bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4+ Regulatory T Cells Specific for the WT1 Antigen Are Present in Acute Myeloid Leukemia Patients: Implication for Immunotherapy.
Authors: Dermime Said , Lehe Cynthia , Ghebeh Hazem , Al-Sulaiman Abdullah , Qudaihi Ghofran Al , Al-Hussein Khaled , Almohareb Fahad , Chaudhri Naeem A. , Alsharif Fahad Z. , Al-Zahrani Hazza , Mohamed Said Y , Tbakhi Abdelghani , Aljurf Mahmoud 
Published: April 2020

Abstract
Compelling evidences indicate a key role for regulatory T cells (Tregs) on the host response to cancer and recent studies indicated that the generation of effective WT1-specific cytotoxic T cells can be largely affected by the presence of Tregs. This is the first study to describe human Tregs generated specifically against the WT1 antigen which is overexpressed in several human leukemias and provide the mechanism by which these anti-WT1 Tregs inhibit the immune response in leukemia patients. We have generated T cell lines and clones that specifically recognized a WT1-84 peptide in an HLA DRB1*0402/TCR-Vb8-restricted manner. Importantly, they recognized HLADRB1* 04-matched fresh leukemic cells expressing the WT1 antigen. These clones exerted a Th2 cytokine profile, had a CD4+CD25+Foxp3+GITR+CD127− Tregs phenotype, and significantly inhibited the proliferative activity of allogeneic T cells independently of cell-contact. Priming of allo-reactive T cells in the presence of Tregs strongly inhibited the expansion of NK; NK-T and CD8+ T cells, had an inhibitory effect on NK/NK-T cytotoxic activity but not on CD8+ T cells. Furthermore, priming of T cells with the WT1- 126 HLA-A0201-restricted peptide in the presence of Tregs strongly inhibited the induction of anti-WT1-126 CD8+ CTL responses as evidenced by both very low cytotoxic activity and IFN-g production. Moreover, these Tregs clones specifically produced Granzyme-B and selectively induced apoptosis in WT1-84 pulsed-autologous APCs but not in apoptoticresistant DR4-matched leukemic cells. Importantly, we have also detected anti-WT1-84 IL-5+/Granzyme-B+/Foxp3+ CD4+ Tregs in 5 out of 8 HLA-DR4+ AML patients. These findings suggest a critical role for anti-WT1 Tregs in the inhibition of T cell responses against leukemia. This study may have important implications for the clinical manipulation of Tregs such as immuno-targeting of TCR-Vb-8 with mAbs to eliminate anti-WT1 Tregs in leukemia patients in order to enhance GVL before vaccination with the WT1 antigen. On the other hand, leukemia patients with GVHD should be clinically-tried for vaccination with the current WT1-84 peptide or adoptively-treated with ex-vivo anti-WT1 Treg cells to specifically enhance their frequency, which is known to be very low in these patients.
Relapsed and Refractory Acute Myeloid Leukemia (AML) Treated with AS1411 and Cytarabine: A Randomized Phase II Trial.
Authors: Stuart Robert Kenneth , Acton Gary ,   AS1411-201 Investigator Group
Published: April 2020

Abstract
Background: AS1411 is an aptamer that binds to nucleolin, which is upregulated and overexpressed in the cytoplasm and on the cell surface of cancer cells. Combination of AS1411 with cytarabine produces synergistic effects on AML cell lines and in vivo models. A phase I trial of AS1411 monotherapy in 30 patients with various advanced cancers revealed no dose-limiting toxicities and showed evidence of activity, including 2 responses among 12 patients with metastatic renal cancer. This phase II study evaluates the addition of AS1411 to high-dose cytarabine in relapsed and refractory AML.
Methods: This open-label randomized phase II trial compares AS1411 plus cytarabine with cytarabine alone in patients with primary refractory or relapsed de novo or secondary AML who have received up to 3 previous induction cycles. Patients in cohort I were randomized in a 1:2 ratio to receive cytarabine (3,000 mg/m2/day) for 4 days or AS1411 (10 mg/kg/day) on days 1–7 plus cytarabine on days 4–7. Following safety assessment, a second cohort was to be randomized 1:2 to receive cytarabine 3,000 mg/m2/day) for 4 days or AS1411 at a higher dose (40 mg/kg/day) on days 1–7 plus cytarabine on days 4–7. Key study objectives are comparison of response rates and safety and tolerability between treatment groups. Patients not achieving a CR after one cycle of single agent cytarabine are eligible for a subsequent cycle of AS1411 plus cytarabine.
Results: Thirty-three patients had been randomized by July 2008, all to the first cohort. Safety findings were available for 27 patients (9 in the cytarabine arm and 18 in the combination arm). Numbers of grade 3 and 4 adverse events per patient were 19 among 9 patients on cytarabine alone and 35 among 18 patients on AS1411 plus cytarabine. The main grade 3/4 toxicities reported were blood and lymphatic system disorders, particularly febrile neutropenia, neutropenia and thrombocytopenia; and infections and infestations. Induction deaths were 1/9 and 0/18, respectively. Response data were available for 20 patients. In the cytarabine-alone group, 0/7 patients achieved a CR, CRp or cytogenetic response. In the cytarabine plus AS1411 group, 3/13 (23%) patients showed responses to treatment, with one CR, one CRp and one cytogenetic response. Three patients from the cytarabinealone group who failed to achieve remission with cytarabine alone crossed over to receive AS1411 plus cytarabine, one of whom experienced a 90% reduction in leukemic blast count.
Conclusion: The combination of AS1411 at 10 mg/kg/day for 7 days with high-dose cytarabine 3,000 mg/m2/day over 4 days appeared to be well tolerated and showed signs of activity in patients with relapsed/refractory AML. Further patients are now being randomized to cytarabine or cytarabine plus the higher dose of 40 mg/kg/day AS1411.
Lenalidomide Enhances Leukaemia Specific T Cell Responses to Dendritic Cell Based Immunotherapy for Myeloid Leukaemias.
Authors: Duncan Caroline J , Johnson Peter R. E. , Roddie Huw 
Published: April 2020

Abstract
Dendritic cell (DC) vaccines in leukaemia show promise as a novel treatment modality aimed at reducing relapse rates by augmenting immune responses when patients are in a state of minimal residual disease. DC vaccination studies to date have not been as successful as hoped and this may be because of insufficient cytotoxic T cell (CTL) responses. Immunomodulatory agents such as 4-IBB ligand, and cytokines such as IL2, IL6 and GM-CSF have been reported to improve vaccine therapy however these agents have to be tolerated clinically and this limits the use of some preparations. Our study aims to generate a more efficient DC vaccine process by using Lenalidomide, a thalidomide analogue and immunomodulatory agent which is a powerful potentiator of CTLs and natural killer cells. It has the advantage of clinical tolerability and is already in use for treating haematological malignancies.
In this in vitro study DCs were generated from monocytes of eight patients in remission following chemotherapy for acute myeloid leukaemia (AML) or chronic myeloid leukaemia (CML) with standard cytokine protocols. The immature DCs were loaded with autologous leukaemia cells from the patients’ presentation samples. The presentation leukaemia cells were treated with UVB irradiation to induce apoptosis. DCs were matured with TNF alpha for two days then co-cultured with autologous T cells for one week with or without the addition of Lenalidomide at ten micromolar. A control group of unstimulated T cells were kept in culture for the same time period. The T cells from the three groups were harvested and their cytoxicity assessed in an Interferon Gamma (IFNγ) ELISPOT assay where the stimulators used were the unmodified blasts. Results in all eight patients show the leukaemia specific CTL responses (as measured by IFNγ release) were markedly improved in the DC/irradiated blasts groups compared with the unstimulated T cells. In six out of eight patients there was a further, significant improvement in the groups where Lenalidomide was added (see Figure 1).
Figure Figure
These results show promise for the use Lenalidomide as an agent to optimise CTL responses to DC based Immunotherapy for myeloid leukaemia and should be investigated further in a clinical trial.
Rituximab for Graft-Versus-Host-Disease-Prophylaxis after Allogeneic Stem Cell Transplantation Given as Treatment of High Risk Relapse of Aggressive Lymphoma: Results of a Randomized Phase II Study.
Authors: Glass Bertram , Hasenkamp Justin , Görlitz Anke , Dreger Peter , Schubert Jörg , Wulf Gerald , Nickelsen Maike , Truemper Lorenz H. , Schmitz Norbert 
Published: April 2020

Abstract
Background: High dose therapy (HDT) followed by autologous stem cell support has poor outcome in patients with primary progressive lymphoma or relapse after primary HDT. Allogeneic SCT may help these patients by exerting an GVL effect. Its use however is hampered by high incidence of severe GVHD and non-relapse mortality in this population. Rituximab has been claimed to reduce the incidene of GVHD without negative impact on the relapse rate.
Patients and Methods : We initiated a randomized phase II study using intermediate conditioning (Fludarabine 125 mg/m2, Busulfan 12 mg/kg and cyclophosphamide 120 mg/kg) followed by GVHD prophylaxis with short term mycophenolat mofetil plus tacrolimus. Anti-thymozyte globulin (ATG) was given due to center decision. Patients were randomized to receive two times four doses of rituximab (375 mg/m2) post transplant starting day +21 and day +175 or no additional GVHD prophylaxis. From June 2004 to July 2007 sixty five patients with aggressive NHL were enrolled and 59 were eligible for analysis. Thirty one pts had diffuse large B cell NHL, 3 patients follicular lymphoma grade 3, 7 pts blastic mantle cell lymphoma, 2 pts aggressive marginal zone lymphoma, 2 patients lymphoblastic B cell lymphoma, and 12 T cell lymphoma. 42 (71%) pts received at least one cycle of HDT and autologous SCT prior to alloSCT; 78% had early relapse ( &lt; 12 months) or primary progressive disease, 59% chemo-refractory disease and 48% had progressive disease with high or high intermediate age adjusted IPI immediately prior to conditioning.
Results: Allo-PBPC were obtained from HLA-identical siblings in 17 pts, from matched unrelated donors in 32 pts and from one locus mismatched unrelated donors in 10 pts. 33 patients did receive ATG. Median observation time of surviving patients is 1,8 years. 30 pts died, in 19 patients death was attributed to treatment related causes. After one year, estimated overall survival is 49%, progression free survival is 39%, relapse rate is 28 % and incidence of GVHD &gt; grade 1 is 73%. The last documented lymphoma progress occurred at day 288 after alloSCT. There are no significant differences in OS, PFS and GvHD in relationship to the application of Rituximab.
Conclusion: Intermediate intensity conditioning followed by allogeneic SCT is a valuable treatment option in patients with high-risk relapse of aggressive NHL. The incidence of GVHD and non-relapse mortality is high. On the background of this very high basic incidence of GVHD, we did not find a significant impact of post transplant rituximab on GVHD, relapse rates or survival, respectively. Therefore, ATG will be added as an obligatory part of the conditioning regimen in the next study phase in additional 30 patients
The Unmet Need for Extended Thromboprophylaxis in Acutely Ill Medical Patients: The Findings of IMPROVE, ENDORSE and EXCLAIM.
Authors: Anderson Frederick A , Hull Russell D , Schellong Sebastian M , Deslandes Bruno , Tapson Victor F , Samama Meyer Michel , Turpie Alexander GG , Yusen Roger D , Decousus Herve , Cohen Alexander T , Monreal Manuel 
Published: April 2020

Abstract
Introduction: Findings from the recent EXCLAIM study demonstrate that selected acutely ill medical patients with reduced mobility benefit from extended-duration enoxaparin venous thromboembolism (VTE) prophylaxis (Blood2007;110:1862). However, it is unknown whether the EXCLAIM population is representative of acutely ill medical patients admitted to hospitals worldwide. In this subanalysis, we assessed whether the EXCLAIM population was representative of the medical patients enrolled in the multinational IMPROVE (Chest2007;132:936–45) and ENDORSE (Lancet2008;371:387–94) registries known to be at risk for VTE.
Methods: Using patient data from IMPROVE and ENDORSE, we applied the EXCLAIM eligibility criteria to a representative, multinational population of acutely ill medical patients at risk for VTE. The IMPROVE and ENDORSE studies assessed VTE-risk and prophylaxis use of enrolled patients according to the 2004 American College of Chest Physicians (ACCP) guidelines (Chest2004;126:338S–400S). ACCP criteria for VTE risk were met in 46% (6,907/15,156) of IMPROVE and 43% (15,487/36,351) of ENDORSE study patients (Chest2007;132:936–45; Lancet2008;371:387–94). The EXCLAIM eligibility criteria required patients to be confined to total bed rest (level 1 immobility), or bed rest with bathroom privileges (level 2 immobility) and have at least 1 of 3 predefined risk factors for VTE (i.e., age &gt; 75 years; history of VTE; active or prior cancer).
Results: EXCLAIM eligibility criteria were met in 30% (2,072/6,907) IMPROVE and 36% (5,535/15,487) ENDORSE medical patients considered at risk for VTE by ACCP. During hospitalization, ACCP-recommended prophylaxis was provided to 69% (1,426/2,072) and 46% (2,548/5,535) of EXCLAIM-eligible patients enrolled in IMPROVE and ENDORSE, respectively. Following discharge from hospital (median length of stay 5 days for US, 8 days for non-US), only 9% (153/1,719) of EXCLAIM-eligible patients in the IMPROVE study received any type of ACCP-recommended VTE prophylaxis.
Conclusions: Evidence from the EXCLAIM study demonstrated that the benefit-to-risk ratio in selected hospitalized medical patients favors the use of prolonged VTE prophylaxis. This population corresponds to one in three of the representative hospitalized patients with acute medical illness enrolled in IMPROVE and ENDORSE. Data on prophylaxis use from the IMPROVE registry suggest that only 9% of such patients are currently receiving optimal VTE prophylaxis following hospital discharge.
Elevated Procoagulant Activity Due to Phosphatidylserine Exposure on Red Blood Cells during Storage.
Authors: Zhou Jin , Lu Chengfang , Yu Hongjuan , Hou Jinxiao , Liu Shuchuan , Ma Ming , Gilbert Gary , Shi Jialan 
Published: April 2020

Abstract
Serious complications and mortality after cardiac surgery are increased when transfused red cells are stored for more than 2 weeks (Koch, N Engl J Med. 2008). However, the mechanism remains unclear and the relationship of procoagulant activity to PS exposure on banked RBCs has not been clarified, although prior studies suggest that banked cells went to apoptosis. Procoagulant activity of RBCs was measured in a modified prothrombin time in which RBCs replaced thromboplastin. The presence of PS in neutrophils and mononuclear cells from healthy donors and banked RBCs was investigated by flow-cytomety and confocal microscopy. The assembly of extrinsic tenase, intrinsic tenase, and prothrombinase complexes on these cells was studied using enzymatic assays employing plasma or purified proteins. Lactadherin, a glycoprotein, was utilized as a probe to track PS exposure and as an agent to block exposed PS. Coagulant activity increased approx 5-fold after cells were banked for 14 days and progressively increases. The percent of phosphatidylserine (PS)-positive cells increased from 7.4% on day 14 to 30% on day 42. RBCs with exposed PS were nearly absent in samples at 7 days but readily evident at 14 days on confocal microscopy. Banked RBCs exhibited patched, a rim, and diffuse-pattern that stained with lactadherin but neutrophils and MNC did not, indicating more PS exposure on banked RBCs from 7 days than the other two cell types. These data reveal a positive correlation between PCA and PS exposure on stored RBCs. Inhibition of PCA by lactadherin further confirms that PS supports the PCA in stored RBCs. Thus, we propose the possible role of PCA due to increased PS exposure on aged RBCs as a potential pathogenetic factor leading to organ injury, aggravated infections and finally higher mortality.
Alemtuzumab (Campath 1-H) in Patients with HTLV-1 Associated Adult T-Cell Leukemia/Lymphoma.
Authors: Sharma Kamal , Janik John E. , O’Mahony Deirdre , Stewart Donn , Pittaluga Stefania , Stetler-Stevenson Maryalice , Jaffe Elaine S. , Raffeld Mark , Fleisher Thomas A. , Lee Cathryn C. , Urquhart Nicole , Steinberg Seth , Waldmann Thomas A. , Morris John C. 
Published: April 2020

Abstract
This study investigated the antitumor activity of alemtuzumab (Campath 1-H) with regard to response rate, time to progression, overall survival and adverse events in patients with human T-cell lymphotrophic virus-1 (HTLV-1)-associated adult T-cell leukemia/ lymphoma (ATL). In a single institution non-randomized open-label phase II trial, 24 patients with chronic (n=2), acute (n=13) and lymphomatous (n=9) ATL were treated with intravenous alemtuzumab 30 mg three times weekly for a maximum of 12 weeks. Patients received antimicrobial prophylaxis from the initiation of treatment continuing for a minimum of 2 months after treatment, or until the peripheral blood CD4+ T-cells were ≥ 200 cells/μL. Tumor responses were assessed at the end of 4, 8, and 12 weeks. All patients were evaluable for toxicity and one patient was not evaluable for response due to early withdrawal. The overall objective response rate was 10 out of 23 patients (95% CI: 23 to 66%). Based on the 10 patients who responded, median time to response was 1.1 months (range, 1.0 to 3.0 months). The median response duration was 3.9 months. Median progression free survival of patients with chronic subtype was 2.0 months, 1.0 month for lymphomatous subtype and 2.4 months for acute subtype. Median time to treatment failure was 1.7 months. At data cut-off, (April 24, 2008), 6 (25%) patients were alive. Overall median survival was 5.9 months. Median overall survival by subtypes was 3.9 months for chronic, 4.8 months for lymphomatous, and 7.6 months for acute. Median survival for all responders from on study date was 8.4 months. Clinical benefit was observed both in responders and in patients with stable disease. The most common adverse events were related to infusion and were generally grade 1 or 2, occurring mainly in the first week of alemtuzumab administration. All patients developed CMV antigenemia; however, only 3 (12.5%) were symptomatic. Grade 3 or 4 infections were reported in 6 (25%) patients. Median time to recovery of ALC to &gt;200 cells/μL was 1.9 months.
Comparative Outcomes Following CP-R, CVP-R and CHOP-R in Patients with Waldenstrom’s Macroglobulinemia.
Authors: Ioakimidis Leukothea , Patterson Christopher , Soumerai Jacob , Manning Robert , Sheehy Patricia , Treon Steven 
Published: April 2020

Abstract
Since the adoption of rituximab as a mainstay of therapy in non-Hodgkin’s lymphoma, there has been growing debate on the importance of adriamycin and vincristine as treatment components used in the therapy of indolent non-Hodgkin’s lymphoma, including Waldenstrom’s macroglobulinemia (WM). We therefore examined the outcome of symptomatic WM patients who required therapy based on consensus guidelines and received treatment at our Institution with CP-R (n=20), CVP-R (n=17), or CHOP-R (n=23). Baseline characteristics for all 3 cohorts were as follows:
Median Age Median Prior Therapies Bone Marrow Involvement sIgM (mg/dL) Hct PLT B2M CP-R 65 (range 42–74) 0 (range 0–2) 45% (range 5–95%) 2620 (range 551–6750) 33.4 270 2.3 CVP-R 60 (range 32–81) 1 (range 0–2) 50% (range 20–90%) 2220 (range 185–8430) 30.0 169 3.3 CHOP-R 54 (range 42–72) 0 (range 0–2) 50% (range 5–90%) 5150 (range 241–12400) 31.0 239 3.6
Responses to therapy, including median decrease in serum IgM and best response for IgM, Hct, and PLT counts were as follows:
ORR(CR+PR+MR) ≥PR CR/nCR % decrease sIgM Post-sIgM Post-Hct Post-PLT p=N.S. for all treatment cohorts. CP-R 90% 80% 0% −54% 1150 38.0 300 CVP-R 88% 71% 12% −67% 790 36.1 219 CHOP-R 83% 70% 17% −63% 794 38.3 230
Adverse events attributed to therapy, including rituximab related IgM flare were as follows:
Neutropenic fever Hospitalizations Treatment related neuropathy IgM flare IgM flare requiring plasmapheresis P=N.S. except as follows: (a) p=0.02; (b) p=0.00006; (c) p=.0.004 versus CPR. CP-R 0% 0% 0% 25% 10% CVP-R 18% 12% 59%b 29% 11% CHOP-R 26%a 17% 35%c 23% 17%
The results of this study demonstrate comparable response characteristics among WM patients treated with CP-R, CVP-R, or CHOP-R though a trend for attainment of more CR/nCR was observed among those patients receiving CVP-R and CHOP-R. Importantly, significantly more toxicity was observed, particularly neutropenic fever and treatment related neuropathy among patients treated with CVP-R and CHOP-R versus CP-R. The results of this study suggest that in WM, the use of CPR may provide analogous treatment responses to more intense cyclophosphamide based regimens, while minimizing treatment related complications.
Lysine-Binding Site-Dependent Interaction with Plasmin and Factor Va Responsible for Plasmin-Catalyzed Factor Va Inactivation.
Authors: Nishiya Katsumi , Nogami Keiji , Okada Kiyotaka , Matsuo Osamu , Ogiwara Kenichi , Shima Midori 
Published: April 2020

Abstract
Plasmin (Plm), an active form of plasminogen (Plg), functions as a key enzyme in the fibrinolytic system. Furthermore, this enzyme directly inactivates various coagulation factors such as factor V (FV) and factor VIII (FVIII) by limited proteolysis, suggesting another role of Plm in the regulation of the coagulation system. We recently reported that Plm/Plg interacts with FVIII and its active form (FVIIIa), both dependently and independently of lysine-binding site (LBS) (Blood2007; 110, 522a). In this study, we attempted to localize a factor Va (FVa)-interactive region on Plm (and Plg) using Plm/Plg kringle fragments. Surface plasmon resonance-based assays showed that FVa directly bound to active-site modified Plm (anhydro-Plm) with an ~2-fold higher affinity, compared to Plg (Kd; 97 and 198 nM, respectively). In particular, FVa bound to the immobilized-Plg fragment consisting of kringle 1-2-3 domains (K1-3) (Kd: 706 nM), whilst FVa failed to bind both the kringle 4 domain (K4) and Plg fragment consisting of kringle 5 and catalytic domains (K5-CD). A similar experiment using immobilized FVa also revealed that the K1-3 solely bound to FVa. These results were quite different from those obtained by FVIII and Plm/Plg binding experiment that the K5-CD bound to FVIII(a) more preferably. Competitive binding assay using 6-aminohexanoic acid (6-AHA), a competitor of LBS of Plm/Plg, showed that 6-AHA markedly inhibited (by &gt;90%) the K1-3 binding to FVa (IC50; ~25 μM), suggesting that interaction of FVa with Plm is mostly dependent upon LBS. According to the one stage-clotting assay, 6-AHA inhibited (&gt;90%) Plm-catalyzed inactivation of FVa in a dose-dependent manner (IC50; ~10 μM). Furthermore, Plm-catalyzed inactivation of FVa was blocked by an anti-K1-3 monoclonal antibody (mAb), not by either anti-K4 or anti-K5-CD mAb, although Plm-catalyzed inactivation of FVIII was blocked by anti-K5-CD mAb. In order to confirm that the inhibitory effect of 6-AHA on the Plm-catalyzed inactivation, we performed SDS-PAGE experiment. Plm cleaves FVa at Lys309 and Arg348 in the heavy chain, and at Arg1752 in the light chain. SDS-PAGE analysis revealed that 6-AHA blocked Plm-catalyzed cleavages of the light chain more prominently than that of the heavy chain (IC50; ~10 and ~&gt;100 μM, respectively). These findings suggest that the K1-3 of Plm (and Plg) interacts with the FVa through the LBS-dependent mechanisms, and these interactions likely contribute to the FVa-catalyzed inactivation by proteolytic cleavages at Arg1752 in the light chain. Present study indicated that plasmin-catalyzed protelytic inactivation of coagulation factor is complicatedly regulated by the LBS dependency in the protein and protein interaction.