bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibodies to the Platelet Factor 4-Heparin Complex and Mortality in Chronic Hemodialysis Patients.
Authors: Carrier Marc , Knoll Greg A. , Fergusson Dean , Doucette Steven , Kovacs Michael J. , Moore Jane , Rodger Marc A. 
Published: October 2019

Abstract
Background: Heparin-induced thrombocytopenia is a serious complication of heparin therapy that can lead to thromboembolism, cardiovascular events or death. Patients with this disorder develop antibodies to the platelet factor 4-heparin (PF4-H) complex. Hemodialysis patients are repeatedly exposed to heparin and are at risk for developing PF4-H antibodies. The clinical impact of asymptomatic PF4-H antibodies in patients on chronic hemodialysis is not known.
Objective: To determine the association between asymptomatic PF4-H antibodies and mortality in a cohort of chronic hemodialysis patients repeatedly exposed to heparin.
Methods: Pre-dialysis blood samples were drawn from 419 asymptomatic patients. All patients received unfractionated heparin (Baxter) while on dialysis. All samples were screened for PF4-H antibodies using an ELISA assay (GTI PF4 Enhanced, GTI Diagnostics). All positive and indeterminate samples were then tested using an IgG-specific PF4-H ELISA assay and a platelet serotonin-release assay. Participants were then followed up prospectively for thromboembolic events, cardiovascular events, or death.
Results: During a median follow-up of 2.5 years there were 129 deaths. After controlling for important potential confounding variables, the relative risk of death was 2.92 (95% CI: 1.18-7.25; P= 0.02) in patients with IgG-specific PF4-H antibodies and 4.08 (95% CI: 1.26–13.2; P= 0.02) in patients with IgG-specific antibodies and an indeterminate serotonin-release assay. Conclusions: PF4-H antibody formation is associated with increased all-cause mortality in patients on chronic hemodialysis. Further investigation is needed to determine if anticoagulation with alternative agents would improve survival in this population.
Combined Immunochemotherapy with Rituximab Improves Overall Survival in Patients with Follicular and Mantle Cell Lymphoma: Updated Meta-Analysis Results.
Authors: Schulz Holger , Bohlius Julia , Skoetz Nicole , Trelle Sven , Reiser Marcel , Kober Thilo , Schwarzer Guido , Herold Michael , Dreyling Martin , Engert Andreas 
Published: October 2019

Abstract
Background
Rituximab (R) has shown impressive response and prolonged progression free survival (PFS) in patients with indolent lymphoma when combined with CHOP. Randomized phase III trials adding rituximab to a variety of different regimen confirmed this benefit in both previously treated and untreated patients with advanced indolent lymphoma. Furthermore these trials indicating a trend towards improved overall survival (OS) for a combined immunochemotherapy with R. Here we report updated results of a comprehensive systematic review in this group of patients comparing R and chemotherapy with chemotherapy alone with respect to OS, disease control, overall response (OR) and toxicity.
Methods
Only randomized controlled trials (RCT) comparing R-chemo with chemotherapy alone in patients with newly diagnosed or relapsed indolent lymphoma and mantle cell lymphoma (MCL) were included. Medical databases (Cochrane Library, MEDLINE, EMBASE) and conference proceedings were searched (1990–2005). We included full-text and abstract publications. Number needed to treat (NNT) were calculated to facilitate interpretation.
Results
We included seven eligible RCTs involving a total of 1943 patients with follicular lymphoma (FL), MCL and other indolent lymphoma. Studies were published as full text (5), and in abstract form (2). OS was statistically significant improved in the R-chemo group when compared to chemotherapy alone (HR; hazard ratio: 0,65; 95% CI 0,54 – 0,78). OR (RR; relative risk: 1.21; 95% CI 1.16–1.27) and disease control (HR: 0.62; 95% CI 0.55–0.71) were also significantly superior after R-chemo. The RR for developing fever and leukocytopenia was significantly higher with R-chemo, but not associated with an increased risk of infection.
Conclusion
The systematic review demonstrated improved OS, OR and disease control for patients with indolent lymphoma and in the subgroups of follicular and mantle cell lymphoma when treated with R-chemo compared to chemotherapy alone.
Bortezomib, Dexamethasone and Rituximab (BDR) Is a Highly Active Regimen in the Primary Therapy of Waldenstrom’s Macroglobulinemia: Planned Interim Results of WMCTG Clinical Trial 05-180.
Authors: Treon Steven P. , Soumerai Jacob D. , Patterson Christopher J. , Hunter Zachary R. , Ghobrial Irene M. , Villarreal Rose , Willen Michael A. , Myers Thomas J. 
Published: October 2019

Abstract
In previous studies, we demonstrated that Rituximab and Bortezomib are active agents as monotherapy in patients with Waldenstrom’s macroglobulinemia (WM), producing response rates of 40–80%. Moreover, we and others have demonstrated synergistic activity for these agents together, and with steroids in preclinical studies. As such, we examined the activity of combined bortezomib, dexamethasone and rituximab in patients with the consensus panel diagnosis of WM. Intended therapy consisted of IV bortezomib at 1.3 mg/m2 and IV dexamethasone 40 mg on days 1,4,8, and 11, and Rituximab at 375 mg/m2 on day 11 which constituted one cycle of therapy. Patients received four consecutive cycles, followed by a three month pause, and then 4 more cycles, each given three months apart. Ten patients are eligible for evaluation at interim analysis. Following a median of 4 cycles of therapy, median serum IgM levels for all evaluable patients declined from 5,095 (range 700–8030 mg/dL) to 2,850 (range 280–3660 mg/dL) (p=0.001). The overall response rate was 100%, with 5 and 5 patients achieving a minor (≥25% decrease in IgM) and major (≥50% decrease in IgM) response, respectively. Responses were prompt, and occurred at a median of 1.1 months. Therapy was well tolerated with III/IV toxicities consisting of sepsis (n=1), pneumonia (n=1), and thrombocytopenia (n=1). Four patients developed herpes zoster while on treatment, resulting in the implementation of prophylaxis for all patients with valcyclovir. At a median of 4 cycles, no sensory or motor neuropathies have occurred. The interim results of this study demonstrate that BDR is a highly active, and well-tolerated regimen in the primary therapy of WM.
A Prognostic Score for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Analysis of 2189 Patients.
Authors: Tsimberidou Apostolia-Maria , McLaughlin Peter , O’Brien Susan , Wen Sijin , Wierda William G. , Manning John , Lerner Susan , Hess Mark A. , Kantarjian Hagop , Freireich Emil J. , Keating Michael J. 
Published: October 2019

Abstract
Introduction: The prognosis of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is heterogeneous. The purpose of this study was to assess factors predicting survival in patients with CLL/SLL.
Methods: Characteristics at diagnosis were collected from 2189 patients with CLL/SLL who presented to The University of Texas M. D. Anderson Cancer Center between 1985 and 2005. Univariate and multivariate analyses for survival were performed. Pretreatment parameters that remained independently significant in the multivariate analysis were used to design a model to predict an individual patient’s risk of death: the CLL/SLL score.
Results. The median age of patients was 58 years (range, 17–90 years). Overall, 1052 patients required treatment for CLL/SLL and 853 (81%) received fludarabine-based therapy. A multivariate analysis of 23 prognostic factors identified the following to have independent adverse significance for survival: 17p del and 6q del +/− other genomic aberrations (p<0.0001), age > 60 years (p<0.0001), albumin < 3.5 g/dL (p<0.0001), β2-microglobulin ≥ 2 mg/L (p<0.0001), creatinine ≥ 1.6 mg/dL (p<0.0001), hemoglobin <11 g/dL (p=0.001), presence of hepatomegaly (p=0.005), male sex (p=0.006), and absolute lymphocyte count ≥ 30 x 109/L (p=0.004). Other factors, such as IgVH mutation and CD38 or ZAP-70 expression, did not significantly correlate with survival, probably because these data were not available in enough patients and follow-up from the testing time was relatively short. The top five pretreatment parameters that remained independently significant in the multivariate analysis were used to design the CLL/SLL score in 1564 patients who had available data for all five parameters. Since the relative risks associated with each of the top five independently significant risk factors were comparable, the relative risk of death could be determined by summing the number of risk factors present at diagnosis. At 5 years, 96%, 79%, 69%, 30%, and 16% of patients with 0, 1, 2, 3, or 4 (including 1 patient with a score of 5) risk factors, respectively, are expected to be alive [insert Figure here].
Conclusions: A prognostic score to predict survival in patients with CLL/SLL is proposed. The score is based on the five most statistically significant independent factors, i.e., 17p or 6q del +/− other genomic aberrations; age; and levels of β2-microglobulin, albumin, and creatinine. This score may be used to identify specific risk groups, to improve treatment choices and to compare different therapeutic approaches in patients with CLL/SLL.
Figure Figure
The CD45−LIN− Adult Marrow-Derived CXCR4+ SSEA-1+ Oct-4+ Very Small Embryonic-Like (VSEL) Stem Cells Form In Vitro Spheres Which May Differentiate into CD45+ Hematopoietic Cells.
Authors: Ratajczak Janina , Kucia Magda , Zuba-Surma Ewa , Reca Ryan , Ratajczak Mariusz Z. 
Published: October 2019

Abstract
Recently we identified in murine BM a homogenous population of rare (~0.01% of BMMNC) Sca-1+ lin− CD45− cells that express by RQ-PCR and immunhistochemistry markers of pluripotent stem cells (PSC) such as SSEA-1, Oct-4, Nanog and Rex-1 and highly express Rif-1 telomerase protein (Leukemia2006;20,857–869). Direct electronmicroscopical analysis revealed that these cells display several features typical for primary embryonic stem cells such as i) a small size (~2–4 μm in diameter), ii) a large nuclei surrounded by a narrow rim of cytoplasm, and iii) open-type chromatin (euchromatin). These cells isolated freshly from the BM neither grow hematopoietic colonies nor radioprotect lethally irradiated recipients. Recently, however, we noticed that purified VSELs in co-cultures with C2C12 murine sarcoma supportive feeder-layer grow spheres and cells from these VSEL-derived spheres (VSEL-DS) are composed of immature cells with large nuclei containing euchromatin, and similarly as VSELs are CXCR4+SSEA-1+Oct-4+. We found that cells from VSEL-DS after re-plating over C2C12 cells may again (up to 5–7 passages) grow new embryoid-like bodies or if plated into cultures promoting tissue differentiation show pluripotency and expand into cells from all three germ-cell layers. Based on this we tested if CD45− VSEL-DS cells could also differentiate into the hematopoietic lineage. To address this issue we employed similar culture conditions that are employed for hematopoietic differentiation of established embryonic stem cell lines. We noticed that VSEL-DS cells if cultured/passaged in methylocellulose cultures supplemented with hematopoietic growth factors (KL, IL-3, EpO and GM-CSF) give rise to colonies composed of myeloid (CD45+ Gr-1+) and erythroid (Terr-119+) hematopoietic cells. The hematopoietic differentiation of VSEL-DS cells was accompanied by upregulation of mRNA for several genes regulating hematopoiesis (e.g. PU-1, c-myb, LMO2, Ikaros). Based on this we postulate that VSELs that reside in bone marrow may contribute to hematopoiesis. We also provide direct evidence that CD45+ cells may derive from a CD45− population. We postulate that VSELs are closely related to a population of long-term engrafting hematopoietic stem cells and currently we are testing this possibility in animal models.
IL-21 Plus CpG ODN Induces Granzyme B-Dependent Induction of Apoptosis in CD5-Positive B Cells Including B-CLL Cells.
Authors: Blackwell Sue E. , Jahrsdoerfer Bernd , Wooldridge James E. , Huang Jian , Andreski Melinda W. , Jacobus Laura S. , Taylor Christiana M. , Weiner George J. 
Published: October 2019

Abstract
Interleukin 21 (IL-21), a recently discovered cytokine with structural homology to IL-2, IL-4 and IL-15, has pleiotropic effects on lymphocyte populations including NK, T and B cells and is currently undergoing early clinical evaluation. We explored the effect of the combination of IL-21 and immunostimulatory CpG ODN on B chronic lymphocytic leukemia (B-CLL), and other CD5-positive B cells. IL-21 plus CpG ODN were synergistic in their ability to induce apoptosis of the B-CLL cells, and also induced production and secretion of granzyme B from the B-CLL cells. B-CLL cells treated with IL-21 and CpG ODN were capable of inducing apoptosis of untreated autologous B-CLL cells. This bystander killing was inhibited by anti-granzyme B antibodies. The effect was observed in all cases of CD5-positive B-CLL, but not in CD5-negative B-CLL samples. IL-21 plus CpG ODN also induced granzyme B production and apoptosis of benign CD5-positive B1 cells obtained from umbilical cord blood. In contrast, the number of CD5-negative B2 cells increased in the same samples during in vitro culture, resulting in a decreased ratio of CD5-positive to CD5-negative cord blood B cells (Fig. 1). Our results indicate the combination of IL-21 and CpG ODN is able to induce apoptosis of both benign and malignant CD5-positive B cells. Given the suspected role of B1 cells in autoimmune diseases, our findings could have important implications for the understanding of their pathogenetic mechanisms. These results might also open new avenues for the development of novel therapies for both autoimmune dieseases and CD5-positive B-CLL.
Figure 1. IL- 21 and CpG ODN therapy selectively eliminates CD5 positive B cells in cord blood. Figure 1. IL- 21 and CpG ODN therapy selectively eliminates CD5 positive B cells in cord blood.
Hexon Specific T-Cells for Adoptive T-Cell Transfer as a Treatment of Adenovirus Infection after Allogeneic Stem Cell Transplantation.
Authors: Feuchtinger Tobias , Richard Celine , Handgretinger Rupert , Braun Christiane , Schumm Michael , Lang Peter 
Published: October 2019

Abstract
Adenovirus infection (ADV) after allogeneic hematopoietic stem cell transplantation (HSCT) is an emerging pathogen causing relevant morbidity and mortality, with preponderance in children. Since a sufficient host T-cell response has been shown essential to clear the virus, diagnostic procedures for detection of virus-specific T-cells have recently developed to asses the specific cellular immune response. Furthermore adoptive immunotherapy is a new treatment option for patients with absent specific T-cell response and present systemic adenoviral infection. The possibility of an adoptive T-cell transfer depends on the availability of GMP compatible protocols and reagents. The adenoviral hexon protein was shown a immunodominant T-cell target within the viral capsid. In the present study we investigate the presence of Hexon-specific T-cell responses in HSCT donors, i.e. the availability of donors for an adoptive T-cell transfer. Secondly, the emergence of Hexon-specific T-cells in recipients post HSCT was analyzed. Thirdly, a protocol was established under GMP-conditions for adoptive T-cell immunotherapy through isolation of IFN-γ secreting T-cells after ex-vivo stimulation with the adenoviral Hexon protein. This procedure resulted in a mixed population of CD4 and CD8 positive T-cells with an effector memory phenotype and Th1 cytokine pattern (n=8). Isolated Hexon-specific T-cells show a strong expansion potential in vitro as well as specific cytotoxic activity. The availability of a donor was evaluated in 76 HSCT donors. Only 17.1% of donors had no ADV-specific T-cell response and 72.4% of donors were eligible for an adoptive T-cell transfer using the presented approach. The Hexon protein was responsible for almost the complete response to ADV, since no significant difference was seen against ADV lysate and the Hexon protein. In 76% HSCT recipients Hexon directed T-cell responses were evaluated and were shown to be responsible for clearance of the viral infection. In conclusion feasibility of an adoptive T-cell transfer for the treatment of ADV infection post HSCT is shown in accordance to current GMP regulations.
Validation of Serum Aspergillus Galactomannan Index as a Surrogate Endpoint for Outcome of Invasive Aspergillosis: Clinical and Research Implications.
Authors: Woods Gail , Miceli Marisa , Grazziutti Monica , Krishna Somashekar , Syed Nayyar , Kiwan Elias , Rahman Mazhar , Barlogie Bart , Anaissie Elias 
Published: October 2019

Abstract
Background: Assessing clinical outcome of aspergillosis with conventional clinical and laboratory criteria is difficult. A composite “global outcome response” (clinical, radiologic, pathologic and microbiologic criteria) is frequently used but suffers from poor sensitivity and specificity, and has not been standardized or validated. A reliable, quantitative, non-invasive, and easy to measure laboratory test than can substitute for this composite endpoint, i.e. serve as a surrogate endpoint for aspergillosis outcome is highly desirable. Galactomannan (GM) is an Aspergillus-specific polysaccharide released during aspergillosis and detected by the serum GM test. The test which is reported as an index of optical density (OD) is an accepted diagnostic marker for aspergillosis and preliminary data suggest a correlation between GM index (GMI) and outcome.
Purpose: To evaluate serum GMI as a surrogate endpoint for outcome of invasive aspergillosis in patients with hematological cancer.
Patients and Methods: patients at risk for aspergillosis (11/03-2/06) underwent GMI screening during periods at risk. The clinical and laboratory findings of patients with ≥ 2 (+) GMI (OD ≥ 0.5) were reviewed. To validate GMI as a surrogate endpoint for aspergillosis, a k correlation concordance coefficient test between GMI and an objective clinical outcome of aspergillosis (death) was applied. The correlation is considered perfect when k is 1.0; excellent when ≥ 0.75.
Results: 30 patients had GMI (+) aspergillosis of the respiratory tract [myeloma 92%; median age: 59 years (27–75); 15 males]. Aspergillosis developed following stem cell transplantation [autologous (11), allogeneic (1)], or after conventional chemotherapy (18). Among 25 neutropenic patients (<1000/ml), persistent GMI elevation was associated with death (5/5 patients) while return to negative values predicted survival (20/20 patients). Among 5 non-neutropenic patients, 1 with persistently elevated GMI died compared to no death among the remaining 4 whose GMI became negative. Overall, the GMI correlated with clinical outcome in all 30 patients with a perfect 1.0 k correlation concordance coefficient.
Conclusion: we have validated GMI as an excellent surrogate endpoint for the outcome of invasive aspergillosis among patients with hematological cancer. This FDA-approved test is reproducible, quantitative, non-invasive, easy to measure and widely available. These findings have important implications for patient care and for the design of clinical trials of mould-active antifungal agents.
Single Nucleotide Polymorphism of CC Chemokine Ligand 5 Promoter Gene in Recipient May Affect on the Development of Chronic Graft-Versus-Host Disease and Its Severity after Allogeneic Transplantation.
Authors: Kim Dong Hwan , Sohn Sang Kyun , Kuruvilla John , Gupta Vikas , Lipton Jeffrey , Messner Hans 
Published: October 2019

Background: The leukocyte trafficking, which is critically regulated by chemokine ligands and their receptors, has been known to be involved in the pathogenesis of graft-versus-host disease (GVHD). CC ligand 5 (CCL5; previously called as RANTES) is expressed on antigen-presenting cells, endothelium, and epithelium, while CC receptor 5 (CCR5) is expressed on type 1 T-cells. The current study analyzed the association of CCR5/CCL5 gene single nucleotide polymorphisms (SNPs) on both side of recipients and donors with acute or chronic GVHD (cGVHD) after allogeneic transplantation.
Methods and patients: We evaluated the SNPs of CCL5 promoter gene at loci −28/−403 and CCR5 gene at 59029 in 72 recipients and 107 donors using PCR/RFLP methods with genomic DNAs. The associations of acute/cGVHD and its severity with CCL5/CCR5 SNPs of recipients/donors were examined using chi-square test, while the incidences of acute/cGVHD were also compared by Log-rank test.
Results: With a median follow up of 924 days for survivors (range 48~2,360 days), the CG genotype of CCL5 gene −28 loci of recipients was significantly associated with a higher incidence of overall cGVHD (p=0.004), extensive cGVHD (p=0.038 by Seattle criteria) and severe grade of cGVHD at presentation compared to CC genotype (p=0.017 by prognostic grading by Apkek et al). The patients with AG haplotype of CCL5 SNP of recipients also showed a higher incidence of overall cGVHD (p=0.003), extensive cGVHD (p=0.023), and more severe grade of cGVHD (p=0.020). However, the CG genotype at CCL5, −28 and AG haplotype did not correlate with the clinical course of cGVHD in terms of GVHD-specific survival or the duration of systemic immunosuppressive therapy. In addition, an association of CCL5/CCR5 SNPs with acute GVHD was not noted. The SNP of CCL5/CCR5 of donors did not influence the occurrence of cGVHD.
Conclusion: The CCL5 promoter gene polymorphism of recipients may be associated with the development of cGVHD and its severity. The current study suggested an involvement of CCL5 in leukocyte trafficking for the development of cGVHD.