bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative HLA Class I Expression and KIR-Mismatch between NK-Cell-Donor and Patient Predict NK Cell Mediated Lysis of Leukemic Cells from Children with Acute Lymphatic Leukemia.
Authors: Pfeiffer Matthias M. , Schumm Michael , Dietz Klaus , Feuchtinger Tobias , Handgretinger Rupert , Lang Peter J. 
Published: October 2019

Abstract
Relapses represent a major problem after transplantations in children with ALL. Natural Killer (NK) cells have been shown to exert remarkable Graft versus Leukemia effects after mismatched stem cell transplantation in myeloic leukemia, whereas the efficacy against lymphatic leukemia is still unclear. We therefore measured intensity of HLA class I expression on leukemic blasts by quantitative FACS analysis and investigated the impact of quantitative HLA class I expression, of several adhesion molecules and of KIR-mismatch on NK cell mediated lysis of the leukemic blasts from 21 pediatric patients with ALL. Expression of HLA class I molecules differed widely from patient to patient (range 5000–500000) and was reduced in comparison to B cells from healthy donors in 70% of cases. NK cells killed leukemic blasts very heterogeneously but a clear association between number of HLA class I molecules per cell and specific lysis (range 13–98%) was found (r2=0.68, p<0.0001). For the subgroup of leukemic blasts without KIR-mismatch, this association was even stronger (r2=0.98), whereas a weak association was found for the subgroup with KIR-mismatch, since most of these targets were lysed more efficiently than one could expect according to HLA class I expression alone. KIR-mismatch alone (t-test, p=0.45) as well as different patterns of adhesion molecules (ICAM1-3, LFA1/3) and CD95 had no significant influence. However, a multivariate model taking both HLA expression and KIR-ligand-mismatch into account, provided an even stronger association (r2=0.87 p<0.0001) for the whole group. Lysis was mainly dependent on HLA class I expression and in addition on KIR-mismatch for these leukemic cells. Assessment of HLA expression on leukemic blasts and KIR-receptor-ligand-mismatch between donor and recipient may be valuable to define patients who will benefit most from a NK mediated GvL effect.
Stimulation of Anti-Tumor Immunity Using Dendritic Cells Transduced with Fowl Pox Vector Expressing MUC-1 and Costimulatory Molecules (PANVAC-F).
Authors: Vasir Baldev , Lenahan Corrine , Rosenblatt Jacalyn , Bissonnette Adam , Wu Zekui , Kufe Donald , Avigan David 
Published: October 2019

Abstract
In pre-clinical models, vaccination with attenuated vaccinia and fowl pox virus expressing tumor antigens and costimulatory molecules (CD54/ICAM-1; CD58/LFA-1 and CD80/B7.1-TRICOM) potently stimulates anti-tumor immune responses. However, vaccine efficacy may be limited by intrinsic deficiencies of native dendritic cells (DC) populations in patients with malignancy that are required to process and present the virally introduced antigens. An alternative strategy involves the transduction of ex vivo generated activated DCs. We have examined the capacity of DCs transduced with a fowl pox vector expressing MUC-1, CEA, and TriCOM (PANVAC-F) to elicit antigen specific responses and expand activated as compared to regulatory T cell populations. Partially mature DCs were generated from leukopak preparations obtained from normal volunteers by culturing adherent peripheral blood mononuclear cells for 5 days with GM-CSF and IL-4. DCs were transduced with PANVAC-F vector and matured with either TNFa or the combination of PG-E2, TNFa, IL-6 and IL-1b. In 5 serial studies, transduction with PANVAC-F resulted in mean MUC1 expression in 64.6% (SEM: ±1.6) of cells with a mean fluorescent intensity (MFI) of 249.8 (SEM: ±45.7). In addition, transduced DCs also demonstrated high levels of expression of class II (99%; MFI:250), CD54 (98.4%;MFI:516), CD58 (98.8%;MFI:155) and CD80 (78.2%; MFI:115). Of note, transduced DCs demonstrated higher levels of the maturation marker CD83 (40.3%; SEM: ±1.6, n=3) as compared to untransduced DCs 19.7% (SEM: ±2.9) (p=0.02) suggesting that transduction enhanced DC maturation and activation. Transduced DCs matured with PGE2, TNFa, IL-6 and IL-1b as compared to TNFa alone demonstrated higher levels of CD83 and CCR7 and a more stable phenotype following withdrawal of cytokine support. To assess the ability of PANVAC-F to stimulate tumor antigen specific responses, the presence of T cells binding the MUC-1 specific tetramer was quantified following stimulation of autologous T cells derived from HLA*0201 healthy donors. An increase in CD8+ and MUC1+ cells were observed (8.3%) with stimulation with PANVAC-F transduced DCs as compared to untransduced DCs (2.5%). The capacity of DCs transduced with PANVAC-F to stimulate interferon gamma producing activated T cells, as compared to CD4+/CD25+/Foxp3+ regulatory T cell populations is being assessed. In summary, PANVAC-F transduced DCs stimulate expansion of antigen specific T cell populations suggesting their potential role as tumor vaccines for MUC-1/CEA expressing tumors. We are initiating a trial for patients with ovarian carcinoma in early (marker only) relapse in which patients will be randomized to undergo serial vaccination with PANVAC-V/PANVAC-F or DCs transduced with PANVAC-F. The capacity to generate anti-tumor immunity in vivo will be assessed as a primary endpoint.
Combination Therapy of Anti-Cancer Drug with FNIII14 Peptide of Fibronectin Effectively Overcome Cell Adhesion Mediated-Drug Resistance of Acute Myelogenous Leukemia.
Authors: Matsunaga Takuya , Fukai Fumio , Tanaka Maki , Kobune Masayoshi , Chiba Hiroki , Niitsu Yoshiro 
Published: October 2019

Abstract
We have previously reported that in acute myelogenous leukemia (AML), drug resistance is induced by the attachment of α4β1-integrin (very late antigen (VLA)-4) on leukemic cells (AML cells) to fibronectin (FN) on bone marrow (BM) stromal cells, and this interaction is crucial in BM minimal residual disease (MRD) and prognosis after chemotherapy (Matsunaga T et al, Nature Med2003, 9, 1158–1165). We also reported a successful overcome of drug resistance in human AML cells transplanted mice with the use of anti-VLA-4 antibody. However, a drawback of progressive multifocal leukoencephalopathy by anti-VLA-4 antibody administration was reported in multiple sclerosis and Chron’s disease patients. Therefore, in this study, we examined whether FNIII14, a 22-mer peptide derived from FN which was reportedly potent to block the interaction between FN and VLA-4, VLA-5 or αvβ3-integrin (Fukai F et al. Clin Cancer Res 2002, 8, 2455–2462), can overcome cell adhesion mediated drug resistance (CAM-DR) induced by VLA-4/FN interaction in AML cells. By in vitro culturing system, FNIII14 dose dependently inhibited adhesion of two AML cell lines (U937 cells, HL-60 cells) and fresh AML cells from patients to FN, and significantly circumvented CAM-DR of these AML cells to cytosine arabinoside (Ara C). The mechanism for this circumvention of CAM-DR involved conformational inactivation of β1-integrin as revealed by FACS through inside out inhibitory signal from complex FNIII14/its 50kDa receptor resulting in down regulation of FAK/Akt/Bcl-2 signal which is responsible for VLA-4/FN induced CAM-DR. In a mouse model of MRD, a 100% survival rate was achieved by combining FNIII14 and Ara C, in contrast to a slight prolongation of survival by Ara C alone. These results indicate that combination treatment of anticancer drugs and FNIII14 is the potent modality for eradication of MRD in BM, and should improve the prognosis of AML.
Multicenter Evaluation of Fungal Prophylaxis in Hematopoietic Stem Cell Transplantation.
Authors: Barron Michelle A. , Fishman Neil , Baillie G. Mark , Brake Helga 
Published: October 2019

Abstract
BACKGROUND: The University HealthSystem Consortium (UHC) conducted a benchmarking study to assess members’ compliance with published guidelines for prevention of fungal infections in hematopoietic stem cell transplant (HSCT) recipients.
METHODS: Adult HSCT patients were evaluated by retrospective chart review of cases discharged between 01/01/04 and 06/30/05. Data collected included demographics, use of prophylaxis (px), and outcomes. Patients were classified as high or low risk for fungal infection according to NCCN and CDC guidelines.
RESULTS: Thirteen UHC member hospitals submitted a total of 242 HSCT cases. Patient characteristics and administration of antifungal therapy are shown in Table 1. 57% (137/242) of patients were classified as high risk for fungal infection. Overall, 85% (205/242) of patients received antifungal px. Compliance with national guideline directed antifungal px was 54%. Of patients who did not receive px, 59% (22/37) were high-risk. 32% (7/22) of these patients required empiric antifungal therapy, 29% (2/7) had a confirmed fungal infection and 1 of these patients died. Of patients who received antifungal px, 44% (90/205) were classified as low risk. 6.7% (6/90) went on to require empiric therapy and 2 died. 84.4% of patients had fluconazole as at least one of their prophylactic agents, and 34% of patients received prophylactic antifungals that provided coverage for both Aspergillus and Candida species. 5.4% (13/242) of HSCT recipients died during the target hospitalization. 76.9% (10/13) of these patients were high risk. 61.5% (8/13) had signs/symptoms of a suspected or definitive fungal infection at the time of death (6 were high risk).
CONCLUSION: Most HSCT patients did not receive appropriate fungal px based on current guidelines. Failure represented both under and over utilization of px. Further study is required to explain poor adherence to current guidelines.
Table 1: Patient Characteristics by Degree of Risk High Risk (n=137) Low Risk (n=105) % (n) % (n) *ABX = broad spectrum antibiotics Chemotherapy prior to admission 53.3% (73) 61.9% (65) Radiation prior to admission 23.4% (32) 17.1% (18) Allogeneic Transplant 75.9% (104) 17.1% (18) Cytomegalovirus disease 11.7% (16) 6.7% (7) GVHD 15.3% (21) 1.0% (1) Mucositis 55.5% (76) 7.6% (8) Systemic corticosteroids 63.5% (87) 44.8% (47) Fever unresponsive to >4 days of ABX 19.0% (26) 12.4% (13) Neutropenia during antifungal therapy 39.4% (54) 27.6% (29) History of Aspergillus infection 3.6% (5) 0.0% (0) Antifungal therapy: Prophylaxis 83.9% (115) 85.7% (90) Failed prophylaxis 21.2% (29) 5.7% (6) Empiric therapy 25.4% (32) 10.5% (11) Definite treatment 6.6% (8) 0.0% (0)
Treatment of Steroid-Resistant Graft-Versus-Host Disease with Monoclonal Antibodies in Children.
Authors: Schechter Tal , Afzal Samina , Finkelstein Yaron , Koren Gideon , Doyle John , Dupuis Laura Lee 
Published: October 2019

Abstract
Acute graft-versus-host disease (aGVHD) carries a major risk of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). The prognosis is poor if aGVHD does not respond to corticosteroid treatment. Recently, monoclonal antibodies such as daclizumab, a humanized monoclonal IgG1, and infliximab, a chimeric monoclonal antibody that binds the precursor of tumor-necrosis factor-alfa, have shown promising results in the treatment of corticosteroid-resistant aGVHD. The reported response rate to monoclonal antibody therapy in adults with aGVHD reaches as high as 67%. Data describing the efficacy of monoclonal antibodies in children with corticosteroid-resistant aGVHD are limited. We conducted a retrospective analysis to evaluate the efficacy of daclizumab and/or infliximab in children diagnosed with steroid-resistant aGVHD in the Hospital for Sick Children, Toronto, from July 2002 to December 2005. Corticosteroid-resistant aGVHD was defined as aGVHD which did not respond or worsened after a minimum of 5 days of corticosteroid therapy. Complete response was defined as full recovery without any signs of aGVHD; partial response was defined as improvement of aGVHD symptoms in at least one organ without worsening in other organs. Sixteen children were treated for aGVHD, thirteen of them had aGVHD grade 3 or 4. The organs involved were gut (n=6), skin (n=4), liver (n=2) and multi-organ involvement (n=4). Thirteen children were given daclizumab; one was treated with infliximab and 2 children with their combination. Fourteen children received a full course of monoclonal antibodies for aGVHD. An additional child died after the first dose (from multi-organ failure) and one child developed reactive arthritis attributed to daclizumab. Seven of the 14 children (50%) who completed treatment responded: 5 had complete response and 2 had a partial response. Nine out of the 16 children died during the study period: 8 due to Transplant Related Mortality (TRM) and 1 due to relapse; three children developed fatal fungal infection and one had fatal adenovirus infection during or shortly after monoclonal antibody treatment. Median length of follow up in the remaining 7 patients was 18 months. We conclude that monoclonal antibodies were effective in the treatment of children with corticosteroid-resistant acute GVHD. The risk for infection, mainly fungal, was high.
The Incidence and Risk Factors of the Euthyroid Sick Syndrome Soon after Allogeneic Hematopoietic Stem Cell Transplantation in Children.
Authors: Cho Bin , Lee Dae-Hyoung , Jeong Dae-Chul , Kwon Young-Joo , Jang Pil-Sang , Chung Nak-Gyun , Kim Hack-Ki , Hwang Hui Sung , Park Young-Shil , Kim Sun Young , Park Ji Kyoung 
Published: October 2019

Abstract
Purpose: In this study, we analyzed the short term change of thyroid function, incidence and risk factors of thyroid dysfunction soon after allogeneic hematopoietic stem cell transplantation(HSCT) in children.
Method: We enrolled 80 pediatric patients following allogeneic HSCT, at the Catholic HSCT center between January, 2004 and February, 2006. Serum TSH(thyroid stimulating hormone), total serum thyroxine, total serum triiodothyronine levels were systematically measured in 80 patients before and 1 month, 6 month and 12 month after HSCT.
Results: Thyroid function was statistically decreased at 1 month after HSCT(P < 0.001). Thyroid dysfunction at 1 month was observed in 43(54%) of 80 patients, 31(39%) of whom presented with euthyroid sick syndrome. Thyroid dysfunction was normalized within 1 year after HSCT(Table).
In univariate analysis, malignant disease and presence of acute GvHD(grade ≥II) were risk factors for euthyroid sick syndrome(P = 0.04, 0.01). In multivariate analysis, we could not detect an independent risk factor for euthyroid sick syndrome(P = 0.19, 0.06).
Conclusion: The present study suggests that the incidence of thyroid dysfunction is high after allogeneic HSCT. Therefore, regular monitoring of thyroid hormone levels after HSCT is required.
Short-term changes in thyroid function after HSCT Pre HSCT Post HSCT 1 month Post HSCT 6 month Post HSCT 12 month T3 (ng/dL) 161 ± 27 100 ± 35 123 ± 35 124 ± 35 T4 (μg/dL) 8.7 ± 1.6 6.5 ± 2.4 7.3 ± 1.8 7.7 ± 1.6 TSH (mIU/L) 2.9 ± 1.9 1.2 ± 1.3 2.4 ± 1.8 2.1 ± 1.3
Inflammatory Events in Early Posttransplantation Period Are Associated with the Relapse Kinetics of Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Kim Sung-Yong , Min Chang-Ki , Lee Mi-Jin , Cho Byung-Sik , Eom Ki-Seong , Kim Yoo-Jin , Lee Seok , Kim Hee-Je , Cho Seok-Goo , Kim Dong-Wook , Lee Jong-Wook , Min Woo-Sung , Park Jong-Won , Kim Chun-Choo 
Published: October 2019

Abstract
Time to relapse of acute leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is variable. The relapse kinetics may be influenced by graft-versus-leukemic (GVL) reaction mediated by donor immune cells and inflammatory cytokines. We wondered if the inflammatory cytokines released during the occurrence of the early post-transplantation inflammatory events may affect GVL effect thus influencing the relapse kinetics. We retrospectively analyzed the correlation between early post-transplantation inflammatory events and relapse kinetics in 55 patients with acute leukemia who relapsed following allo-HSCT. Patients were divided into two groups, early and late-relapsed group according to the time to relapse from transplantation. Multivariate logistic regression analysis revealed that the incidences of conditioning associated diarrhea (CAD) ≥ 500ml/day and febrile episode (FE) were significantly lower in the early-relapsed group than in the late-relapsed group (P=0.046 and 0.014, respectively). Serum levels of C-reactive protein, a surrogate marker of inflammation, on day 21 after transplantation (CRP21) were significantly lower in the early-relapsed group than in the late-relapsed group (P=0.009). FE, CAD ≥ 500ml/day and CRP21 were independent predictable factors for relapse kinetics based on multivariate Cox regression analysis (P=0.037, 0.002 and 0.025; hazard ratio=0.360, 0.221 and 0.971, respectively). Our analysis indicated the inflammatory events in early post-transplantation period could delay the relapse of acute leukemia early after allo-HSCT presumably because GVL effect was enhanced with the cytokines released by the events.
Figure 1 Cumulative Incidences of relapse according to the presence of febrite episode (A) and conditioning regimens associated diarrhea ≥ 500mg/day (B) based on multivariate Cox regression analysis. The patients who had either febrite episode (FE) or server conditioning regimens associated diarrhea (CAD) ≥ 500mg/day in early posttransplantation period at longer relapse free survival compared with the patients who did not (P=0.035 and 0.002). Figure 1. Cumulative Incidences of relapse according to the presence of febrite episode (A) and conditioning regimens associated diarrhea ≥ 500mg/day (B) based on multivariate Cox regression analysis. The patients who had either febrite episode (FE) or server conditioning regimens associated diarrhea (CAD) ≥ 500mg/day in early posttransplantation period at longer relapse free survival compared with the patients who did not (P=0.035 and 0.002).
Role of Intensive Conditioning Regimens Followed by Allogeneic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: A Long-Term Follow-Up.
Authors: Minami Jiro , Asai Osamu , Dobashi Nobuaki , Yano Shingo , Osawa Hiroshi , Takei Yutaka , Yahagi Yuichi , Takahara Shinobu , Ogasawara Yoji , Otsubo Hiroko , Yamaguchi Yuko , Saito Takeshi , Maruyama Dai , Kobayashi Tatsunosuke , Hoshi Yasutaka , Usui Noriko 
Published: October 2019

Abstract
Purpose: Acute lymphoblastic leukemia (ALL) remains a difficult disease to treat in adults and less than 40% of ALL patients could be alive at 5 years post-diagnosis. We investigated whether intensive conditioning regimens improve outcome of patients with ALL.
Methods: Retrospectively, we analyzed 24 patients (median age; 29 years) with ALL who underwent allogeneic transplantation in our institute between February 1991 and October 2003. The median follow-up time was 7.7 years. Sixteen patients were in first complete remission (CR1) and five patients were in second CR (CR2) and three patients did not attain CR (non-CR) at the time of transplantation. Five patients with Philadelphia (Ph) chromosome-positive ALL were included. Preparative regimens were cyclophosphamide (CY), total body irradiation (TBI) and etoposide based regimen (n=23) or CY, TBI, and cytosine arabinoside (n=1) followed by marrow (n=21) or peripheral blood (n=3) transplant from unrelated (n=7) or related donors (n=17).
Results: The 8-year overall survival (OS) rate and the 8-year disease-free survival rate for all cases were 48% and 39%, respectively. The 8-year OS of Ph negative and positive patients were 56% and 20%. The 8-year OS of CR1, CR2 and non-CR patients were 50%, 60% and 0%, respectively. Overall probability of the 8-year relapse rate was 47%. Treatment related mortality was 25%.
Conclusion: These results suggest that CY/TBI based intensive regimens are feasible for ALL patients and may be effective for Ph negative ALL patients in not only CR1 but also CR2.
In Multiple Myeloma (MM) CAMPATH-1 Antibodies “In the Bag” Reduce the Early Toxicity of Stem Cell Transplantation from Graft vs. Host Disease (GvHD) and Seem To Be Associated with Improved Long Term Outcome.
Authors: Novitzky Nicolas , Thomas Valda , Toit Cecile du 
Published: October 2019

Abstract
Introduction: Although allogeneic stem cell transplantation remains the only curative approach in patients with MM, its role remains controversial. Early high treatment related mortality, particularly from infections, GvHD and later, from disease recurrence remains substantial challenges. This study reviewed the outcome of consecutive patients who received T-cell depleted grafts from HLA identical siblings.
Patients and Methods: Patients with symptomatic MM (stage II, n= 4 & III, n=17) who had an HLA identical sibling were initially treated until response with anthracycline or steroid based combinations. Three patients had, in addition, undergone autografting. Individuals who received cytokine mobilized peripheral blood progenitor cell (PBPC) grafts were also prescribed therapeutic serum levels of cyclosporine for 90 days post transplantation. The objective of the study was to determine transplant related mortality OS and DFS.
Results: Twenty one patients with a median age of 44 (range 37– 56) years who had responded to chemotherapy (CR or VGPR) received stem cell enriched grafts from HLA identical siblings. Median performance status was 1 (0 – 2). Five individuals had significant organ dysfunction from effects of the disease. At presentation median albumin and β2MG blood levels were 30 g/L and 3.2 ng/mL, respectively. Myeloablative conditioning was radiotherapy (n= 12) or chemotherapy (n= 9) based. GvHD prophylaxis consisted of T-cell depletion with CAMPATH-1G (n=7) or H (n=14) antibodies “in the bag”. BM had all been treated with ex vivo with CAMPATH-1G (median 20 mg) while PBPC grafts in 14 patients were incubated with CAMPATH-1H (median 10 mg). Patients received a median of 23 ×104/kg CFU-GM in 0.87 BM mononuclear cells or 9.22 ×108/kg PBPC (CD34+: 4.46 ×106/kg). Median time to engraftment was 12 days. Two patients developed GvHD (grade 2) and 3 limited chronic form (1 progressed from acute). The 1 year non relapse mortality was 19%. Six patients suffered disease recurrence. One refused further therapy. Three of 5 responded to DLI and 2 remain in unsustained remission. Fatal events appeared lower in patients receiving chemotherapy based conditioning (mortality 11% vs. 50; p= 0.06), exposure of stem cells to CAMPATH-1H (15% vs. 62.5%; p= 0.04) and a lower median CAMPATH-1 dose given (p= 0.01). Cox analysis confirmed that lower CAMPATH-1 dose was associated with improved outcome. Fourteen (67%) patients survive at a median of 1101 days (range 385–5309) and 62% are disease free.
Conclusions: In this cohort of chemotherapy responsive patients with advanced myeloma, ex vivo T-cell depletion of allogeneic grafts was associated with good protection from GvHD and 19% 1-year transplant related mortality. Low grades of GvHD post transplantation were associated with a favourable impact in the long term survival.