bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thromboelastometry in Patients Receiving Platelet Transfusion after Chemotherapy.
Authors: Dehmel Henning , Tiede Andreas , Horter Silvia , Ganser Arnold , von Depka Mario 
Published: October 2019

Abstract
Prophylactic platelet transfusion is frequently administered to reduce the risk of hemorrhage in patients undergoing chemotherapy for leukemia or cancer. A platelet count of 10 or 20x109 L−1 is often used as an occasion for platelet transfusion. In clinical studies, the bleeding risk was similar using either threshold (Rebulla, NEJM1997; 337:1870, Wand, Blood1998; 91:3601). Moreover, serious bleeding events were not related to the patients’ platelet count. Thromboelastometry with ROTEM® Whole-Blood Coagulation Analyzer (Pentapharm, Munich, Germany) is a method that may provide a better estimate of the risk of hemorrhage because it also depends on platelet function and plasma coagulation. We therefore performed a pilot study in 13 adult patients receiving prophylactic platelet transfusion after chemotherapy for leukemia or lymphoma. ROTEM® was performed using an ellagic acid based activating reagent (in-TEM®, Pentapharm). Clotting profiles were evaluated using the following thromboelastometric measures: clotting time (CT), clot formation time (CFT), and maximum clot firmness (MCF). The median platelet count before transfusion was 9x109 L−1 (range 1 to 20). CT was within the normal range in all patients (median 168 s, range 125–212, reference range 100–240). In contrast, a prolonged CFT (median 139 s, range 51–4526, reference range 30–110) and reduced MCF (median 34 mm, range 19–54, reference range 50–72) was recorded. Correlation between platelet count and CFT (R=−0.41, Spearman) or MCF (R=+0.48) was weak and not statistically significant. 15 min after platelet transfusion, there was an increase in platelet count (median 39x109 L−1, range 23–48) and a substantial improvement of CFT (median 99 s, range 44–332) and MCF (median 49 mm, range 40–64). Changes in thromboelastometric measures were due to platelet transfusion as the addition of cytochalasin D (fib-TEM®, Pentapharm) resulted in identical profiles before and after transfusion. Changes in platelet count correlated with changes in MCF (R=+0.73, P<0.01), but not CFT (R=−0.40, P=0.17). Comparing patients who had a maximum of one mild bleeding symptom (n=9) with patients who experienced one severe or at least two mild bleeding symptoms (n=4), there was no difference in platelet counts (median 10 vs. 9x109 L−1, p=0.77). In contrast, there was a trend towards a shorter CFT (median 111 vs. 388 s, P=0.09) and higher MCF (median 39 vs. 29.5 mm, P=0.09) in the group of non-bleeding patients. In summary, ROTEM® seems to be a sensitive method to detect hemostatic changes in patients with severe thrombocytopenia receiving platelet transfusion and to identify thrombocytopenic patients with an increased bleeding risk. Therefore, further studies to evaluate ROTEM® as a means to estimate the bleeding risk in thrombocytopenic patients are warranted.
Treatment with rhEPO Decreases the Need for Transfusion in Patients with βThalassemia.
Authors: Bachir Dora , Habibi Anoosha , Pissard Serge , Ourabah Zohra , Galacteros Frederic 
Published: October 2019

Abstract
The usage of human recombinant erythropoietin (rhEPO) in βthalassemia shows in many sudies, that not only it increases the synthesis of γ chains, but it also improves erythroid parameters. Among our population of thalassemic patients, eight patients with βthalassemia intermedia that were regulary transfused, were given escalating doses of rhEPO mostly darpoietin-α. Before receiving rhEPO, all patients had undergone splenectomy, also received iron chelation therapy, and folic acid supplementation. No patient received iron supplementation together with rhEPO.
With rhEPO, two patients were able to discontinue their requirements for transfusions. In the others, haemoglobin level was maintained above 8 g/dl. Four patients experienced bone pain which was successfully treated with hydroxyurea. All patients had improvement in their quality of life. This small series illustrates that rhEPO may be useful and cost effective in the long term (considering the risks of red blood cell transfusion) in some selected splenectomized transfusion-dependent patients with βthalassemia intermedia.
Results
Transfusion requirements (ml/kg/year) Patients Year of birth Sex Final doses of rhEPO (UI*kg/week) Follow-up (months) Before After Hydroxyurea * interruption of rhEPO because of participation to ICL 670 A 0107 protocol 1 1975 M 970 33 150 75 + 2 1973 F 1365 34 125 0 + 3 1965 M 820 33 130 0 + 4 1959 F 650 27 125 98 + 5 1979 F 715 15 210 160 * + 6 1978 M 1035 7 255 90 − 7 1987 F 450 3 135 80 − 8 1974 M 900 7 190 75 +
Impact of Plasmacytoid Dendritic Cell (PDC) Recovery on Outcome after Reduced-Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (Allo-SCT).
Authors: Mohty Mohamad , Blaise Didier , Faucher Catherine , Bardou Valerie-Jeanne , Gastaut Jean-Albert , Viens Patrice , Olive Daniel , Gaugler Beatrice 
Published: October 2019

Abstract
Dendritic cells (DCs) are crucial in the induction of immune responses. Among DC subsets, the reconstitution of the natural type I-interferon-producing plasmacytoid DCs (PDC) has been proposed to play a major role in establishing immune competence, given the capacity of PDCs to efficiently expand either specific cytotoxic T lymphocytes, or to promote regulatory T cells, contributing to an impaired immune response. Therefore, we investigated the impact of circulating PDCs measured at the third month after RIC-allo-SCT, in 54 patients with hematological and non-hematological malignancies who received a RIC-allo-SCT from an HLA-identical sibling, in order to determine whether this could provide a convenient indicator for long term outcome. The median absolute count of PDCs measured at 3 months after RIC-allo-SCT was 0.725/μL (range, 0–23.2). In a multiple logistic regression analysis including all relevant parameters (demographic and graft characteristics, RIC regimens, CMV infections, and acute GVHD), only the absence of clinically significant grade II-IV acute GVHD was associated with an improved PDC recovery at 3 months (P=0.003; OR=6.4; 95%CI, 1.9–22). Being the major type I IFN-secreting cells, we also investigated whether PDCs recovered after allo-SCT are functional in response to viral stimulation. Patients experiencing grade 0-I acute GVHD could secrete significantly higher amounts of IFN-alpha as compared to patients with grade II–IV aGVHD (mean, 91 pg/ml vs. 0 pg/ml respectively; P=0.002), likely highlighting the deleterious impact of corticosteroids therapy on PDC function. The CD34+ stem cell dose and other lymphoid subsets infused with the allograft did not affect PDC recovery. Though PDC count could not predict death from progression or relapse, patients with a “high” PDC recovery profile had an improved overall survival (OS; P=0.03), in contrast to patients with a “low” PDC recovery profile who had an increased incidence of late transplant-related mortality (GVHD, infections) (P=0.03). In addition, the overall incidence of late infections (viral, fungal and bacterial) was significantly higher in the “low” PDC recovery group as compared to the “high” PDC recovery group (59% vs. 19%; P=0.002), illustrating the importance of PDCs in anti-infectious immune responses. In a multivariate analysis, only a “high” PDC count was significantly predictive of a decreased risk of death (P=0.04; RR=0.34; 95%CI, 0.12–0.96). The role and impact of rare immune effector cells would tend to be more evident in truly RIC and less toxic regimens. In this study, we could show that monitoring of PDCs may be useful for patients’ management (closer surveillance, infection prophylaxis…), and may have a significant impact on the probability of a favorable outcome in the context of RIC-allo-SCT.
Inhibitory Effects of Lactic Acid on Human Antigen-Specific CD8+ T-Cells.
Authors: Kreutz Marina , Fischer Karin , Hoffmann Petra , Volkl Simon , Edinger Matthias , Andreesen Reinhard , Mackensen Andreas 
Published: October 2019

Abstract
A characteristic feature of inflammatory lesions or tumor sites is local acidosis, which is attributed to the local increase in lactic acid production. We studied the effect of such an acidic environment on the immune functions of antigen-specific CD8+ T-cells by incubating the cells in the presence of various concentrations of lactic acid for up to 48h. CD8+ T-cells were isolated from healthy donors and expanded by weekly stimulation with autologous dendritic cells pulsed with a mutated HLA-A2-binding Melan-A (ELAGIGILTV) peptide. The obtained T cell population consisted of at least 90% CD8+ and about 60% Melan-A specific T cells, as determined by Melan-A multimer staining. Incubation of CD8+ T cells with up to 20mM lactic acid for 24h did not cause T-cell apoptosis or cell death as determined by combined annexin/propidium iodide staining. However, the proliferative capacity of CD8+ T cells, as determined by 3H-thymidine uptake, was strongly inhibited. Similar results were obtained when we determined cytokine production and cytotoxic activity of the cells after a 24h culture period in 5-20 mM lactic acid. Production of both, IL-2 and IFN-gamma was strongly diminished in comparison to untreated cells, as determined by intracellular staining after stimulation with PMA/ionomycin for 5h in the presence of monensin. Analysis of the antigen-specific cytolytic capacity revealed that CD8+ T cells pre-cultured with lactic acid were less effective in killing antigen-loaded T2 target cells as compared to untreated CD8+ T cells. In parallel, the intracellular contents of the cytotoxic effector molecules granzyme-B and perforin was diminished. Re-adjusting the pH of the medium to a physiological value of pH7.4 could partially revert the effect of lactic acid. Treatment of CD8+ T cells with sodium lactate instead of lactic acid had no inhibitory effect. We conclude, that lactic acid is an important modulator of CD8+ T-cell function and may contribute, together with other factors, to immune escape mechanisms in the tumor environment.
Effect of ADP and ATP Receptor Antagonism on Erythrocytosis-Induced Platelet Aggregate Formation under Dynamic Flow Conditions.
Authors: Peerschke Ellinor I.B. , Silver Richard T. , Weksler Babette , Savion Naphtali , Varon David 
Published: October 2019

Abstract
Red blood cells (RBC) contribute significantly to hemostasis and thrombosis under oscillatory flow conditions, and erythrocytosis has been associated with increased thrombotic risk. To capture dynamic effects of RBC on platelets, we used a recently described Cone and Plate (let) Analyzer (CPA), to evaluate the effect of hematocrit (Hct) on platelet function in whole blood under arterial flow conditions (1800 sec-1, 2 min, 25°C). Anticoagulated blood, reconstituted to varying hematocrits with autologous RBC, demonstrated a significant increase (30–50%, n= 12, p < 0.05) in adherent platelet aggregate size at Hct levels >45%. No significant effect on platelet adhesion was noted. Increases in aggregate size were not accompanied by significant platelet dense or alpha granule secretion, measured using 14C-serotonin release and Platelet Factor 4 ELISA assays, respectively. However, when cell-free supernatants (SNT) were prepared post shearing to investigate the presence of proaggregatory activity by adding SNT to fresh PRP (1:10 SNT: PRP ratio), and quantifying the formation of small platelet aggregates with a laser light scatter aggregometer, SNT derived from sheared high Hct samples contained nearly twice (1.75 + 0.16, n=5, p < 0.05) the activity of sheared normal Hct samples. The erythrocytosis-induced increase in platelet aggregate size was not affected by pretreatment of blood with 0.05 mM aspirin, but could be prevented completely by antagonism of P2Y1 (MRS2179, 200 μM), P2Y12 (2-methylthioadenosine 5′-monophosphate, 10–100 μM), or P2X1 (MRS2159, 200 μM), ADP and ATP receptors, respectively, as well as by converting exogenous ADP to ATP with a combination of creatine phosphate (2 mM) and creatine phosphokinase (20 U/ml). Whereas negligible platelet granule secretion was measured post shear, metabolic inhibition of RBC with 1% sodium azide or 0.25% glutaraldehyde fixation (2 h, 37°C) fully inhibited erythrocytosis-enhanced increases in platelet aggregate size. Thus, the adenine nucleotides contributing to erythrocytosis-enhanced platelet aggregate formation under physiologic shear appear to be derived predominantly from RBC. Taken together, the data suggest that ADP and ATP are both required for erythrocytosis-induced large platelet aggregate formation, but that the presence of ATP alone is not sufficient. The results may further suggest a role for direct ADP or ATP receptor blockade for the prevention of erythrocytosis-associated thrombotic complications.
Expression of Protein Z-Dependent Protease Inhibitor (ZPI) In Situ in Different Malignant Tumors.
Authors: Sierko Ewa , Ramlau Rodryg , Zimnoch Lech , Broze George J. , Wojtukiewicz Marek 
Published: October 2019

Abstract
Cancer progression is often associated with thromboembolic complications. Coagulation factors and inhibitors influence various processes involved in malignant tumor growth and metastatic dissemination. Recently a new coagulation inhibitor - protein Z-dependent protease inhibitor (ZPI) has been characterized. ZPI is a plasma proteinase inhibitor in the serpin superfamily. ZPI inhibits factor Xa activity in the presence of calcium and phospholipids. Protein Z augments its activity by more than 1000-fold. ZPI also attenuates the activity of factor XIa in the reaction which does not require the presence of calcium and phospholipids. ZPI inhibits the coagulation response prior to the formation of the prothrombinase complex. Up to now the data on the presence of ZPI in malignant tumors are obscure. The purpose of the study was to elucidate the solid phase interactions between various types of maligant tissues and ZPI that may contribute to tumor progression. The tissues from colon, breast, gastric, renal, pancreatic, endometrial carcinoma, non-small cell lung cancer (NSCLC) as well as from glial neoplasms were obtained at surgical resection during radical treatment. The patients undergoing surgery have not received any previous antineoplastic therapy. Tumor fragments were processed acc. to AMeX method and then embedded in paraffin. Immunohistochemical studies (avidin-biotin complex-ABC - technique) were performed using a monoclonal antibody against ZPI. Expression of ZPI was observed in cancer cell bodies of colon, breast, gastric, renal, endometrial, pancreatic cancer, NSCLC and glial neoplasms. The staining intensity for ZPI was irregular: both strong and weak expression of ZPI was observed. Moreover, various percentages of ZPI-positive cancer cells were revealed in different specimens of examined tissues. Macrophages and mucin also revealed expression of ZPI in the case of colon cancer. The presence of ZPI was demonstrated in the stroma of renal cancer. The obtained results suggest that ZPI being an inhibitor of coagulation might additionally play a role in the regulation of cancer progression.
The Effect of Platelet -, and Leukocyte Count on the Thrombelastograph® (TEG) Parameters.
Authors: Roeloffzen W.W.H. , Kluin-Nelemans J.C. , de Wolf Joost 
Published: October 2019

Abstract
Background. The TEG is used in situations were point of care testing of hemostasis is desired, although its value is still controversially because of insufficient test validation. The main parameters of the TEG are (a) the reaction time (R), the time until the initial fibrin formation and comparable with the coagulation times PT and APTT; (b) clotting time (K), the time until a fixed level of clot firmness is reached; (c) the angle (α) is closely related to K and measures the rapidity of fibrin build up and gives information about the clot strength; R, K and α are prolonged by anticoagulants and factor deficiencies; (d) maximum amplitude (MA) is a measurement of maximum strength or stiffness of the developed clot; it is especially influenced by platelets and fibrin.
Methods. We performed a multivariate analysis using the Cox multiple-regression model to study the effects of Leukocytes, Hb, and platelet count on the TEG parameters.
Results. Ninety native whole blood samples from 19 patients undergoing consolidation chemotherapy were studied; in the post chemotherapy phase in which platelets decreased from normal to < 10 x 109/l samples were taken; in all these cases PT, APTT and Fibrinogen were within normal limits. Platelets significantly influenced all parameters: R (p<0.001, r=−0.5), K (p<0.001, r=−0.7), α (p<0.001, r=+0.7), MA (p<0.001, r=+0.6) whereas Leukocytes influenced MA as well (p<0.001, r=0.3). In normal controls K is 9 ± 3 min (n=110), in patients with platelet count 50–100, 25–50 and <25 x 109/l K was resp. 17 ± 9, 30 ± 13 and 46 ± 10 min. In normal controls MA was 46 ± 7 mm, in patients MA became significant smaller with platelets < 25 x 109/l: 30 ± 5 mm. In patients with leukocytes ranging from 0–0.1, 0.1–1.0, 1.0–3.5 and > 3.5 x 109/l the MA was resp. 44 ± 14, 49 ± 15, 54 ± 9, and 58 ± 8 mm. As the MA is considered the parameter most influenced by platelet count, we calculated the sensitivity, specificity, pos and neg predictive value of MA to detect a platelet count less then 50 x 109/l, they were resp. 35%, 100%, 100% and 73%.
Conclusion. Firstly, platelet count not only influences MA but also the coagulation parameters R, K and α; besides leukocytes influences the clot strength; this is in agreement with the new conceptual cell based model of hemostasis; secondly, the TEG should be considered as additive to platelet count and plasmatic coagulation tests and not as a replacement.
Incidence of Extramedullary Relapse of Acute Myeloid Leukemia Following Transplantation with Busulfan-Based Conditioning Regimens.
Authors: Blum William , Penza Sam , Farag Sherif , Avalos Belinda , Marcucci Guido , Lin Thomas , Byrd John C. , Elder Patrick , Copelan Edward A. 
Published: October 2019

Abstract
Rates of extramedullary relapse are reported to be more than twice as high following transplantation with busulfan-based conditioning regimens (Simpson et al, Bone Marrow Transplantation 1998, Lee et al, Bone Marrow Transplantation 2000) compared to total body irradiation (TBI)-based regimens (Mortimer et al, J. Clin Oncol 1989) in acute myeloid leukemia (AML). Up to 50% of relapses following transplantation with busulfan-based therapies are reported to be extramedullary, with more than 25% as isolated extramedullary relapses. We analyzed 228 consecutive AML patients who underwent allogeneic (n=192) or autologous (n=36) transplantation following busulfan-based conditioning regimens between 2/84 and 12/03. One hundred twenty-three patients were in remission at the time of transplantation, 67 had relapsed disease, and 38 had never achieved remission. One hundred twenty-seven patients received BuCy, 77 received BuCyVP16, and 24 (all autologous) received BuVP16. All patients had a lumbar puncture demonstrating no evidence of leukemia, and all received intrathecal methotrexate prophylaxis prior to receiving busulfan. Seventy-nine patients (35%) relapsed (any site) at a median of 6 months (range, 1 to 44 months) after transplantation. Fifteen patients (7%) relapsed at extramedullary sites, including 7 in the CNS. Ten patients (4%) had isolated extramedullary relapses at a median of 13 months (range, 1 to 44 months) after transplantation. Four had isolated CNS relapses, and 4 had isolated cutaneous relapses. Of patients transplanted in remission, only 2 relapsed at extramedullary sites, including one patient with an isolated CNS relapse.
This retrospective study includes a substantially larger cohort of patients with longer follow-up than prior studies examining extramedullary relapse in patients with AML following transplantation with busulfan-based conditioning. In contrast to other reports, these results demonstrate that the incidence of extramedullary relapse is comparable to that reported with TBI-based conditioning regimens for patients with AML.
A Pilot Trial of Valproic Acid in Patients with Kaposi’s Sarcoma: A Multi-Center Trial of the AIDS Malignancy Consortium.
Authors: Lechowicz Mary Jo , Lee Jeannette , Dittmer Dirk , Krown Susan , Said Jonathan , Ambinder Richard F. 
Published: October 2019

Abstract
PURPOSE: Although the use of highly active antiretroviral therapy (HAART) has led to improvements in the management of AIDS-associated Kaposi’s sarcoma (KS), KS may persist or progress despite HAART. It has been hypothesized that activation of KS-associated herpesvirus (KSHV, HHV8) lytic expression might render tumor cells susceptible to immune surveillance by cytotoxic T cells. Alternatively, it has been suggested that lytic induction could lead to tumor progression. In vitro, valproic acid (VA) and other histone deacetylase inhibitors induce KSHV lytic gene expression in primary effusion lymphoma cell lines. We investigated VA in AIDS/KS patients to assess its safety and its impact on lytic viral gene expression in tumor and viral copy number in blood.
PATIENTS AND METHODS: VA was given orally to patients with AIDS and cutaneous KS on stable antiviral regimens; the dose was titrated to maintain trough concentrations between 50 and 100 mcg/mL. VA was given daily for 28 days followed by a rapid taper and patients were then followed for 6 months. Quantitative real time PCR was used to assess viral DNA in plasma and PBMC, and viral RNA in tumor specimens. Immunohistochemistry was used to assess viral antigen expression in tumor specimens.
RESULTS: 18 patients were treated. 15/18 patients completed therapy; 3 patients discontinued therapy early, one secondary to grade 2 toxicity and 2 to patient preference. One patient showed a partial response and 17 showed stable disease at the completion of therapy. No patients progressed during treatment. There were no differences between KSHV copy number in plasma or PBMC before, during, or after therapy. Similarly, although serial biopsies in some patients showed an increase in lytic gene expression, these changes did not achieve statistical significance. However, in multivariate analyses, viral lytic RNA increased in tumor biopsies on day 8 as a function of VA level. There was no change in HIV viral load with VA treatment.
CONCLUSION : VA was well tolerated in AIDS patients, was not associated with accelerated disease progression, but rarely induced tumor regression after short-term treatment. In patients who achieved the highest serum VA levels there was increased lytic viral RNA expression. These findings support investigation of more potent HDAC inhibitors over longer treatment courses in patients with AIDS-associated KS.