 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…

  14. Sources of Elementary School Grading.

    ERIC Educational Resources Information Center

    Leiter, Jeffrey; Brown, James S.

    The objective and subjective determinants that influence the way elementary school teachers grade students were explored. A longitudinal study was made of 213 students in 6 elementary schools as the students progressed from the first to the third grade. Possible determinants for assigning grades included student acquisition of valuable skills as…

  15. 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…

  16. 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…

  17. [Infant acute leukemia].

    PubMed

    Brethon, Benoît; Cavé, Hélène; Fahd, Mony; Baruchel, André

    2016-03-01

    If acute leukemia is the most frequent cancer in childhood (33%), it remains a very rare diagnosis in infants less than one year old, e.g. less than 5% of cases. At this age, the frequency of acute lymphoblastic leukemia (ALL) (almost all of B-lineage) is quite similar to the one of myeloblastic forms (AML). Infant leukemia frequently presents with high hyperleucocytosis, major tumoral burden and numerous extra-hematological features, especially in central nervous system and skin. Whatever the lineage, the leukemic cell is often very immature cytologically and immunologically. Rearrangements of the Mixed Lineage Leukemia (MLL) gene, located on band 11q23, are the hallmark of these immature leukemias and confer a particular resistance to conventional approaches, corticosteroids and chemotherapy. The immaturity of infants less than 1-year-old is associated to a decrease of the tolerable dose-intensity of some drugs (anthracyclines, alkylating agents) or asks questions about some procedures like radiotherapy or high dose conditioning regimen, responsible of inacceptable acute and late toxicities. The high level of severe infectious diseases and other high-grade side effects limits also the capacity to cure these infants. The survival of infants less than 1-year-old with AML is only 50% but similar to older children. On the other hand, survival of those with ALL is the same, then quite limited comparing the 80% survival in children over one year. Allogeneic stem cell transplantations are indicated in high-risk subgroups of infant ALL (age below 6 months, high hyperleucocytosis >300.10(9)/L, MLL-rearrangement, initial poor prednisone response). However, morbidity and mortality remain very important and these approaches cannot be extended to all cases. During the neonatal period, the dismal prognosis linked to the high number of primary failures or very early relapses and uncertainties about the late toxicities question physicians about ethics. It is an emergency to

  18. Selective nonoperative management of high grade splenic trauma.

    PubMed

    Branco, Bernardino C; Tang, Andrew L; Rhee, Peter; Fraga, Gustavo Pereira; Nascimento, Bartolomeu; Rizoli, Sandro; O'Keeffe, Terence

    2013-01-01

    The "Evidence-based Telemedicine - Trauma & Acute Care Surgery" (EBT-TACS) Journal Club performed a critical review of the literature and selected three up-to-date articles on the management of splenic trauma. Our focus was on high-grade splenic injuries, defined as AAST injury grade III-V. The first paper was an update of the 2003 Eastern Association for the Surgery of Trauma (EAST) practice management guidelines for nonoperative management of injury to the spleen. The second paper was an American Association for the Surgery of Trauma (AAST) 2012 plenary paper evaluating the predictive role of contrast blush on CT scan in AAST grade IV and V splenic injuries. Our last article was from Europe and investigates the effects of angioembolization of splenic artery on splenic function after high-grade splenic trauma (AAST grade III-V). The EBT-TACS Journal Club elaborated conclusions and recommendations for the management of high-grade splenic trauma. PMID:23912375

  19. 7 CFR 810.1404 - Grades and grade requirements for sorghum.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 7 2010-01-01 2010-01-01 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...

  20. 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...

  1. 7 CFR 810.1404 - Grades and grade requirements for sorghum.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 7 2011-01-01 2011-01-01 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...

  2. 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...

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

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 7 2014-01-01 2014-01-01 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. [Low grade sinonasal adenocarcinoma].

    PubMed

    Sayilgan, Ayşe Tülay; Kamali, Gülçin; Ozcan, Deniz; Emre, Funda; Hatıpoğlu, Ayşe

    2012-01-01

    Sinonasal adenocarcinoma is a rare neoplasm which is classified as 'intestinal' or 'nonintestinal' type, depending on its resemblance to gastrointestinal mucosa. These tumors are associated with occupational and environmental carcinogens. In this study, a fifty-year-old oil-painter male patient with a low-grade nonintestinal type sinonasal adenocarcinoma originating from the left middle concha and ethmoid sinus is presented. Microscopical examination revealed many infiltrative glandular structures, most of which were cystically dilated and some of which were smaller in diameter, arranged back to back in loose fibrous stroma as well as intraglandular papillary and micropapillary structures forming complex branches or a cribriform pattern. The glands were lined by epithelial cells that were faintly eosinophilic and relatively abundant cubical/ cylinderical cytoplasms and mildly pleomorphic round/oval nuclei, with rare mitotic figures. Intraluminal and focally intracytoplasmic mucin was demonstrated with Alcian Blue, mucicarmin and PAS stains. Immunohistochemically, tumor cells were strongly and diffusely positive with CK7; focally and weakly positive with CK20 and negative with CDX2 in accordance with the nonintestinal type. S-100, Actin and p63, applied for investigating the myoepithelial and salivary glandular origins, were all negative. Prognostic markers, TTF-1 and p53 were negative; while the Ki-67 index was 2%. The fact that intestinal type sinonasal adenocarcinomas are generally high grade, while nonintestinal tumors are histologically low grade makes this morphological and immunohistochemical-based classification valuable in predicting the prognosis of the disease. In addition to the morphological and immunohistochemical findings, clinical information stands out in the differentiation of the tumor from benign or malignant primary lesions or metastatic adenocarcinoma.

  5. 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

  6. 7 CFR 810.106 - Grade designations.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD ADMINISTRATION (FEDERAL GRAIN INSPECTION SERVICE), DEPARTMENT OF AGRICULTURE OFFICIAL UNITED STATES STANDARDS FOR GRAIN General Provisions Grades, Grade Requirements, and Grade Designations § 810.106 Grade...

  7. 7 CFR 810.106 - Grade designations.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD ADMINISTRATION (FEDERAL GRAIN INSPECTION SERVICE), DEPARTMENT OF AGRICULTURE OFFICIAL UNITED STATES STANDARDS FOR GRAIN General Provisions Grades, Grade Requirements, and Grade Designations § 810.106 Grade...

  8. 7 CFR 810.106 - Grade designations.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD ADMINISTRATION (FEDERAL GRAIN INSPECTION SERVICE), DEPARTMENT OF AGRICULTURE OFFICIAL UNITED STATES STANDARDS FOR GRAIN General Provisions Grades, Grade Requirements, and Grade Designations § 810.106 Grade...

  9. 7 CFR 810.106 - Grade designations.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD ADMINISTRATION (FEDERAL GRAIN INSPECTION SERVICE), DEPARTMENT OF AGRICULTURE OFFICIAL UNITED STATES STANDARDS FOR GRAIN General Provisions Grades, Grade Requirements, and Grade Designations § 810.106 Grade...

  10. 7 CFR 810.106 - Grade designations.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Agriculture Regulations of the Department of Agriculture (Continued) GRAIN INSPECTION, PACKERS AND STOCKYARD ADMINISTRATION (FEDERAL GRAIN INSPECTION SERVICE), DEPARTMENT OF AGRICULTURE OFFICIAL UNITED STATES STANDARDS FOR GRAIN General Provisions Grades, Grade Requirements, and Grade Designations § 810.106 Grade...

  11. 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.

  12. Asthma in adults (acute)

    PubMed Central

    2011-01-01

    Introduction About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild to moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 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 100 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: beta2 agonists (plus ipratropium bromide, pressured metered-dose inhalers, short-acting continuous nebulised, short-acting intermittent nebulised, short-acting iv, and inhaled formoterol); corticosteroids (inhaled); corticosteroids (single oral, combined inhaled, and short courses); education about acute asthma; generalist care; helium–oxygen mixture (heliox); magnesium sulphate (iv and adding isotonic nebulised magnesium to inhaled beta2 agonists); mechanical ventilation; oxygen supplementation (controlled 28% oxygen and controlled 100% oxygen); and specialist care. PMID:21463536

  13. Engineering graded tissue interfaces.

    PubMed

    Phillips, Jennifer E; Burns, Kellie L; Le Doux, Joseph M; Guldberg, Robert E; García, Andrés J

    2008-08-26

    Interfacial zones between tissues provide specialized, transitional junctions central to normal tissue function. Regenerative medicine strategies focused on multiple cell types and/or bi/tri-layered scaffolds do not provide continuously graded interfaces, severely limiting the integration and biological performance of engineered tissue substitutes. Inspired by the bone-soft tissue interface, we describe a biomaterial-mediated gene transfer strategy for spatially regulated genetic modification and differentiation of primary dermal fibroblasts within tissue-engineered constructs. We demonstrate that zonal organization of osteoblastic and fibroblastic cellular phenotypes can be engineered by a simple, one-step seeding of fibroblasts onto scaffolds containing a spatial distribution of retrovirus encoding the osteogenic transcription factor Runx2/Cbfa1. Gradients of immobilized retrovirus, achieved via deposition of controlled poly(L-lysine) densities, resulted in spatial patterns of transcription factor expression, osteoblastic differentiation, and mineralized matrix deposition. Notably, this graded distribution of mineral deposition and mechanical properties was maintained when implanted in vivo in an ectopic site. Development of this facile and robust strategy is significant toward the regeneration of continuous interfacial zones that mimic the cellular and microstructural characteristics of native tissue.

  14. Prevention of GVHD by modulation of rat bone marrow with UV-B irradiation. II. Kinetics of migration of UV-B-irradiated bone marrow cells in naive and lethally irradiated rats

    SciTech Connect

    Oluwole, S.F.; Engelstad, K.; Hardy, M.A. )

    1990-06-01

    UV-B irradiation (700 J/m2) of bone marrow (BM) cells prior to transplantation into lethally gamma-irradiated (1050 rad) allogeneic rats prevents the development of GVHD and results in a stable mixed lymphohematopoietic chimerism. To better understand the underlying mechanisms of the development of stable radiation chimeras in this model, this study was designed to examine whether the dose (700 J/m2) of UV-B irradiation used for the modulation of the BM inoculum would affect the homing pattern of radiolabeled BM cells compared to that of thoracic duct lymphocytes (TDL) in the naive and lethally irradiated recipients. The results showed that intravenously administered, 111Indium-oxine-labeled, unmodified TDL home specifically to the spleen, lymph nodes, and BM compartments with a subsequent recirculation of a large number of cells from the spleen to the lymph nodes. In contrast, radiolabeled, unmodified BM cells migrate specifically to the spleen, liver, and BM with the lymph nodes, thymus, and nonlymphoid organs containing very little amounts of radioactivity. The stable concentrations of radioactivity in the lymphoid and nonlymphoid compartments between 3 and 72 hr after injection suggest that BM cells, unlike TDL, do not recirculate. The migration pattern of BM cells in the naive recipient was not significantly different from that seen in lethally irradiated animals except for the higher concentration of radioactivity in the spleen and BM of irradiated animals compared to that seen in naive recipients. The similarity of tissue localization of BM cells in naive or in irradiated syngeneic recipients to that of allogeneic recipients suggests that the homing of BM cells is not MHC restricted.

  15. Acute sinusitis.

    PubMed

    Feldt, Brent; Dion, Gregory R; Weitzel, Erik K; McMains, Kevin C

    2013-10-01

    Sinusitis is a common patient complaint that carries with it a large economic burden. It is one of the most common reasons patients visit their primary care physician. Acute bacterial rhinosinusitis (ABRS) can be distinguished from other forms of rhinosinusitis based on symptom duration of <4 weeks in a patient with purulent rhinorrhea associated with facial pain or pressure. Native upper aerodigestive tract bacteria are the most common etiologic agents. Treatment of ABRS is targeted primarily at symptom improvement. Amoxicillin can be used based on the clinical scenario and patient comorbidities. Computed tomographic scans are reserved for complicated presentations or when there is concern for intracranial extension or other complications. A systematic approach to ABRS will allow for improved patient quality of life and a decreased overall economic burden of this common entity.

  16. Impact of cytomegalovirus reactivation on relapse and survival in patients with acute leukemia who received allogeneic hematopoietic stem cell transplantation in first remission

    PubMed Central

    Yoon, Jae-Ho; Lee, Seok; Kim, Hee-Je; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Lee, Dong-Gun; Eom, Ki-Seong; Kim, Yoo-Jin; Min, Chang-Ki; Cho, Seok-Goo; Min, Woo-Sung; Lee, Jong Wook

    2016-01-01

    Cytomegalovirus (CMV)-reactivation is associated with graft-vs-leukemia (GVL) effect by stimulating natural-killer or T-cells, which showed leukemia relapse prevention after hematopoietic stem cell transplantation (HSCT). We enrolled patients with acute myeloid leukemia (n = 197) and acute lymphoid leukemia (n = 192) who underwent allogeneic-HSCT in first remission. We measured RQ-PCR weekly to detect CMV-reactivation and preemptively used ganciclovir (GCV) when the titer increased twice consecutively, but GCV was sometimes delayed in patients without significant graft-vs-host disease (GVHD) by reducing immunosuppressive agents. In the entire group, CMV-reactivation showed poor overall survival (OS). To evaluate subsequent effects of CMV-reactivation, we excluded early relapse and deaths within 100 days, during which most of the CMV-reactivation occurred. Untreated CMV-reactivated group (n = 173) showed superior OS (83.8% vs. 61.7% vs. 74.0%, p < 0.001) with lower relapse rate (10.1% vs 22.1% vs. 25.5%, p = 0.004) compared to GCV-treated CMV-reactivated group (n = 122) and CMV-undetected group (n = 42). After excluding chronic GVHD, untreated CMV-reactivated group still showed lower relapse rate (9.4% vs. 24.1% vs. 30.2%, p = 0.006). Multivariate analysis showed adverse-risk karyotype and patients in other than untreated CMV-reactivated group were independent factors for relapse prediction. Our data showed possible GVL effect of CMV-reactivation and minimizing antiviral therapy may benefit for relapse prevention in acute leukemia. PMID:26883100

  17. Ferritin concentrations correlate to outcome of hematopoietic stem cell transplantation but do not serve as biomarker of graft-versus-host disease.

    PubMed

    Großekatthöfer, M; Güclü, E D; Lawitschka, A; Matthes-Martin, S; Mann, G; Minkov, M; Peters, C; Seidel, M G

    2013-08-01

    Clinical presentation and laboratory data are often too unspecific to distinguish the onset or activity of graft-versus-host disease (GvHD) from infections or toxicity. Antigen-presenting cells such as monocytes/macrophages and dendritic cells are involved in GvHD pathogenesis after allogeneic hematopoietic stem cell transplantation (HSCT). To test whether ferritin, an iron storage marker and macrophage activation-linked acute-phase protein, represents a candidate biomarker for acute or chronic GvHD in pediatric HSCT, we retrospectively evaluated a 2-year follow-up data from 131 eligible consecutive patients with different malignant and nonmalignant diseases who underwent allogeneic HSCT. Thirteen patients (10 %) suffered from acute GvHD II-IV°, 18 (14 %) had limited, and 14 (11 %) had extensive chronic GvHD. In extension of previous studies in adults investigating pre-transplant ferritin, our data show that post-HSCT hyperferritinemia (analyzed on days 0, +30, +60, +100, +180, +360, and +720) was significantly associated with decreased long-term survival (p < 0.001-0.03) in children and adolescents. Increased ferritin concentrations were associated with number and timing of red blood cell transfusions and toxic or infectious multi-organ failure but did not show significant differences between patients without GvHD and with acute grades II-IV, limited, or extensive chronic GvHD. Thus, our data do not identify ferritin as specifically GvHD-linked biomarker; however, they support the prognostic value of ferritin levels for outcome after HSCT in children.

  18. Does anti-thymocyte globulin have a place in busulfan/fludarabine conditioning for matched related donor hematopoietic stem cell transplantation?

    PubMed Central

    Ji, Young Sok; Lee, Min Sung; Min, Chang Wook; Park, Seong Kyu; Kim, Se Hyung; Yun, Jina; Kim, Hyun Jung; Kim, Kyoung Ha; Kim, Chan Kyu; Lee, Kyu-Taek; Won, Jong-Ho; Hong, Dae Sik

    2016-01-01

    Background/Aims: There is controversy about the prophylactic effect of anti-thymocyte globulin (ATG) on graft versus host disease (GVHD) in the setting of matched related-donor hematopoietic stem cell transplantation (HSCT). This study assessed the inf luences of ATG on the incidences of acute and chronic GVHD and other clinical outcomes in matched related-donor HSCT. Methods: Sixty-one patients received allogeneic HSCT from human leukocyte antigen-matched, related donors. Patients received busulfan/fludarabine conditioning regimens and standard GVHD prophylaxis with or without additional ATG. Results: There was no significant difference in the cumulative incidences of overall acute GVHD, grade II to IV acute GVHD at day 100, and chronic GVHD during the follow-up period between the ATG and non-ATG groups. Three-year overall survival rates were very similar, but three year disease-free survival of the non-ATG group was higher than that of the ATG group (56.2% for ATG vs. 63.1% for non-ATG, p = 0.597). Relapse rate at 3 years in the ATG group was slightly higher than that of the non-ATG group (37.5% vs. 20%, p = 0.29). Non-relapse mortality rate at 3 years was lower in the ATG group (6.25% vs. 15.6%, p = 0.668). Conclusions: Although the addition of ATG doesn’t guarantee a reduction in the incidences of acute and chronic GVHD, pre-transplantation ATG may result in lower non-relapse mortality in the context of matched related-donor HSCT with a busulfan/fludarabine conditioning regimen. However, caution is needed when using ATG because of a possibility to increase relapse rate. PMID:27017944

  19. Effect of race on outcomes after allogeneic hematopoietic cell transplantation for severe aplastic anemia.

    PubMed

    Eckrich, Michael J; Ahn, Kwang-Woo; Champlin, Richard E; Coccia, Peter; Godder, Kamar; Horan, John; Margolis, David; Deeg, H Joachim; Eapen, Mary

    2014-02-01

    We compared outcomes after hematopoietic cell transplantation in patients of African American (n = 84) and Caucasian (n = 215) descent with severe aplastic anemia. African Americans and Caucasians were matched for age, donor-recipient human leukocyte antigen match, graft type, and transplantation year. The median follow-up of surviving patients was 5 years. In multivariate analysis, overall mortality risks were higher for African Americans compared to Caucasians (relative risk 1.73, P = 0.01). The 5-year probabilities of overall survival adjusted for interval from diagnosis to transplantation, and performance score was 58% for African Americans and 73% for Caucasians. The day-100 cumulative incidence of grade III-IV, but not grade II-IV acute graft-versus-host disease (GVHD), was higher in African Americans compared to Caucasians (29% vs. 13%, P = 0.006). Although the 5-year cumulative incidence of chronic GVHD was not significantly different between the racial groups, African Americans were more likely to have extensive chronic GVHD compared to Caucasians (72% vs. 49%, P = 0.06). Survival differences between Caucasians and African Americans can be attributed to multiple factors. Our data suggest that some of the observed survival differences between Caucasians and African Americans may be explained by higher rates of acute GVHD and severity of chronic GVHD.

  20. Grade Point Average and Changes in (Great) Grade Expectations.

    ERIC Educational Resources Information Center

    Wendorf, Craig A.

    2002-01-01

    Examines student grade expectations throughout a semester in which students offered their expectations three times during the course: (1) within the first week; (2) midway through the semester; and (3) the week before the final examination. Finds that their expectations decreased stating that their cumulative grade point average was related to the…

  1. 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…

  2. Analysis of prognostic significance of ventricular arrhythmias after myocardial infarction. Shortcomings of Lown grading system.

    PubMed Central

    Bigger, J T; Weld, F M

    1981-01-01

    The Lown grading system for ventricular arrhythmias has been used in observational and experimental studies of ischaemic heart disease. This grading system uses three levels of ventricular premature depolarisation frequency and four complex features to assign patients to one of seven grades. We tested several of the major assumptions of the Lown grading system in a group of 400 patients who had recently experienced acute myocardial infarction. The Lown grading system assumes that the frequency of ventricular extrasystoles exerts a negligible risk force in patients who have complex ventricular extrasystoles. We found, however, that the frequency of ventricular extrasystoles contributed significant additional risk for cardiac death even in the three highest Lown grades, 4A, 4B, and 5. The Lown grading system assumes that, of the four complex features used, R on T ventricular extrasystoles have the greatest risk for subsequent cardiac death. We found that paired ventricular extrasystoles and ventricular tachycardia had more prognostic significance than R on T ventricular extrasystoles. It is important for prognostic stratification that subgroups which are merged into a given Lown grade should be relatively homogeneous with respect to outcome. We found a lack of homogeneity in the three highest Lown grades. Grade 5 contained 16 subgroups with a mortality risk which ranged from 0 to 75 per cent; statistically significant differences in subsequent mortality were found among these subgroups. Most of the shortcomings of the Lown grading system in our acute myocardial infarction population resulted from failure to give sufficient weight to ventricular extrasystoles frequency and to repetitive ventricular extrasystoles. PMID:7259921

  3. Distinguishing grade I meningioma from higher grade meningiomas without biopsy

    PubMed Central

    Varlotto, John; Flickinger, John; Pavelic, Martin T.; Specht, Charles S.; Sheehan, Jonas M.; Timek, Dana T.; Glantz, Michael J.; Sogge, Steven; Dimaio, Christopher; Moser, Richard; Yunus, Shakeeb; Fitzgerald, Thomas J.; Upadhyay, Urvashi; Rava, Paul; Tangel, Matthew; Yao, Aaron; Kanekar, Sangam

    2015-01-01

    Background Many meningiomas are identified by imaging and followed, with an assumption that they are WHO Grade I tumors. The purpose of our investigation is to find clinical or imaging predictors of WHO Grade II/III tumors to distinguish them from Grade I meningiomas. Methods Patients with a pathologic diagnosis of meningioma from 2002–2009 were included if they had pre-operative MRI studies and pathology for review. A Neuro-Pathologist reviewed and classified all tumors by WHO 2007. All Brain MRI imaging was reviewed by a Neuro-radiologist. Pathology and Radiology reviews were blinded from each other and clinical course. Recursive partitioning was used to create predictive models for identifying meningioma grades. Results Factors significantly correlating with a diagnosis of WHO Grade II-III tumors in univariate analysis: prior CVA (p = 0.005), CABG (p = 0.010), paresis (p = 0.008), vascularity index = 4/4: (p = 0.009), convexity vs other (p = 0.014), metabolic syndrome (p = 0.025), non-skull base (p = 0.041) and non-postmenopausal female (p = 0.045). Recursive partitioning analysis identified four categories: 1. prior CVA, 2. vascular index (vi) = 4 (no CVA), 3. premenopausal or male, vi < 4, no CVA. 4. Postmenopausal, vi < 4, no CVA with corresponding rates of 73, 54, 35 and 10% of being Grade II-III meningiomas. Conclusions Meningioma patients with prior CVA and those grade 4/4 vascularity are the most likely to have WHO Grade II-III tumors while post-menopausal women without these features are the most likely to have Grade I meningiomas. Further study of the associations of clinical and imaging factors with grade and clinical behavior are needed to better predict behavior of these tumors without biopsy. PMID:26472106

  4. 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).

  5. Health Curriculum Guide. Fourth Grade.

    ERIC Educational Resources Information Center

    Syosset Central School District 2, NY.

    GRADES OR AGES: Grade four. SUBJECT MATTER: Health education. ORGANIZATION AND PHYSICAL APPEARANCE: This illustrated guide 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 Community Health; and Education for Survival. For…

  6. Elementary Science Curriculum, Grade 1.

    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…

  7. 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…

  8. Upgrading Metallurgical-Grade Silicon

    NASA Technical Reports Server (NTRS)

    Woerner, L. M.; Moore, E. B.

    1985-01-01

    Closed-loop process produces semiconductor-grade silicon. Metallurgical-grade silicon converted to ultrapure silicon by reacting with hydrogen and silicon tetrahalide to form trihalosilane, purifying this intermediate and again decomposing to high purity silicon in third stage. Heterogeneously and homogeneously nucleated polycrystalline silicon used in semiconductor device applications and in silicon photovoltaic solar cell fabrication.

  9. 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…

  10. Grade 3 Science Curriculum Specifications.

    ERIC Educational Resources Information Center

    Alberta Dept. of Education, Edmonton. Curriculum Branch.

    The specific content areas and objectives from which the Alberta, Canada, Grade 3 Science Achievement Test questions were derived are outlined in this bulletin. The document contains: (1) curriculum summary (providing a general listing of the process skills, psychomotor skills, attitudes, and subject matter covered at the grade 3 level); (2) a…

  11. 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…

  12. Nonpunitive Grading Practices and Policies.

    ERIC Educational Resources Information Center

    Elsner, Paul A.; Brydon, Charles W.

    Information pertaining to the overall grading standards and practices within the five Peralta Colleges is compiled and analyzed here. The report is presented in three parts. The first part deals with the historical background of traditional and non-punitive grading, the national trends toward innovation and experimentation with various forms of…

  13. 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…

  14. Teaching Literacy in Second Grade

    ERIC Educational Resources Information Center

    Paratore, Jeanne R.; McCormack, Rachel L.

    2005-01-01

    Second-grade classrooms are exciting places to visit. Children are consolidating their growing reading and writing expertise, exploring new genres, and becoming more effective communicators. This book takes the reader into several exemplary second-grade classrooms to demonstrate what teachers can do to optimize literacy learning for their…

  15. 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…

  16. 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…

  17. 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…

  18. 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…

  19. 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…

  20. 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…

  1. 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)

  2. 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…

  3. 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…

  4. 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…

  5. 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…

  6. Towards Uniformity in Grading Standards.

    ERIC Educational Resources Information Center

    Bay, Libby; McCulloch, Elizabeth

    To study grading standards and consistency within the English department, 1600 freshmen at Rockland Community College were asked to complete a uniform exit essay at the end of English 101. After developing criteria for grading the papers, members of the department marked their own papers and one other set. Eight months later, 240 of the papers…

  7. [Regression grading in gastrointestinal tumors].

    PubMed

    Tischoff, I; Tannapfel, A

    2012-02-01

    Preoperative neoadjuvant chemoradiation therapy is a well-established and essential part of the interdisciplinary treatment of gastrointestinal tumors. Neoadjuvant treatment leads to regressive changes in tumors. To evaluate the histological tumor response different scoring systems describing regressive changes are used and known as tumor regression grading. Tumor regression grading is usually based on the presence of residual vital tumor cells in proportion to the total tumor size. Currently, no nationally or internationally accepted grading systems exist. In general, common guidelines should be used in the pathohistological diagnostics of tumors after neoadjuvant therapy. In particularly, the standard tumor grading will be replaced by tumor regression grading. Furthermore, tumors after neoadjuvant treatment are marked with the prefix "y" in the TNM classification. PMID:22293790

  8. Multi-Institutional Study of Post-Transplantation Cyclophosphamide As Single-Agent Graft-Versus-Host Disease Prophylaxis After Allogeneic Bone Marrow Transplantation Using Myeloablative Busulfan and Fludarabine Conditioning

    PubMed Central

    Kanakry, Christopher G.; O'Donnell, Paul V.; Furlong, Terry; de Lima, Marcos J.; Wei, Wei; Medeot, Marta; Mielcarek, Marco; Champlin, Richard E.; Jones, Richard J.; Thall, Peter F.; Andersson, Borje S.; Luznik, Leo

    2014-01-01

    Purpose The clinical safety and efficacy of intravenous busulfan and fludarabine (IV Bu/Flu) myeloablative conditioning as well as graft-versus-host disease (GVHD) prophylaxis with high-dose, post-transplantation cyclophosphamide (PTCy) have been demonstrated independently in several single-institutional studies. We hypothesized that combining these two promising approaches in a multi-institutional study of human leukocyte antigen (HLA) -matched bone marrow transplantation would provide low rates of severe acute and chronic GVHD, low toxicity, and effective disease control. Patients and Methods Ninety-two adult patients (median age, 49 years; range, 21 to 65 years) with high-risk hematologic malignancies were enrolled at three centers (clinical trial No. NCT00809276). Forty-five patients received related allografts, and 47 received unrelated allografts. GVHD prophylaxis was solely with PTCy at 50 mg/kg/day on post-transplantation days +3 and +4. Results The cumulative incidences of grades 2 to 4 acute, grades 3 to 4 acute, and chronic GVHD were 51%, 15%, and 14%, respectively. Nonrelapse mortality (NRM) at 100 days and 1 year were 9% and 16%, respectively. With a median follow-up period of 2.2 years, the 2-year disease-free survival (DFS) and overall survival (OS) rates were 62% and 67%, respectively. Donor relatedness did not affect NRM, DFS, or OS. Patients in complete remission (CR) without evidence of minimal residual disease (MRD) had markedly better DFS (80%) and OS (80%) than patients in CR with MRD or with active disease at the time of transplantation (DFS, P = .0005; OS, P = .019). Conclusion This multi-institutional study demonstrates that PTCy can be safely and effectively combined with IV Bu/Flu myeloablative conditioning and confirms PTCy's efficacy as single-agent, short-course GVHD prophylaxis for both acute and chronic GVHD after bone marrow transplantation from HLA-matched donors. PMID:25267759

  9. [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. PMID:24684818

  10. [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.

  11. 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...

  12. 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...

  13. 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...

  14. A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients.

    PubMed

    Osunkwo, Ifeyinwa; Bessmertny, Olga; Harrison, Lauren; Cheung, Ying-Kuen; Van de Ven, Carmella; del Toro, Gustavo; Garvin, James; George, Diane; Bradley, M Brigid; Wolownik, Karen; Wischhover, Cheryl; Levy, Joseph; Skerrett, Donna; Cairo, Mitchell S

    2004-04-01

    Tacrolimus (FK506)/mycophenolate mofetil (MMF) has been demonstrated to be an effective salvage therapy for steroid-resistant chronic graft-versus-host disease (GVHD), but its effectiveness as prophylaxis for acute GVHD (aGVHD) is unknown. We investigated the safety and efficacy of FK506/MMF in preventing aGVHD and sparing the use of methotrexate and methylprednisolone in childhood and adolescent allogeneic stem cell transplant (AlloSCT) recipients. Thirty-four childhood and adolescent patients (median age, 7 years; range, 0.5-21 years; 24 males and 10 females) undergoing 37 AlloSCTs for malignant (n = 22) and nonmalignant (n = 12) disorders received FK506 (0.03 mg/kg/d by continuous intravenous infusion) and MMF (15 mg/kg per dose orally or intravenously twice daily). Stem cell sources included 22 umbilical cord blood donors (21 unrelated and 1 related), 6 related bone marrow donors, and 9 related peripheral blood donors. Malignant diagnoses included 7 acute lymphoblastic leukemias, 3 acute myeloid leukemias, 1 acute promyelocytic leukemia, 2 non-Hodgkin lymphomas, 4 Hodgkin diseases, 3 chronic myeloid leukemias, and 2 neuroblastomas; nonmalignant diagnoses included 2 beta-thalassemias, 1 sickle cell disease, 4 aplastic anemias, 1 Wiskott-Aldrich syndrome, 1 Hurler syndrome, 2 hemophagocytic lymphohistiocytoses, and 1 myelodysplastic syndrome. The probability of developing grade > or =II aGVHD was 45.4% +/- 9.7% (7 related bone marrow/related peripheral blood; 5 umbilical cord blood), and for chronic GVHD it was 38.1% +/- 19.7%. FK506/MMF was well tolerated. Three patients had grade III to IV neurotoxicity (disorientation and leukoencephalopathy); 4 patients developed grade III to IV nephrotoxicity (all received concomitant nephrotoxins). Patients who achieved target mycophenolic acid levels (1.0-3.5 microg/mL) before day +30 had a significantly reduced incidence of developing grade >/=II aGVHD (16.7% +/- 15.2% versus 100%; P <.02). These results suggest that FK

  15. Stimulation of systemic low-grade inflammation by psychosocial stress.

    PubMed

    Rohleder, Nicolas

    2014-04-01

    Psychosocial stress is an important precursor of disease and reduced quality of life in humans. The biological pathways between stress exposure and pathophysiological processes underlying disease have received substantial scientific attention, although the roles of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system remain insufficiently understood. Recent attention has focused on chronic systemic low-grade inflammation as a promising pathway because elevated inflammation often accompanies chronic psychosocial distress. These alterations of inflammatory activity play a key role in the pathophysiology of diseases that are adversely affected by chronic distress, such as cardiovascular disease. Transient increases in systemic inflammation are observed in response to acute psychosocial stress, with larger responses among individuals reporting adverse psychosocial states or conditions such as depression, lower self-esteem, or lower self-compassion. Recent evidence shows that lower subjective social status and perceived purpose in life are associated with sensitization of inflammatory stress responses to repeated stress exposure. The aims of this selective review article are to summarize current knowledge of the role of acute and chronic psychosocial stress on low-grade inflammation in humans and to discuss potential relationships between inflammatory responses to acute psychosocial stress and long-term development of disease.

  16. Endoscopic sphincterotomy in acute biliary pancreatitis: A question of anesthesiological risk

    PubMed Central

    Pezzilli, Raffaele

    2009-01-01

    Two consecutive surveys of acute pancreatitis in Italy, based on more than 1000 patients with acute pancreatitis, reported that the etiology of the disease indicates biliary origin in about 60% of the cases. The United Kingdom guidelines report that severe gallstone pancreatitis in the presence of increasingly deranged liver function tests and signs of cholangitis (fever, rigors, and positive blood cultures) requires an immediate and therapeutic endoscopic retrograde cholangiopancreatography (ERCP). These guidelines also recommend that patients with gallstone pancreatitis should undergo prompt cholecystectomy, possibly during the same hospitalization. However, a certain percentage of patients are unfit for cholecystectomy because advanced age and presence of comorbidity. We evaluated the early and long-term results of endoscopic intervention in relation to the anesthesiological risk for 87 patients with acute biliary pancreatitis. All patients underwent ERCP and were evaluated according to the American Society of Anesthesiology (ASA) criteria immediately before the operative procedure. The severity of acute pancreatitis was positively related to the anesthesiological grade. There was no significant relationship between the frequency of biliopancreatic complications during the follow-up and the ASA grade. The frequency of cholecystectomy was inversely related to the ASA grade and multivariate analysis showed that the ASA grade and age were significantly related to survival. Finally, endoscopic treatment also appeared to be safe and effective in patients at high anesthesiological risk with acute pancreatitis. These results further support the hypothesis that endoscopic sphincterotomy might be considered a definitive treatment for patients with acute biliary pancreatitis and an elevated ASA grade. PMID:21160646

  17. 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)

  18. Extracorporeal Photochemotherapy as a Challenging Treatment for Cutaneous T-Cell Lymphoma, Acute and Chronic Graft-versus-Host Disease, Organ Rejection and T-Lymphocyte-Mediated Autoimmune Diseases

    PubMed Central

    Perseghin, Paolo

    2008-01-01

    Summary 20 years ago, in 1987, Edelson and co-workers published their first report on the effectiveness of a new procedure, called extracorporeal photochemotherapy (ECP), in patients with advanced stage cutaneous T-cell lymphoma (CTCL). The positive response (>70% overall) achieved in those patients encouraged several groups to try out this new technology in other T-lymphocyte-mediated autoimmune diseases and a number of dermatological diseases, which sometimes gave conflicting results. In the following years, ECP obtained FDA approval as first line treatment in CTCL. In the 1990s ECP was applied to acute and chronic graft-versus-host disease (GvHD) refractory to conventional immunosuppressive therapy and proved to be effective in >60% of cases of this larger patient population. Today, although the effectiveness of ECP in GvHD is generally acknowledged, this is mainly based on retrospective or observational studies, as data from large, randomized multicenter trials, has yet to be published. Moreover, ECP's real mechanism of action and optimal treatment schedule are still under investigation. The aim of this review is to summarize knowledge acquired to date about ECP. PMID:21547105

  19. 7 CFR 810.2204 - Grades and grade requirements for wheat.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 7 2010-01-01 2010-01-01 false Grades and grade requirements for wheat. 810.2204... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Wheat Principles Governing the Application of Standards § 810.2204 Grades and grade requirements for wheat. (a) Grades and grade...

  20. 7 CFR 810.2204 - Grades and grade requirements for wheat.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 7 2014-01-01 2014-01-01 false Grades and grade requirements for wheat. 810.2204... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Wheat Principles Governing the Application of Standards § 810.2204 Grades and grade requirements for wheat. (a) Grades and grade...

  1. 7 CFR 810.2204 - Grades and grade requirements for wheat.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 7 2011-01-01 2011-01-01 false Grades and grade requirements for wheat. 810.2204... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Wheat Principles Governing the Application of Standards § 810.2204 Grades and grade requirements for wheat. (a) Grades and grade...

  2. 7 CFR 810.2204 - Grades and grade requirements for wheat.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 7 2012-01-01 2012-01-01 false Grades and grade requirements for wheat. 810.2204... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Wheat Principles Governing the Application of Standards § 810.2204 Grades and grade requirements for wheat. (a) Grades and grade...

  3. 7 CFR 810.2204 - Grades and grade requirements for wheat.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 7 2013-01-01 2013-01-01 false Grades and grade requirements for wheat. 810.2204... OFFICIAL UNITED STATES STANDARDS FOR GRAIN United States Standards for Wheat Principles Governing the Application of Standards § 810.2204 Grades and grade requirements for wheat. (a) Grades and grade...

  4. Low relapse without excessive transplant related mortality following myeloablative cord blood transplantation for acute leukemia in complete remission: a matched cohort analysis

    PubMed Central

    Gutman, Jonathan A; Leisenring, Wendy; Appelbaum, Frederick R; Woolfrey, Ann E; Delaney, Colleen

    2009-01-01

    Growing evidence supports the efficacy of cord blood transplantation (CBT), and the number of CBTs is increasing. Numerous studies confirm the presence of a graft-versus-leukemia effect following CBT, and preliminary data suggests that double unit CBT may be associated with a decreased risk of relapse. We have observed a low relapse rate following CBT among patients with acute leukemias in morphologic CR at the time of myeloablative transplant. To further assess this observation we conducted a matched cohort analysis comparing relapse rates and outcomes for patients receiving CBTs versus patients receiving matched unrelated donor (MURD) and mismatched unrelated donor (MMURD) transplants at our center. Thirty-one consecutive CBT patients (ages 0.6–42, median 22) transplanted between April 2006 and June 2008 were compared to matched subjects selected on the basis of disease type and remission number, cytogenetic risk status, minimal residual disease status (MRD), time from diagnosis to first relapse (for patients beyond CR1), use of imatinib for CML and Philadelphia chromosome positive ALL patients, age, and date of transplant. With a median follow-up among surviving CBT patients of 21.1 months (range 6.6–32.6), there has been one relapse among cord patients versus eight relapses among MURD patients (p=0.018) and seven relapses among MMURD patients (p=0.019). Transplant related mortality (TRM) between cohorts is comparable. Though we have observed a high incidence of acute graft-versus-host disease (GVHD) following CBT, the incidence of National Institutes of Health (NIH) consensus criteria chronic GVHD has been low. These data support increased investigation of the use of CBT. PMID:19660726

  5. Allogeneic hematopoietic stem cell transplantation for non-malignant hematological disorders

    PubMed Central

    Mahmoud, Hossam K.; Elhaddad, Alaa M.; Fahmy, Omar A.; Samra, Mohamed A.; Abdelfattah, Raafat M.; El-Nahass, Yasser H.; Fathy, Gamal M.; Abdelhady, Mohamed S.

    2014-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a geno-identical matched sibling (MSD) is one of the most successful therapies in patients with non-malignant hematological disorders. This study included 273 patients with severe aplastic anemia (SAA), 152 patients with B-Thalassemia major (BTM), 31 patients with Fanconi’s anemia (FA), 20 patients with congenital immunodeficiency diseases (ID), and 13 patients with inherited metabolic disorders (IMD) allografted from a MSD. In SAA, the 8-year overall survival (OS) of the whole group patients was 74%. OS was significantly better in patients conditioned with fludarabine and cyclophosphamide (Flu/Cy) than in those who received cyclophosphamide and antithymocyte globulin (Cy/ATG) (p = 0.021). Acute graft-versus-host disease (aGVHD) grade II–IV occurred in 15% while chronic GVHD (cGVHD) occurred in 28%. In BTM, the 12-year disease-free survival (DFS) of the whole group of BTM patients was 72.4%. DFS was 74% for peripheral blood stem cell (PBSC) group compared to 64% in the BM stem cell group. The incidence of graft rejection was significantly lower in patients who received PBSC than in those who received BM (9% vs 25%) (p = 0.036). AGVHD grade II–IV and cGVHD occurred in 15% and 12% of the whole group of BTM patients respectively. In FA, the 5-year OS was 64.5%. Graft rejection occurred in 10% of patients. Grade II–IV aGVHD occurred in 16% while cGVHD occurred in 4%. In ID, the 5-year OS was 62%. Graft rejection occurred in two (10%) patients. Three patients (15%) developed grade II–IV aGVHD, 2 of them progressed to secondary cGVHD. In IMD, OS was 46% at 5 years. Graft rejection occurred in 8% of patients. AGVHD grade II–IV occurred in 15% while cGVHD occurred in 14%. In conclusion, Allo-HSCT provides a higher DFS rate over conventional therapies for patients with non-malignant hematological disorders with prolonged survival. PMID:26257943

  6. 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)

  7. Thermal rectification in graded materials.

    PubMed

    Wang, Jiao; Pereira, Emmanuel; Casati, Giulio

    2012-07-01

    In order to identify the basic conditions for thermal rectification we investigate a simple model with nonuniform, graded mass distribution. The existence of thermal rectification is theoretically predicted and numerically confirmed, suggesting that thermal rectification is a typical occurrence in graded systems, which are likely to be natural candidates for the actual fabrication of thermal diodes. In view of practical implications, the dependence of rectification on the asymmetry and system's size is studied.

  8. 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 ...

  9. 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 ...

  10. Acute arterial occlusion - kidney

    MedlinePlus

    Acute renal arterial thrombosis; Renal artery embolism; Acute renal artery occlusion; Embolism - renal artery ... main artery to the kidney is called the renal artery. Reduced blood flow through the renal artery ...

  11. Acute cerebellar ataxia

    MedlinePlus

    Cerebellar ataxia; Ataxia - acute cerebellar; Cerebellitis; Post-varicella acute cerebellar ataxia; PVACA ... virus. Viral infections that may cause this include chickenpox , Coxsackie disease, Epstein-Barr, and echovirus . Other causes ...

  12. Imaging of Acute Pancreatitis.

    PubMed

    Thoeni, Ruedi F

    2015-11-01

    Acute pancreatitis is an acute inflammation of the pancreas. Several classification systems have been used in the past but were considered unsatisfactory. A revised Atlanta classification of acute pancreatitis was published that assessed the clinical course and severity of disease; divided acute pancreatitis into interstitial edematous pancreatitis and necrotizing pancreatitis; discerned an early phase (first week) from a late phase (after the first week); and focused on systemic inflammatory response syndrome and organ failure. This article focuses on the revised classification of acute pancreatitis, with emphasis on imaging features, particularly on newly-termed fluid collections and implications for the radiologist.

  13. The Betrayal of the Gatekeepers: Grade Inflation.

    ERIC Educational Resources Information Center

    Goldman, Louis

    The problem of grade inflation and explanations for this phenomena are considered. Grade inflation is described as the positive change in grade point average of large numbers of students generally, over an extended period of time. The following array of causes or explanations are discussed: awarding high grades so that a student could go to…

  14. 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...

  15. 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...

  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, 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...

  18. 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…

  19. 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...

  20. On-Demand Grades: The Effect of Online Grade Book Access on Student Mastery and Performance Goal Orientations, Grade Orientation, Academic Self Efficacy, and Grades

    ERIC Educational Resources Information Center

    Seldow, Adam Lowell

    2010-01-01

    With the widespread growth of broadband Internet access, teachers, and in many cases, schools and school districts are transitioning from traditional paper-based grade books to student accessible online (Web-based) grade books. Online grade books offer students 24/7, on demand access to grades and various other student data, and have the potential…

  1. 7 CFR 58.155 - Grading.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... SPECIFICATIONS FOR APPROVED PLANTS AND STANDARDS FOR GRADES OF DAIRY PRODUCTS 1 General Specifications for Dairy Plants Approved for USDA Inspection and Grading Service 1 Inspection, Grading and Official Identification... provisions of this subpart may be graded by the grader in accordance with the U.S. Standards for...

  2. 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. PMID:22856061

  3. 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…

  4. Common Errors in Calculating Final Grades

    ERIC Educational Resources Information Center

    Francis, Richard W.

    2006-01-01

    The author has discovered that errors in grades often occur when scores are combined for final marks. These errors are not related to the grading individual assignments. Rather, they occur when teachers at all grade levels bring individual test and assignment scores together for the students' final grades. Unfortunately, professors of mathematics…

  5. 7 CFR 52.772 - Grades.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... PROCESSED FRUITS AND VEGETABLES, PROCESSED PRODUCTS THEREOF, AND CERTAIN OTHER PROCESSED FOOD PRODUCTS 1 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...

  6. Teaching More by Grading Less (or Differently)

    ERIC Educational Resources Information Center

    Schinske, Jeffrey; Tanner, Kimberly

    2014-01-01

    This article explores a brief history of grading in higher education in the United States. Authors, Schinske and Tanner then follow up with considerations of the potential purposes of grading and insights from research literature that has explored the influence of grading on teaching and learning. Schinske and Tanner then ask: Does grading provide…

  7. Grading Adaptations for Students with Disabilities

    ERIC Educational Resources Information Center

    Silva, Melissa; Munk, Dennis D.; Bursuck, William D.

    2005-01-01

    Issues surround grading for all students, especially those with disabilities, who are at increased risk for grades that are low, inaccurate, and lacking in meaning. Teachers often recognize grading issues and will exercise judgment in making informal adaptations to the regular grading system. When chosen collaboratively and implemented…

  8. 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

  9. 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.

  10. Are antibiotics a safe and effective treatment for acute uncomplicated appendicitis?

    PubMed

    Moraga, Felipe; Ahumada, Vanessa; Crovari, Fernando

    2016-01-01

    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. PMID:26817927

  11. 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.

  12. 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…

  13. Comparing Chemistry Faculty Beliefs about Grading with Grading Practices

    ERIC Educational Resources Information Center

    Mutambuki, Jacinta; Fynewever, Herb

    2012-01-01

    In this study, we seek to understand the beliefs that chemistry faculty hold when grading student solutions in problem solving situations. We are particularly interested in examining whether a conflict exists between the chemistry faculty beliefs and the score they assign to students' solutions. The three categorical values identified in a similar…

  14. Effect of Grade Retention in First Grade on Psychosocial Outcomes

    ERIC Educational Resources Information Center

    Wu, Wei; West, Stephen G.; Hughes, Jan N.

    2010-01-01

    In a 4-year longitudinal study, the authors investigated effects of retention in first grade on children's externalizing and internalizing behaviors; social acceptance; and behavioral, cognitive, and affective engagement. From a large multiethnic sample (n = 784) of children below the median on literacy at school entrance, 124 retained children…

  15. Lessons in Law for Middle Grades: Grade Four.

    ERIC Educational Resources Information Center

    North Carolina State Dept. of Public Instruction, Raleigh. Div. of Social Studies Education.

    These lessons are part of a project to make the study of law and legal concepts an integral part of the North Carolina social studies state curriculum, and the materials are correlated to this curriculum. Six lesson goals and numerous activities focus on the legal concepts of authority, justice, and responsibility. This packet for grade four…

  16. Lessons in Law for Middle Grades: Grade Five.

    ERIC Educational Resources Information Center

    North Carolina State Dept. of Public Instruction, Raleigh. Div. of Social Studies Education.

    These lessons are part of a project to make the study of law and legal concepts an integral part of the North Carolina social studies state curriculum, and these materials are correlated to this curriculum. Six lesson goals and numerous activities focus on the legal concepts of authority, justice, and responsibility. This packet for grade five…

  17. Contrast-Induced Acute Kidney Injury.

    PubMed

    McCullough, Peter A; Choi, James P; Feghali, Georges A; Schussler, Jeffrey M; Stoler, Robert M; Vallabahn, Ravi C; Mehta, Ankit

    2016-09-27

    Coronary angiography and percutaneous intervention rely on the use of iodinated intravascular contrast for vessel and chamber imaging. Despite advancements in imaging and interventional techniques, iodinated contrast continues to pose a risk of contrast-induced acute kidney injury (CI-AKI) for a subgroup of patients at risk for this complication. There has been a consistent and graded signal of risk for associated outcomes including need for renal replacement therapy, rehospitalization, and death, according to the incidence and severity of CI-AKI. This paper reviews the epidemiology, pathophysiology, prognosis, and management of CI-AKI as it applies to the cardiac catheterization laboratory. PMID:27659469

  18. [Evaluation and management of acute radiation dermatitis].

    PubMed

    Modesto, A; Faivre, J-C; Granel-Brocard, F; Tao, Y-G; Pointreau, Y

    2012-09-01

    Acute radiation dermatitis remains one of the most commonly observed side effect during radiation therapy leading to complication such as superinfection or treatment disruption. Its management is characterized by a great heterogeneity. Few strategies have demonstrated a benefit in preventing radiation dermatitis, which relies mostly on decreasing dose delivered to the skin and skin care practices. Simple emollients and use of topical steroids can be useful in early stages. The singularity of the skin toxicity seen with cetuximab and radiotherapy warrants a specific grading system and distinctive clinical treatment with use of antibiotics.

  19. Acute chylous peritonitis due to acute pancreatitis.

    PubMed

    Georgiou, Georgios K; Harissis, Haralampos; Mitsis, Michalis; Batsis, Haralampos; Fatouros, Michalis

    2012-04-28

    We report a case of acute chylous ascites formation presenting as peritonitis (acute chylous peritonitis) in a patient suffering from acute pancreatitis due to hypertriglyceridemia and alcohol abuse. The development of chylous ascites is usually a chronic process mostly involving malignancy, trauma or surgery, and symptoms arise as a result of progressive abdominal distention. However, when accumulation of "chyle" occurs rapidly, the patient may present with signs of peritonitis. Preoperative diagnosis is difficult since the clinical picture usually suggests hollow organ perforation, appendicitis or visceral ischemia. Less than 100 cases of acute chylous peritonitis have been reported. Pancreatitis is a rare cause of chyloperitoneum and in almost all of the cases chylous ascites is discovered some days (or even weeks) after the onset of symptoms of pancreatitis. This is the second case in the literature where the patient presented with acute chylous peritonitis due to acute pancreatitis, and the presence of chyle within the abdominal cavity was discovered simultaneously with the establishment of the diagnosis of pancreatitis. The patient underwent an exploratory laparotomy for suspected perforated duodenal ulcer, since, due to hypertriglyceridemia, serum amylase values appeared within the normal range. Moreover, abdominal computed tomography imaging was not diagnostic for pancreatitis. Following abdominal lavage and drainage, the patient was successfully treated with total parenteral nutrition and octreotide.

  20. Acute chylous peritonitis due to acute pancreatitis

    PubMed Central

    Georgiou, Georgios K; Harissis, Haralampos; Mitsis, Michalis; Batsis, Haralampos; Fatouros, Michalis

    2012-01-01

    We report a case of acute chylous ascites formation presenting as peritonitis (acute chylous peritonitis) in a patient suffering from acute pancreatitis due to hypertriglyceridemia and alcohol abuse. The development of chylous ascites is usually a chronic process mostly involving malignancy, trauma or surgery, and symptoms arise as a result of progressive abdominal distention. However, when accumulation of “chyle” occurs rapidly, the patient may present with signs of peritonitis. Preoperative diagnosis is difficult since the clinical picture usually suggests hollow organ perforation, appendicitis or visceral ischemia. Less than 100 cases of acute chylous peritonitis have been reported. Pancreatitis is a rare cause of chyloperitoneum and in almost all of the cases chylous ascites is discovered some days (or even weeks) after the onset of symptoms of pancreatitis. This is the second case in the literature where the patient presented with acute chylous peritonitis due to acute pancreatitis, and the presence of chyle within the abdominal cavity was discovered simultaneously with the establishment of the diagnosis of pancreatitis. The patient underwent an exploratory laparotomy for suspected perforated duodenal ulcer, since, due to hypertriglyceridemia, serum amylase values appeared within the normal range. Moreover, abdominal computed tomography imaging was not diagnostic for pancreatitis. Following abdominal lavage and drainage, the patient was successfully treated with total parenteral nutrition and octreotide. PMID:22563182

  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. Acute mastoiditis--revisited.

    PubMed

    Luntz, M; Keren, G; Nusem, S; Kronenberg, J

    1994-09-01

    The clinical course and causative organisms were studied in 18 patients with acute mastoiditis, 13 of whom (72%) had no previous history of middle ear disease. Their age ranged from 5 months to 21 years, and duration of middle ear symptoms immediately prior to admission ranged from 1 to 45 days (average 9.7 days). None had undergone a myringotomy prior to admission, while 13 (72%) had been receiving antibiotic treatment for acute otitis media. Three were admitted with intracranial complications. Bacteria were isolated in 10 of the 16 patients in whom samples were available for bacterial culture, and included Streptococcus pneumonia (2), Streptococcus pyogenes (2), Staphylococcus aureus (2), Staphlococcus coagulase negative (2), Klebsiella pneumonia (1), and Pseudomonas aeruginosa (1). Of the 17 patients treated by us, 11 received surgery. Acute otitis media, secretory otitis media, acute mastoiditis, subacute mastoiditis and masked mastoiditis create a continuum. Antibiotic treatment for acute otitis media cannot be considered as an absolute safeguard against acute mastoiditis. When antibiotics are prescribed for acute mastoiditis before culture result is available, an anti-staphylococcal agent should be included. At least some patients with acute mastoiditis develop a primary infection of the bony framework of the middle ear cleft. The prevalence of the intracranial complications in acute mastoiditis is still high and may appear soon after or concomitant with the first sign of acute mastioditis.

  3. Unique patterns of CD8+ T-cell-mediated organ damage in the Act-mOVA/OT-I model of acute graft-versus-host disease.

    PubMed

    Érsek, Barbara; Lupsa, Nikolett; Pócza, Péter; Tóth, Anett; Horváth, Andor; Molnár, Viktor; Bagita, Bence; Bencsik, András; Hegyesi, Hargita; Matolcsy, András; Buzás, Edit I; Pós, Zoltán

    2016-10-01

    T-cell receptor (TCR)-transgenic models of acute graft-versus-host disease (aGvHD) offer a straightforward and highly controlled approach to study the mechanisms and consequences of T-cell activation following allogeneic hematopoietic stem cell transplantation (aHSCT). Here, we report that aHSCT involving OT-I mice as donors, carrying an ovalbumin-specific CD8+ TCR, and Act-mOVA mice as recipients, expressing membrane-bound ovalbumin driven by the β-actin promoter, induces lethal aGvHD in a CD8+ T-cell-dependent, highly reproducible manner, within 4-7 days. Tracking of UBC-GFP/OT-I graft CD8+ T cells disclosed heavy infiltration of the gastrointestinal tract, liver, and lungs at the onset of the disease, and histology confirmed hallmark features of gastrointestinal aGVHD, hepatic aGvHD, and aGvHD-associated lymphocytic bronchitis in infiltrated organs. However, T-cell infiltration was virtually absent in the skin, a key target organ of human aGvHD, and histology confirmed the absence of cutaneous aGVHD, as well. We show that the model allows studying CD8+ T-cell responses in situ, as selective recovery of graft CD45.1/OT-I CD8+ T cells from target organs is simple and feasible by automated tissue dissociation and subsequent cell sorting. Assessment of interferon-gamma production by flow cytometry, granzyme-B release by ELISA, TREC assay, and whole-genome gene expression profiling confirmed that isolated graft CD8+ T cells remained intact, underwent clonal expansion, and exerted effector functions in all affected tissues. Taken together, these data demonstrate that the OT-I/Act-mOVA model is suitable to study the CD8+ T-cell-mediated effector mechanisms in a disease closely resembling fatal human gastrointestinal and hepatic aGVHD that may develop after aHSCT using HLA-matched unrelated donors.

  4. Cytotoxic Capacity of IL-15-Stimulated Cytokine-Induced Killer Cells Against Human Acute Myeloid Leukemia and Rhabdomyosarcoma in Humanized Preclinical Mouse Models

    PubMed Central

    Rettinger, Eva; Meyer, Vida; Kreyenberg, Hermann; Volk, Andreas; Kuçi, Selim; Willasch, Andre; Koscielniak, Ewa; Fulda, Simone; Wels, Winfried S.; Boenig, Halvard; Klingebiel, Thomas; Bader, Peter

    2012-01-01

    Allogeneic stem cell transplantation (allo-SCT) has become an important treatment modality for patients with high-risk acute myeloid leukemia (AML) and is also under investigation for soft tissue sarcomas. The therapeutic success is still limited by minimal residual disease (MRD) status ultimately leading to patients’ relapse. Adoptive donor lymphocyte infusions based on MRD status using IL-15-expanded cytokine-induced killer (CIK) cells may prevent relapse without causing graft-versus-host-disease (GvHD). To generate preclinical data we developed mouse models to study anti-leukemic- and anti-tumor-potential of CIK cells in vivo. Immunodeficient mice (NOD/SCID/IL-2Rγc−, NSG) were injected intravenously with human leukemic cell lines THP-1, SH-2 and with human rhabdomyosarcoma (RMS) cell lines RH41 and RH30 at minimal doses required for leukemia or tumor engraftment. Mice transplanted with THP-1 or RH41 cells were randomly assigned for analysis of CIK cell treatment. Organs of mice were analyzed by flow cytometry as well as quantitative polymerase chain reaction for engraftment of malignant cells and CIK cells. Potential of CIK cells to induce GvHD was determined by histological analysis. Tissues of the highest degree of THP-1 cell expansion included bone marrow followed by liver, lung, spleen, peripheral blood (PB), and brain. RH30 and RH41 engraftment mainly took place in liver and lung, but was also detectable in spleen and PB. In spite of delayed CIK cell expansion compared with malignant cells, CIK cells injected at equal amounts were sufficient for significant reduction of RH41 cells, whereas against fast-expanding THP-1 cells 250 times more CIK than THP-1 cells were needed to achieve comparable results. Our preclinical in vivo mouse models showed a reliable 100% engraftment of malignant cells which is essential for analysis of anti-cancer therapy. Furthermore our data demonstrated that IL-15-activated CIK cells have potent cytotoxic capacity against AML

  5. A conditioning platform based on fludarabine, busulfan, and 2 days of rabbit antithymocyte globulin results in promising results in patients undergoing allogeneic transplantation from both matched and mismatched unrelated donor.

    PubMed

    Devillier, Raynier; Fürst, Sabine; Crocchiolo, Roberto; El-Cheikh, Jean; Castagna, Luca; Harbi, Samia; Granata, Angela; D'Incan, Evelyne; Coso, Diane; Chabannon, Christian; Picard, Christophe; Etienne, Anne; Calmels, Boris; Schiano, Jean-Marc; Lemarie, Claude; Stoppa, Anne-Marie; Bouabdallah, Reda; Vey, Norbert; Blaise, Didier

    2014-01-01

    Conditioning regimen including fludarabine, intravenous busulfan (Bx), and 5 mg/kg total dose of rabbit antithymocyte globulin (r-ATG) (FBx-ATG) results in low incidence of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) from HLA-matched related or unrelated donors (MUD). However, whether this platform produces similar results in the setting of one mismatch unrelated donor (MMUD) Allo-HSCT is not known. We retrospectively analyzed patients aged less than 65 years who were diagnosed with hematological malignancies and received FBx-ATG regimen prior to Allo-HSCT from MUD (N = 74) or MMUD (N = 40). We compared outcome of MUD versus MMUD patients. There was no difference in the cumulative incidence of grades II-IV acute GVHD (MUD: 34% vs. MMUD: 35%, P = 0.918), but MMUD patients developed more grade III-IV acute GVHD (MUD: 5% vs. MMUD: 15%, P = 0.016). The cumulative incidences of overall chronic GVHD (MUD: 33% vs. MMUD: 22%, P = 0.088) and extensive chronic GVHD (MUD: 20% vs. MMUD: 19%, P = 0.594) were comparable. One-year NRM was similar in both groups (MUD: 16% vs. MMUD: 14%, P = 0.292); similarly, progression-free survival (MUD: 59% vs. MMUD: 55%, P = 0.476) and overall survival (MUD: 63% vs. MMUD: 61%, P = 0.762) were not different between both groups. With a median follow up of 24 months, 35 of 74 MUD patients (47%) and 19 of 40 MMUD patients (48%) were free of both disease progression and immunosuppressive treatment. We conclude that the FBx-ATG regimen results in low incidences of NRM and GVHD in both MUD and the MMUD recipients.

  6. [Grading of gynecological tumors : Current aspects].

    PubMed

    Horn, L-C; Mayr, D; Brambs, C E; Einenkel, J; Sändig, I; Schierle, K

    2016-07-01

    Histopathological assessment of the tumor grade and cell type is central to the management and prognosis of various gynecological malignancies. Conventional grading systems for squamous carcinomas and adenocarcinomas of the vulva, vagina and cervix are poorly defined. For endometrioid tumors of the female genital tract as well as for mucinous endometrial, ovarian and seromucinous ovarian carcinomas, the 3‑tiered FIGO grading system is recommended. For uterine neuroendocrine tumors the grading system of the gastrointestinal counterparts has been adopted. Uterine leiomyosarcomas are not graded. Endometrial stromal sarcomas are divided into low and high grades, based on cellular morphology, immunohistochemical and molecular findings. A chemotherapy response score was established for chemotherapeutically treated high-grade serous pelvic cancer. For non-epithelial ovarian malignancies, only Sertoli-Leydig cell tumors and immature teratomas are graded. At this time molecular profiling has no impact on the grading of tumors of the female genital tract. PMID:27379622

  7. Ninth Grade English: Curriculum Guide.

    ERIC Educational Resources Information Center

    Harlandale Independent School District, San Antonio, TX. Career Education Center.

    The guide is arranged in vertical columns relating curriculum concepts in English to curriculum performance objectives, career concepts and career performance objectives, suggested teaching methods, and resource materials. State concepts for ninth grade English, as outlined in the Texas Education Agency "Bulletin 615" for instruction, are used in…

  8. Eighth Grade English: Curriculum Guide.

    ERIC Educational Resources Information Center

    Harlandale Independent School District, San Antonio, TX. Career Education Center.

    The guide is arranged in vertical columns relating curriculum concepts in English to curriculum performance objectives, career concepts and career performance objectives, suggested teaching methods, and resource materials. State concepts for eighth grade English, as outlined in the Texas Education Agency "Bulletin 615" for instruction, are used in…

  9. 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…

  10. 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…

  11. 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…

  12. 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.…

  13. 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…

  14. 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.…

  15. 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 through…

  16. Patriotic Observances. Grades K-6.

    ERIC Educational Resources Information Center

    Manitoba Dept. of Education, Winnipeg.

    Materials and suggestions to help teachers in grades K-6 highlight special dates that hold significance for Canadian children are provided. The purpose is to arouse an awareness in children of their Canadian identity. The "patriotic observances" should take place at the beginning of every school day. Materials concerning Canadian natural wonders,…

  17. 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…

  18. 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…

  19. Industrial Education. Drafting. [Grade 9].

    ERIC Educational Resources Information Center

    Parma City School District, OH.

    Part of a series of curriculum guides dealing with industrial education in junior high schools, this guide provides a course on drafting to be used in the ninth grade. Thirteen goals are identified for the students to demonstrate: (1) a knowledge of the relationship between drafting and the work of designers, engineers, and architects; (2) an…

  20. 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…

  1. 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…

  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. 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;…

  4. 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…

  5. 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…

  6. 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)…

  7. 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…

  8. Algebra: Grades 8-12.

    ERIC Educational Resources Information Center

    Instructional Objectives Exchange, Los Angeles, CA.

    A complete set of behavioral objectives for first-year algebra taught in any of grades 8 through 12 is presented. Three to six sample test items and answers are provided for each objective. Objectives were determined by surveying the most used secondary school algebra textbooks. Fourteen major categories are included: (1) whole numbers--operations…

  9. Determinants of Grades in Economics.

    ERIC Educational Resources Information Center

    Fox, Pauline

    Interest in the relationship between student characteristics and interests and economics grades led to the administration of a questionnaire to 565 students enrolled in principles of economics classes. The students who completed the questionnaire were among 1,000 students in 27 sections of macro and micro principles courses at Southeast Missouri…

  10. 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 cover the…

  11. 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…

  12. Social Studies Handbook, First Grade.

    ERIC Educational Resources Information Center

    Ventura County Superintendent of Schools, CA.

    The handbook outlines a course of study in social studies for grade 1. The overall course objective is to teach children about the family's needs, the ways in which it satisfies them, and the interdependence of people in families and communities. Questioning techniques are used throughout the course. Questions which develop student thinking…

  13. The Ninth-Grade Challenge

    ERIC Educational Resources Information Center

    Habeeb, Scott

    2013-01-01

    Across the country, high schools have found that their ninth-grade students have the highest rates of truancy, discipline referrals, failures, and retentions. A school's worst data points are usually found among freshmen. For this reason, proactive schools seek strategies for transitioning freshmen into high school. An effective freshman…

  14. 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…

  15. Sociology. Grades 11 & 12. Revised.

    ERIC Educational Resources Information Center

    Hamilton Township Schools, NJ.

    This curriculum guide presents both general information on K-12 social studies curriculum development and information specific to designing an 11th and 12th grade sociology curriculum. A foreword and preface describe Hamilton Township's (New Jersey) K-12 social studies program sequence, curriculum and instruction design criteria, and support…

  16. City Planning Unit: Grade 6.

    ERIC Educational Resources Information Center

    Dalton, William Edward

    Described is a project designed to make government lessons and economics more appealing to sixth-grade students by having them set up and run a model city. General preparation procedures and set-up of the project, specific lesson plans, additional activities, and project evaluation are examined. An actual 3-dimensional model city was set up on…

  17. Outdoor Education--Fifth Grade.

    ERIC Educational Resources Information Center

    Harris, Jean, Comp.; And Others

    Learning activities; lesson plans, and various resource materials are contained in this guide for the fifth grade outdoor education program in the Dixon Public Schools, Dixon, Illinois. Well over 100 activities are suggested, and many of these are described in detail. Although some information is specific to the Dixon program, which has access to…

  18. Science Equity in Third Grade

    ERIC Educational Resources Information Center

    Kohlhaas, Kay; Lin, Hsin-Hui; Chu, Kwang-Lee

    2010-01-01

    The earliest national accountability tests occur at the fourth-grade level and the outcomes are aggregated. This national study exposes the depth of science education inequities a full year earlier by disaggregating third graders' demographic data with the science performance. A full 3-way ANOVA model was applied to test the 3 main effects…

  19. TEAM TEACHING IN ELEMENTARY GRADES.

    ERIC Educational Resources Information Center

    Educational Research Service, Arlington, VA.

    INFORMATION ON THE PRACTICE OF TEAM TEACHING IN THE ELEMENTARY GRADES DRAWN FROM A SURVEY OF SCHOOL SYSTEMS HAVING SUCH PROBLEMS IS PRESENTED IN THIS CIRCULAR. OVER 400 SCHOOL SYSTEMS WITH ENROLLMENTS OF 12,000 AND ABOVE WERE INITIALLY SURVEYED, AND THE 169 WHICH INDICATED THEY USED SOME TEAM TEACHING WERE SENT QUESTIONNAIRES. THE PROGRAMS OF 76…

  20. [Pathogenesis of acute encephalitis and acute encephalopathy].

    PubMed

    Shiomi, Masashi

    2011-03-01

    Many aspects of the pathogenesis of acute encephalitis and acute encephalopathy have been clarified in this decade, although many unknown mechanisms remain to be elucidated. According to progress of MRI and neuroimmunological analysis and the observation of clinical findings, many new syndromes were found, which enhanced our understanding of acute encephalitis and acute encephalopathy. The pathogenesis of encephalitis is divided into infection and immune mediated mechanisms. The antibodies to neuronal surface antigens(NSA) such as NMDA receptors, leucin-rich glioma inactivated 1 (LGI1) and aquaporin 4 were demonstrated in specific encephalitis, limbic encephalitis and neuromyelitis optica. Anti-NSA antibody encephalitis should be treated by immunotherapy such as corticosteroid and plasmapheresis. Acute encephalitis with refractory repetitive partial seizures (AERRPS) is a devastating postinfectious disease in children and adults, although the pathogenesis of AERRPS is poorly understood. Influenza associated encephalopathy(IAE) is characterized by it's high incidence in Japanese children between 1 year and 5 years of age, its onset in the first or the second day of illness and its high mortality (15-30%) and morbidity (25-40%). We proposed the classification of IAE with poor prognosis from the neuroradiological findings. Four types of encephalopathy seem to be differentiated from each other, acute necrotizing encephalopathy (ANE) type, hemorrhagic shock and encephalopathy syndrome (HSES) type, acute brain swelling (ABS) type, febrile convulsive status epilepticus (FCSE) type. The notable radiological features are thalamic lesions in ANE, diffuse cerebral cortical cytotoxic edema in HSES, reversible cerebral swelling in ABS which sometimes reaches lethal brain herniation, and in FCSE type, dendritic high signal in subcortical white matter by DWI ("bright tree appearance") appears simultaneously with the later onset of repetitive focal seizure. These four types are

  1. Acute Vision Loss.

    PubMed

    Bagheri, Nika; Mehta, Sonia

    2015-09-01

    Acute vision loss can be transient (lasting <24 hours) or persistent (lasting >24 hours). When patients present with acute vision loss, it is important to ascertain the duration of vision loss and whether it is a unilateral process affecting one eye or a bilateral process affecting both eyes. This article focuses on causes of acute vision loss in the nontraumatic setting and provides management pearls to help health care providers better triage these patients.

  2. Acute Vision Loss.

    PubMed

    Bagheri, Nika; Mehta, Sonia

    2015-09-01

    Acute vision loss can be transient (lasting <24 hours) or persistent (lasting >24 hours). When patients present with acute vision loss, it is important to ascertain the duration of vision loss and whether it is a unilateral process affecting one eye or a bilateral process affecting both eyes. This article focuses on causes of acute vision loss in the nontraumatic setting and provides management pearls to help health care providers better triage these patients. PMID:26319342

  3. [Acute mastoiditis in children].

    PubMed

    Kajosaari, Lauri; Sinkkonen, Saku T; Laulajainen-Hongisto, Anu; Jero, Jussi

    2014-01-01

    Acute mastoiditis in children develops when acute otitis media (AOM) spreads into the mastoid air cells inside the temporal bone. The diagnosis is based on clinical findings of AOM with simultaneous signs of infection in the mastoid area. The most common pathogen causing acute mastoiditis in children is Streptococcus pneumoniae. Intravenous antimicrobial medication, tympanostomy and microbial sample are the cornerstones of the treatment. If a complication of mastoiditis is suspected, imaging studies are needed, preferably with magnetic resonance imaging. The most common complication of acute mastoiditis is a subperiosteal abscess. PMID:24660384

  4. Tacrolimus and mycophenolate mofetil after nonmyeloablative matched-sibling donor allogeneic stem-cell transplantations conditioned with fludarabine and low-dose total body irradiation.

    PubMed

    Nieto, Yago; Patton, Nigel; Hawkins, Timothy; Spearing, Ruth; Bearman, Scott I; Jones, Roy B; Shpall, Elizabeth J; Rabinovitch, Rachel; Zeng, Chan; Barón, Anna; McSweeney, Peter A

    2006-02-01

    We evaluated tacrolimus/mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after a nonmyeloablative stem cell transplantation (NST) from a matched sibling donor (MSD). Thirty-two patients (median age, 57 years) with advanced hematologic malignancies, who were poor candidates for a conventional myeloablative transplantation, received fludarabine (30 mg/m(2), day -4 to day -2), total-body irradiation (TBI) (200 cGy, day 0), infusion of donor peripheral blood progenitor cells (day 0), oral tacrolimus 0.06 mg/kg twice daily (from day 3), and oral MMF at 15 mg/kg twice daily (days 0-+27). Tacrolimus was tapered from day +100 to day +180 in those patients with indolent malignancies (n = 25), and from day +35 to day +56 in those with aggressive tumors (n = 7). Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a nonfatal graft rejection. Rates of grades II-IV and III-IV acute GVHD were 15.6% and 3%, respectively. Acute GVHD was diagnosed at median day +78 (range, days +31-+84). Extensive chronic GVHD was observed in 10 of 24 evaluable patients (41.6%) at a median onset of day +198 (range, days +128-+277), either spontaneously (n = 5) or elicited after tumor progression (n = 5). Five patients experienced transplantation-related mortality (TRM) (15.6%) from either acute GVHD-related multiorgan failure (MOF) (n = 3) or infectious complications (n = 2). At median follow-up of 19 months (range, 2-41 months), the overall survival, progression-free survival, and disease-free survival rates are 62.5%, 50%, and 40%, respectively. In conclusion, the use of tacrolimus/MMF after MSD NST is associated with encouraging rates of GVHD control.

  5. Interferon-α: A Potentially Effective Treatment 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

    2015-11-01

    In this prospective clinical study, the safety and efficacy of preemptive interferon-α (IFN-α) treatment were investigated and compared with preemptive donor lymphocyte infusion (DLI) in patients who were minimal residual disease (MRD)-positive after allogeneic hematopoietic stem cell transplantation (HSCT). Patients undergoing allogeneic HSCT were eligible if they had acute leukemia or myelodysplastic syndrome and were MRD-positive after HSCT. Patients who were able to receive DLI were assigned to a preemptive DLI group (n = 45); patients who could not or did not agree to receive DLI after HSCT received preemptive IFN-α. A total of 22 patients received preemptive IFN-α; the median treatment duration was 35 days (range, 4 to 180 days). Seven patients relapsed, and 1 patient died from severe pneumonia. The 1-year cumulative incidence of chronic graft-versus-host disease (cGVHD) after intervention was 90.9% for the IFN-α group and 62.9% for the DLI group (P < .001). MRD status after preemptive intervention was comparable in the 2 groups, and the 1-year cumulative incidence of relapse after intervention was 27.3% for the IFN-α group and 35.6% for the DLI group (P = .514). The 1-year cumulative incidence of nonrelapse mortality after intervention was 4.5% for the IFN-α group and 4.4% for the DLI group (P = .985). The 1-year probability of disease-free survival after intervention was 68.2% for the IFN-α group and 60.0% for the DLI group (P = .517). In multivariate analysis, early-onset MRD, persistent MRD after intervention, and absence of cGVHD after intervention were significantly associated with poorer clinical outcomes. Thus, preemptive IFN-α may be a potential alternative for MRD-positive patients who cannot receive preemptive DLI after HSCT.

  6. Acute Skin Toxicity Following Stereotactic Body Radiation Therapy for Stage I Non-Small-Cell Lung Cancer: Who's at Risk?

    SciTech Connect

    Hoppe, Bradford S.; Laser, Benjamin; Kowalski, Alex V.; Fontenla, Sandra C.; Pena-Greenberg, Elizabeth; Yorke, Ellen D.; Lovelock, D. Michael; Hunt, Margie A.; Rosenzweig, Kenneth E.

    2008-12-01

    Purpose: We examined the rate of acute skin toxicity within a prospectively managed database of patients treated for early-stage non-small-cell lung cancer (NSCLC) and investigated factors that might predict skin toxicity. Methods: From May 2006 through January 2008, 50 patients with Stage I NSCLC were treated at Memorial Sloan-Kettering Cancer Center with 60 Gy in three fractions or 44-48 Gy in four fractions. Patients were treated with multiple coplanar beams (3-7, median 4) with a 6 MV linac using intensity-modulated radiotherapy (IMRT) and dynamic multileaf collimation. Toxicity grading was performed and based on the National Cancer Institute Common Terminology Criteria for Adverse Effects. Factors associated with Grade 2 or higher acute skin reactions were calculated by Fisher's exact test. Results: After a minimum 3 months of follow-up, 19 patients (38%) developed Grade 1, 4 patients (8%) Grade 2, 2 patients (4%) Grade 3, and 1 patient Grade 4 acute skin toxicity. Factors associated with Grade 2 or higher acute skin toxicity included using only 3 beams (p = 0.0007), distance from the tumor to the posterior chest wall skin of less than 5 cm (p = 0.006), and a maximum skin dose of 50% or higher of the prescribed dose (p = 0.02). Conclusions: SBRT can be associated with significant skin toxicity. One must consider the skin dose when evaluating the treatment plan and consider the bolus effect of immobilization devices.

  7. A phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease.

    PubMed

    Herrera, Alex F; Kim, Haesook T; Bindra, Bhavjot; Jones, Kyle T; Alyea, Edwin P; Armand, Philippe; Cutler, Corey S; Ho, Vincent T; Nikiforow, Sarah; Blazar, Bruce R; Ritz, Jerome; Antin, Joseph H; Soiffer, Robert J; Koreth, John

    2014-11-01

    Chronic graft-versus-host disease (GVHD) induces significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Corticosteroids are standard initial therapy, despite limited efficacy and long-term toxicity. Based on our experience using bortezomib as effective acute GVHD prophylaxis, we hypothesized that proteasome-inhibition would complement the immunomodulatory effects of corticosteroids to improve outcomes in chronic GVHD (cGVHD). We undertook a single-arm phase II trial of bortezomib plus prednisone for initial therapy of cGVHD. Bortezomib was administered at 1.3 mg/m(2) i.v. on days 1, 8, 15, and 22 of each 35-day cycle for 3 cycles (15 weeks). Prednisone was dosed at .5 to 1 mg/kg/day, with a suggested taper after cycle 1. All 22 enrolled participants were evaluable for toxicity; 20 were evaluable for response. Bortezomib plus prednisone therapy was well tolerated, with 1 occurrence of grade 3 sensory peripheral neuropathy possibly related to bortezomib. The overall response rate at week 15 in evaluable participants was 80%, including 2 (10%) complete and 14 (70%) partial responses. The organ-specific complete response rate was 73% for skin, 53% for liver, 75% for gastrointestinal tract, and 33% for joint, muscle, or fascia involvement. The median prednisone dose decreased from 50 mg/day to 20 mg/day at week 15 (P < .001). The combination of bortezomib and prednisone for initial treatment of cGVHD is feasible and well tolerated. We observed a high response rate to combined bortezomib and prednisone therapy; however, in this single-arm study, we could not directly measure the impact of bortezomib. Proteasome inhibition may offer benefit in the treatment of cGVHD and should be further evaluated. PMID:25017765

  8. Suggestions for Responding to the Dilemma of Grading Students' Writing.

    ERIC Educational Resources Information Center

    Anderson, Rebecca S.; Speck, Bruce W.

    1997-01-01

    Discusses the four-week summer Memphis (Tennessee) Urban Writing Institute, during which a furor erupted over the dilemma of grading. Provide a number of approaches to grading students' writing, including minimalist grading, cassette grading, collaborative grading, and portfolio grading. Suggests that teachers consider the grading dilemma and…

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 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...

  14. T cell–depleted stem-cell transplantation for adults with hematologic malignancies: sustained engraftment of HLA-matched related donor grafts without the use of antithymocyte globulin

    PubMed Central

    Small, Trudy N.; Young, James W.; Kernan, Nancy A.; Castro-Malaspina, Hugo; Hsu, Katherine C.; Perales, Miguel-Angel; Collins, Nancy; Cisek, Christine; Chiu, Michelle; van den Brink, Marcel R. M.; O'Reilly, Richard J.; Papadopoulos, Esperanza B.

    2007-01-01

    Antithymocyte globulin (ATG) has been used in allogeneic stem-cell transplantation to prevent graft rejection and graft-versus-host disease (GvHD). Its use, however, has been associated with delayed T-cell reconstitution and prolonged susceptibility to opportunistic infections (OIs) especially in patients undergoing T cell–depleted (TCD) transplantation. Recently, a prospective trial was conducted in 52 adult patients (median age, 47 years) with various hematologic malignancies undergoing TCD transplantation from HLA-matched related donors without the use of ATG. The cytoreductive regimen consisted of hyperfractionated total body irradiation (HFTBI), thiotepa, and fludarabine. The preferred source of the graft was peripheral blood stem cells (PBSCs). No additional graft rejection or GvHD prophylaxis was given. All evaluable patients engrafted without any immune-mediated graft rejections. Disease-free survival (DFS) at 3 years was 61% in all patients, and 70% in patients with standard-risk disease. Acute GvHD was limited to grade 2 in 8% and chronic GvHD in 9% of patients. Life-threatening OIs occurred in 3 of 52 patients and was fatal in 1. This study demonstrates durable engraftment with a low incidence of GvHD despite the lack of ATG, as well as the curative potential of this regimen. PMID:17717135

  15. A Prospective Study of an Alemtuzumab Containing Reduced-intensity Allogeneic Stem Cell Transplantation Program in Patients with Poor-Risk and Advanced Lymphoid Malignancies

    PubMed Central

    Sauter, Craig S.; Chou, Joanne F.; Papadopoulos, Esperanza B.; Perales, Miguel-Angel; Jakubowski, Ann A.; Young, James W.; Scordo, Michael; Giralt, Sergio; Castro-Malaspina, Hugo

    2015-01-01

    Reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (allo-SCT) have used alemtuzumab to abrogate the risk of graft-versus-host disease (GVHD). Thirty-eight advanced lymphoma patients underwent a prospective phase II study of melphalan, fludarabine and alemtuzumab containing RIC allo-SCT from 20 matched related and 18 unrelated donors with cyclosporin-A as GVHD prophylaxis. The cumulative incidence of grade II-IV acute GVHD at 3 months was 10.5% and three evaluable patients experienced chronic GVHD. Progression-free (PFS) and overall (OS) survival at 5 years is 25% (95% CI: 13-40) and 44% (95% CI: 28-59%) respectively. Previous high-dose therapy and autologous stem cell transplantation (HDT-ASCT) and elevated LDH at the time of allo-SCT resulted in inferior OS. Within this cohort of high-risk lymphoma patients, alemtuzumab containing RIC resulted in a low risk of GVHD and a high incidence of POD, especially in those with poor-risk features defined by elevated LDH pre-allo-SCT and previous HDT-ASCT. PMID:24528216

  16. A prospective study of an alemtuzumab containing reduced-intensity allogeneic stem cell transplant program in patients with poor-risk and advanced lymphoid malignancies.

    PubMed

    Sauter, Craig S; Chou, Joanne F; Papadopoulos, Esperanza B; Perales, Miguel-Angel; Jakubowski, Ann A; Young, James W; Scordo, Michael; Giralt, Sergio; Castro-Malaspina, Hugo

    2014-12-01

    Reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplant (allo-SCT) have used alemtuzumab to abrogate the risk of graft-versus-host disease (GVHD). Thirty-eight patients with advanced lymphoma underwent a prospective phase II study of melphalan, fludarabine and alemtuzumab containing RIC allo-SCT from 20 matched related and 18 unrelated donors with cyclosporine-A as GVHD prophylaxis. The cumulative incidence of grade II-IV acute GVHD at 3 months was 10.5% and three evaluable patients experienced chronic GVHD. Progression-free (PFS) and overall (OS) survival at 5 years was 25% (95% confidence interval [CI]: 13-40%) and 44% (95% CI: 28-59%), respectively. Previous high-dose therapy and autologous stem cell transplant (HDT-ASCT) and elevated lactate dehydrogenase (LDH) at the time of allo-SCT resulted in inferior OS. Within this cohort of patients with high-risk lymphoma, alemtuzumab containing RIC resulted in a low risk of GVHD and a high incidence of progression of disease, especially in those with poor-risk features defined by elevated LDH pre-allo-SCT and previous HDT-ASCT.

  17. High-Grading Lunar Samples

    NASA Technical Reports Server (NTRS)

    Allen, Carlton; Sellar, Glenn; Nunez, Jorge; Mosie, Andrea; Schwarz, Carol; Parker, Terry; Winterhalter, Daniel; Farmer, Jack

    2009-01-01

    Astronauts on long-duration lunar missions will need the capability to high-grade their samples to select the highest value samples for transport to Earth and to leave others on the Moon. We are supporting studies to define the necessary and sufficient measurements and techniques for high-grading samples at a lunar outpost. A glovebox, dedicated to testing instruments and techniques for high-grading samples, is in operation at the JSC Lunar Experiment Laboratory. A reference suite of lunar rocks and soils, spanning the full compositional range found in the Apollo collection, is available for testing in this laboratory. Thin sections of these samples are available for direct comparison. The Lunar Sample Compendium, on-line at http://www-curator.jsc.nasa.gov/lunar/compendium.cfm, summarizes previous analyses of these samples. The laboratory, sample suite, and Compendium are available to the lunar research and exploration community. In the first test of possible instruments for lunar sample high-grading, we imaged 18 lunar rocks and four soils from the reference suite using the Multispectral Microscopic Imager (MMI) developed by Arizona State University and JPL (see Farmer et. al. abstract). The MMI is a fixed-focus digital imaging system with a resolution of 62.5 microns/pixel, a field size of 40 x 32 mm, and a depth-of-field of approximately 5 mm. Samples are illuminated sequentially by 21 light emitting diodes in discrete wavelengths spanning the visible to shortwave infrared. Measurements of reflectance standards and background allow calibration to absolute reflectance. ENVI-based software is used to produce spectra for specific minerals as well as multi-spectral images of rock textures.

  18. Grade Organization Patterns. ERS Reporter.

    ERIC Educational Resources Information Center

    American Association of School Administrators, Washington, DC.

    Information regarding grade organization patterns in 449 of the 515 school districts enrolling 12,000 or more pupils is reported in this national survey, which repeated a similar survey made in 1963. Results show that the predominant plan is that which follows the 6-3-3 pattern. Of interest are the four percent rise in the 4-4-4 or 5-3-4 middle…

  19. Standardization of grading embryo morphology.

    PubMed

    Racowsky, Catherine; Vernon, Michael; Mayer, Jacob; Ball, G David; Behr, Barry; Pomeroy, Kimball O; Wininger, David; Gibbons, William; Conaghan, Joseph; Stern, Judy E

    2010-08-01

    Standardization of morphologic assessment for an embryo grading system was developed and is being implemented by the Society for Assisted Reproductive Technology (SART). A recent European consensus conference of embryologists from Europe and America is working toward adopting an embryo classification system modeled similarly to that of SART that, if adopted, would produce a de facto international standard to aid cross-border collaboration. PMID:20580357

  20. Hepatic encephalopathy in acute-on-chronic liver failure.

    PubMed

    Lee, Guan-Huei

    2015-10-01

    The presence of hepatic encephalopathy (HE) within 4 weeks is part of the criteria for defining acute-on-chronic liver failure (ACLF). The pathophysiology of HE is complex, and hyperammonemia and cerebral hemodynamic dysfunction appear to be central in the pathogenesis of encephalopathy. Recent data also suggest that inflammatory mediators may have a significant role in modulating the cerebral effect of ammonia. Multiple prospective and retrospective studies have shown that hepatic encephalopathy in ACLF patients is associated with higher mortality, especially in those with grade III-IV encephalopathy, similar to that of acute liver failure (ALF). Although significant cerebral edema detected by CT in ACLF patients appeared to be less common, specialized MRI imaging was able to detect cerebral edema even in low grade HE. Ammonia-focused therapy constitutes the basis of current therapy, as in the treatment of ALF. Emerging treatment strategies focusing on modulating the gut-liver-circulation-brain axis are discussed.

  1. N-Acetylcysteine Use in Non-Acetaminophen-Induced Acute Liver Failure.

    PubMed

    McPheeters, Chelsey M; VanArsdale, Vanessa M; Weant, Kyle A

    2016-01-01

    This article will review the available evidence related to the management of non-acetaminophen induced acute liver failure with N-acetylcysteine. Randomized controlled trials and a meta-analysis were included in this review. The efficacy of N-acetylcysteine in the treatment of acute liver failure from causes other than acetaminophen toxicity was evaluated. The efficacy of N-acetylcysteine in non-acetaminophen-induced acute liver failure is limited to specific patient populations. Patients classified as Coma Grade I or II are more likely to benefit from the use of this agent. The use of N-acetylcysteine is associated with improved transplant-free survival, not overall survival, in adults. N-Acetylcysteine does not improve the overall survival of patients with non-acetaminophen-induced acute liver failure but may be beneficial in those patients with Coma Grades I-II. Liver transplantation remains the only definitive therapy in advanced disease. PMID:27482990

  2. Grade Distribution. Community Colleges, Fall 1978.

    ERIC Educational Resources Information Center

    Hawaii Univ., Honolulu. Community Coll. System.

    Data on the grade point ratios (GPR's) and the distribution of grades earned were gathered and analyzed for all students enrolled in credit courses at the seven Hawaii community colleges during Fall 1978. These data indicate that the average assigned grade was 2.7, and that the credits-earned rate was 71%. As in previous semesters, the…

  3. 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…

  4. REORGANIZED SCIENCE CURRICULUM, 8, GRADE EIGHT SUPPLEMENT.

    ERIC Educational Resources Information Center

    Minneapolis Special School District 1, Minn.

    THE FOURTEENTH IN A SERIES OF 17 VOLUMES, THIS VOLUME PROVIDES THE EIGHTH GRADE TEACHER WITH A GUIDE TO THE REORGANIZED SCIENCE CURRICULUM OF THE MINNEAPOLIS PUBLIC SCHOOLS. THE MATERIALS ARE AUGMENTED AND REVISED AS THE NEED ARISES. A CHART INDICATES CONCEPT BRIEF SUMMARY OF SUBJECT MATTER CONTENT FOR GRADE 8, AND A CHART OF THE GRADE CONTENT FOR…

  5. Teachers' Belief Systems and Grading Practices.

    ERIC Educational Resources Information Center

    Frank, Harry; Brown, Clarence

    This report investigated two hypotheses: 1) junior high school teachers with concrete belief systems would assign more unsatisfactory citizenship grades and lower academic grades than more abstract teachers; and 2) the correlation between citizenship and academic grades would be higher for concrete than abstract teachers. Ten teachers from…

  6. The Effect of Effort Grading on Learning

    ERIC Educational Resources Information Center

    Swinton, Omari H.

    2010-01-01

    In the fall of 2004, Benedict College--a Historically Black College in Columbia, SC--began enforcing a new grading policy called Success Equals Effort (SE[squared]). Under this policy, students taking freshman and sophomore level courses were assigned grades that explicitly rewarded not only content learning ("knowledge" grade) but also measures…

  7. First Grade Teacher Expectations in Mathematics.

    ERIC Educational Resources Information Center

    Funkhouser, Charles P.

    The focus of this study was on the expectations that first-grade teachers have of the mathematics skills of their incoming first-grade students. At the end of one school year and at the beginning of the next school year, first-grade teachers (n=64) in rural and urban settings completed the Mathematics Skills Expectations Survey (MSES). The MSES…

  8. Graded Course of Study, Science (K-12).

    ERIC Educational Resources Information Center

    Euclid City Schools, OH.

    This course of study specifies the science skills and concepts that are to be taught in the various grades of the Euclid (Ohio) City Schools. Included are instructional objectives for the life, physical, and earth sciences for grades K to 6, suggested field trips and planetarium schedules (by elementary grade levels), and scope and sequence charts…

  9. Elementary Mathematics, Grades 1-6.

    ERIC Educational Resources Information Center

    Nederland Independent School District, TX.

    GRADES OR AGES: Grades 1-6. SUBJECT MATTER: Elementary math. ORGANIZATION AND PHYSICAL APPEARANCE: Introductory material focuses on the philosophy and objectives of instructional material. The guide is divided into six units covering grades 1-6. Each unit presents the general goals, materials needed, minimum program, skills to be developed,…

  10. Science for Grades 6-9.

    ERIC Educational Resources Information Center

    Nederland Independent School District, TX.

    GRADES OR AGES: Grades 6-9. SUBJECT MATTER: General science, life science, earth science, and physical science. ORGANIZATION AND PHYSICAL APPEARANCE: The guide is divided into separate sections for each grade. Each section is further subdivided into units. The major portion of each unit is laid out in four columns; column headings are concepts,…

  11. 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…

  12. Community College Grading Policies. Agenda Item 5.

    ERIC Educational Resources Information Center

    Petersen, Allan

    Background information and a discussion of major issues accompany recommended state minimum standards for grading as presented by an ad hoc Grading Policy Study Group to the Board of Governors of the California Community Colleges. The report first notes the diversity of grading policies among the colleges and then outlines the Group's…

  13. Predicting Turkish Ninth Grade Students' Algebra Performance

    ERIC Educational Resources Information Center

    Erbas, Ayhan Kursat

    2005-01-01

    The prediction of students' achievement in algebra in eighth and ninth grades has become a research interest for practical issues of placement. A group of simple, easily accessible variables was used to predict student performance in algebra after completion of eighth grade. The three variables of school type, grade level, and previous year…

  14. Analysis of Fall 1996 Course Grades.

    ERIC Educational Resources Information Center

    McGregor, Ellen N.; Reece, Dee; Garner, Doris

    This report provides data on withdrawal and success rates and grades earned in fall 1996 at the five campuses of Pima Community College (PCC) in Arizona. Following a literature review on national course grades, descriptions are provided of the following: (1) grades and withdrawals for 1981, 1986, 1991, and 1996, indicating that the number of A…

  15. Analysis of Fall 1995 Course Grades.

    ERIC Educational Resources Information Center

    Pima Community Coll., Tucson, AZ. Office of Institutional Research.

    This report provides data on withdrawal and success rates and grades earned in fall 1995 at the five campuses of Pima Community College (PCC) in Arizona. Following a literature review on national course grades, descriptions are provided of the following: (1) grades and withdrawals for 1980, 1985, 1990, and 1995, indicating that the number of A…

  16. Analysis of Fall 1994 Course Grades.

    ERIC Educational Resources Information Center

    Pima Community Coll., Tucson, AZ. Office of Research and Planning.

    This report provides data on withdrawal and success rates and grades earned in fall 1994 at the five campuses of Pima Community College (PCC), in Arizona. Following a literature review on national course grades, descriptions are provided of the following: (1) grades and withdrawals for fall 1979, 1984, 1989, and 1994, indicating that the number of…

  17. 7 CFR 29.1022 - Grade.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... INSPECTION Standards Official Standard Grades for Flue-Cured Tobacco (u.s. Types 11, 12, 13, 14 and Foreign Type 92) § 29.1022 Grade. A subdivision of a type according to group, quality, and color. ... 7 Agriculture 2 2012-01-01 2012-01-01 false Grade. 29.1022 Section 29.1022 Agriculture...

  18. 7 CFR 29.1022 - Grade.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... INSPECTION Standards Official Standard Grades for Flue-Cured Tobacco (u.s. Types 11, 12, 13, 14 and Foreign Type 92) § 29.1022 Grade. A subdivision of a type according to group, quality, and color. ... 7 Agriculture 2 2010-01-01 2010-01-01 false Grade. 29.1022 Section 29.1022 Agriculture...

  19. 7 CFR 29.1022 - Grade.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... INSPECTION Standards Official Standard Grades for Flue-Cured Tobacco (u.s. Types 11, 12, 13, 14 and Foreign Type 92) § 29.1022 Grade. A subdivision of a type according to group, quality, and color. ... 7 Agriculture 2 2014-01-01 2014-01-01 false Grade. 29.1022 Section 29.1022 Agriculture...

  20. 7 CFR 29.1022 - Grade.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... INSPECTION Standards Official Standard Grades for Flue-Cured Tobacco (u.s. Types 11, 12, 13, 14 and Foreign Type 92) § 29.1022 Grade. A subdivision of a type according to group, quality, and color. ... 7 Agriculture 2 2013-01-01 2013-01-01 false Grade. 29.1022 Section 29.1022 Agriculture...