bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromosome 1p21 Deletion Defines a Subgroup of Multiple Myeloma with Poor Clinical Outcomes Independent of del (13q), del(p53), t(4;14) or 1q21 Amplification.
Authors: Chang Hong , Qi Connie , Jiang Allan , Xu Wei , Young Trieu , Mikhael Joe , Trudel Suzanne , Chen Christine , Reece Donna 
Published: April 2020

Abstract
Amplifications involving chromosome 1q and deletions involving 1p are frequent events in multiple myeloma (MM). The pathogenesis and clinical significance of these anomalies is largely unknown but CKS1B amplification at 1q21 detected in 30–40% of MM patients is associated with disease progression. As karyotyping and SNP based mapping analysis identify a minimal common deletion region involving the 1p21 locus, we used FISH combined with cytoplasmic light chain detection (cIg-FISH) to investigate the prevalence and prognostic significance of del(1p21) in a cohort of 186 MM patients undergoing autologous stem cell transplant. CIg-FISH detected hemizygous 1p21 deletions in 18% of the cases. The median percentage of clonal plasma cells harboring del(1p21) was 55% (range 20–95%). The presence of 1p21 deletions was strongly correlated with CKS1B amplification (p=0.004), t(4;14) (p= 0.027), and del(p53) (p=0.04), but not with del(13q) or t(11;14). There was no association between del (1p21) and other biological factors including age, gender, Hb, albumin, C-reactive protein, beta-2 microglobulin level, isotype or bone marrow plasmacytosis. Patients with 1p21 deletions had significantly shorter progression-free (median 10.5 vs. 25.4 months, p=0.0001) and overall survivals (median 33.9 months vs. not reached, p=0.001) than those without such deletions. On multivariate analysis, del(1p21) was an independent risk factor for progression free (p&lt; 0.0001) and overall survivals (p=0.0005) after adjusting for other genetic risk factors including del(13q), del(p53), t(4;14) and CKS1B amplification. Our results indicate that del(1p21) is a novel genetic risk factor and warrant inclusion of this genetic aberration in the risk-stratification of MM. Further studies are required to identify candidate tumor suppressor gene(s) at the 1p21 locus and explore their role in the molecular pathogenesis of MM.
The Clonal Inventory of Gene Corrected Hematopoiesis in Three Successful Clinical Gene Therapy Trials
Authors: Schwarzwaelder Kerstin , Schmidt Manfred , Deichmann Annette , Howe Steven J. , Ott Marion G. , Stein Stefan , Siler Ulrich , Hacein-Bey-Abina Salima , Glimm Hanno , Hoelzer Dieter , Cavazzana-Calvo Marina , Thrasher Adrian J. , Seger Reinhard , Grez Manuel , von Kalle Christof 
Published: April 2020

Abstract
To enhance the safety and efficacy of future gene therapy trials using integrating vector systems it is necessary to analyse the clonality of the genetically modified cell pool. The comparative analyses of integration site distribution and cellular gene expression will further reveal causal mechanisms of in vivo clone selection. We followed the repopulation clonality of 21 patients which participated in 3 successful clinical gene therapy trials via linear amplification mediated PCR (LAM PCR). We identified the integration sites (IS) of pre and post transplantation samples by Sanger sequencing and accomplished RNA analyses. The comparative results from all trials showed that vector integration is favoured in gene coding regions, in particular transcriptional start sites. In both X-SCID trials significantly more post transplantation IS were located in or in the vicinity of genes encoding proteins with kinase or transferase activity. In pre transplantation samples no uniform gene class was overrepresented. In both trials we detected common insertion sites mainly post transplantation and the effect was more pronounced in the trial where 4 patients developed vector induced leukemia. Notably, we detected no significant differences regarding the IS distribution in leukemic versus non leukemic patients. The gene corrected repopulation of patient 1 and 2 of the X-CGD trial was polyclonal until 542 and 777 days after transplantation, respectively. 5 months after therapy dominant clones appeared. In patient 1, between 616 and 820 days post transplantation (post mortem time point) the number of participating clones and the contribution of a dominant clone decreased while the contribution of another dominant clone increased. In both patients the integrated vector induced the upregulation of the genes MDS1/EVI1, PRDM16 or SETBP1 and thus led to the in vivo expansion of affected cell clones. From these trials we sequenced &gt;2000 unique IS by Sanger sequencing and several thousand via pyrosequencing (datamining is ongoing). Our data show that the integration site distribution was non random, that the integrated vector influenced the cellular gene expression which caused subtle to massive changes in the repopulation clonality and that it will soon be possible to define the clonal inventory of patients using next generation sequencing technologies.
Deferasirox Might Induce Immunosuppression Comparable to Deferoxamine.
Authors: Jeong Dae-Chul , Chung Nack-Gyun , Cho Bin , Kim Sung-Yong , Han Chi Wha , Kim Hack Ki 
Published: April 2020

Abstract
Background: The iron chelating agents (ICA) have various biological effects besides iron chelation, including induction of apoptosis and immune modulation. Deferoxamine (DFO) is known to have some immunosuppressive effects. Deferasirox (DFS) is a new oral iron chelating agent, and its biologic effects are not known clearly. We investigated the immunosuppressive effects of DFS in comparison with DFO.
Materials and Methods: We obtained spleen cells (SP) from 5 week-old female C57BL/6 (B6, H-2b) and BLAB/c (H-2d). The cytotoxicity of ICA at various concentrations was examined by CCK8 method for 48 hours. The cell proliferation assay (CPA) was done with B6 SP and irradiated BALB/c SP under various concentrations of DFO or DFS with phytohemaglutinin by ELISA method (n = 6). Stimulation index (SI) was defined as the ratio of experimental OD compared with OD of control. Experimental design was as follows: control (without any treatment), DFO 5, 10, 50, 100 μM, and DFS 15, 30, 50, 100 μM. Also, CPA was performed after 12 hours incubation with 20 μM ferric chloride (FE) (n = 6). For cytokine analysis, IL-2, IL-10, and TGF-β were measured from supernatants collected during CPA.
Results: There was over 100% viability after 48 hours of incubation at various concentrations, and similarly under FE. In DFO group, there was inhibition of cell proliferation at all concentrations with or without FE. Inhibition was greater at DFO10 and DFO50 than others with treatment of FE (P &lt; 0.01). In DFS group, SI without FE diminished regardless of concentration. SI with FE showed significant decrease at DFS levels higher than 30mM (P &lt; 0.01). Decrement of SI in DFS group was comparable to that in DFO group. TGF-b and IL-10 levels were not significant at any concentration of both ICAs (P &gt; 0.05). However, IL-10 was diminished according to DFS or DFO concentration without statistical significance (P &gt; 0.05). In DFS group, the level of IL-2 was higher at 30 μM than others (P &lt; 0.01). In DFO group, IL-2 level did not change according to concentration.
Conclusion: These data suggest that ICAs may have immune suppressive effects which may not be dependent on cytokines. We conclude that DFS, a new oral iron chelating agent, induce immunosuppression comparable to DFO.
Evaluation of Deferasirox (Exjade®, ICL670) Therapy in Patients with Transfusional Iron Overload Who Achieve Serum Ferritin (SF) ≤1000 ng/mL in Long-Term Studies.
Authors: Cappellini Maria Domenica , Vichinsky Elliott , Ford John M. , Rabault Bertrand , Porter John 
Published: April 2020

Abstract
Background: Maintaining SF levels below 1000 ng/mL offers significant clinical benefits in patients with transfusional iron overload. However, low SF levels can be associated with an increased risk for iron chelator toxicity. This analysis was performed to assess safety parameters during deferasirox treatment in patients with transfusion-dependent anemias who reached SF levels ≤1000 ng/mL on at least two consecutive visits during the extension phases of four core studies.
Methods: Patients (≥2 years old) with β-thalassemia, MDS, sickle cell disease or other transfusion-dependent anemias enrolled in four clinical trials were treated for 1 year with deferasirox 5–30 mg/kg/d, followed by extension phases of 4 years. In the extension phases, patients either continued receiving deferasirox (deferasirox cohort) or crossed over from DFO to deferasirox (crossover cohort), while receiving dose modifications based on efficacy and safety parameters. Efficacy was monitored by monthly SF readings; safety was assessed by the incidence and type of adverse events (AEs).
Results: Following dose adjustments at the end of the core trials, 163/652 (25%) patients in the deferasirox cohort reached SF levels ≤1000 ng/mL on at least two consecutive visits after a median of 1.2 years on deferasirox therapy. Median SF levels over the course of the studies are presented in Table. At month 22, the overall mean dose was 20 mg/kg/d, which was generally maintained in all dose groups until month 42. At baseline, overall mean (±SD) ALT and AST values were 44.2 (36.2) and 39.2 (27.4) U/L, respectively. Overall ALT and AST levels decreased by 16.5 (±38.7) and 11.7 (±30.5) U/L, respectively, at month 42.
Median SF (ng/mL) Initial dose group Month 5 and 10 mg/kg/d 20 mg/kg/d 30 mg/kg/d (n) (n) (n) *Dose modifications to most appropriate dose Baseline 1295 (55) 1520 (43) 2311 (65) 1 1475 (54) 1616 (42) 2284 (65) 6 1612 (54) 1383 (39) 1596 (60) 12* 1697 (53) 1165 (42) 1168 (62) 18 1818 (45) 1362 (39) 1307 (51) 24 1287 (49) 1161 (34) 1236 (52) 30 966 (44) 1046 (33) 1047 (54) 36 788 (37) 1010 (30) 991 (50) 42 884 (37) 1040 (34) 850 (50)
10 (6.1%) patients experienced two consecutive serum creatinine increases &gt;33% above baseline and &gt;ULN. Most of these increases were only marginally &gt;ULN and none were &gt;2 x ULN. Creatinine increases were non-progressive and generally fell promptly following dose reductions of 5–10 mg/kg/d. No new AEs or safety concerns have been reported thus far in this population.
Conclusions: With appropriate deferasirox dosing, iron overloaded patients can effectively achieve and maintain low SF levels. There were no major safety issues observed in achieving SF levels of ≤1000 ng/mL in this population. Decreases in liver enzymes suggest improvement in liver function, probably as a result of reduced iron burden.
Building and Clinical Use of Activated Plasma Clotting Time Test and the Value of APCT on Predicting the Bleeding Due to Leukemia Chemotherapy-Induced Thrombocytopenia.
Authors: Chen Bao-An , Li Jin-Jin , Huang Cheng-Yin , Gao Feng , Chen Jian , Gao Chong , Sun Yun-Yu , Wang Jun , Zhao Gang , Ding Jia-Hua , Chen Ning-Na , Pei Xiao-Ping 
Published: April 2020

Abstract
Objective This study was aimed to determine the optimal concertration of C-PG in activated plasma clotting time (APCT) test and build the APCT test.To investigate the value of activated plasma clotting time test (APCT) on predicting the bleeding due to Leukemia chemotherapy-induced thrombocytopenia.
Method We collected healthy blood donors’venous blood, prepared watched platelet suspension and platelet rich plasma in a normal way to which we add different concertrations of C-PG, then test expression of AnnexinV in the surface of activated platelet by FCM. Prepared platelet rich plasma and platelet poor plasma in a normal way to which we add different concertrations of C-PG, then count the plasma clotting time.Forty-one patients with leukemia chemotherapy, twenty-one patients with petechiae or epistaxis or gum bleeding and twenty patients without bleeding symptoms, were involved in the test. Drawed their venous blood and collected in 3.2% buffered sodium citrate(9:1), the platelet counts and APCT, PT, APTT, TT, Fig were assesed.
Result Bleeding group’s APCT was obviously prolonged contrast to the non-bleeding group’s. Platelet counts and APCT of the bleeding group and the non-bleeding group were (7.2±2.9) ×109/L, (105.9±8.1)s and (23.0±12.2) ×109/L,(71.4±9.0)s respectively. There was significant difference between the two groups (P&lt;0.01). Using APCT≥90s as the cut-off point to predict the bleeding caused by chemotherapy-induced thrombocytopenia, the sensibility was 100%, and the specificity was 95.7%. Using platelet counts ≤15*109/L, the sensibility and the specificity was 95.2% and 69.0%. PT, APTT, TT, Fig of the bleeding group and the non-bleeding group were 11.7±1.1)S,(31.5±1.3)S,(11.1±1.2)S,(2.37±0.41)g/L and (12.1±0.8)S,(30.8±2.1)S,(10.7±0.9)S,(2.64±0.27)g/L respectively. The results of the two groups were all not significantly different (P&gt;0.05).
Conclusion APCT is a good indication of predicting the bleeding due to leukemia chemotherapy -induced thrombocytopenia.
Reduced Bone Mineral Density in Hemophilia.
Authors: Alrustamani Ahmad , Walker Irwin 
Published: April 2020

Abstract
Rationale: Hemophilias are hereditary bleeding disorders usually presenting with muscloskeletal bleeding (for example, hemarthroses, synovitis and hematomas). Recently it has been suggested that patients with hemophilia are at increased risk of osteoporosis. The arthropathy associated with hemophilia, along with the treatments for human immune defeciency virus (HIV) and hepatitis C virus (HCV) may predispose affected individuals to osteoporosis and pathologic fractures.
Methods: This was a retrospective study that included unselected male patients aged 18 yrs old and over with severe hemophilia managed and followed in the Hamilton-Niagara Regional Hemophilia Program. All patients have been recommended to have bone mineral density studies (BMD). BMD was performed using dual x ray absorptiometry.
Results: There were 19 patients, mean age 29 years, range 18–43. Prophylactic treatment with recombinant factors was received by 12/19 patients (63%); HCV infection was present in 14/19 (73%) and HIV in 6/19 (31%) patients, the latter all receiving HAART treatment. A reduced BMD (osteopenia) as defined by the World Health Organization was detected in 42% of patients (5/13 or 38% of Hemophilia A and 3/6 or 50% of Hemophilia B participants). Among those who received prophylactic recombinant factors, 5/12 had reduced BMD. There was a trend towards decreased BMD in patients with HIV or HCV.
Conclusions: Individuals with severe hemophilia are at increased risk of having low bone mineral density. Those with coexistent HIV and HCV infections may be at higher risk. There was no clear correlation in this small series between BMD and age, and the use of prophylactic factor concentrate. Further study is required to obtain a more precise prevalence of disease, and clarification of the risk factors; however, a high prevalence of osteopenia in such a young cohort of individuals is concerning and estimation of BMD in all individuals with severe hemophilia is advised.
Final Results of a Phase II Danish Trial Testing Low Dose Total Body Irradiation Following Six Bi-Weekly RCHOP-14 Plus 2 Extra Rituximab in Elderly High risk Patients with Aggressive CD20+ Diffuse Large B-Cell Lymphoma (DLBCL).
Authors: Safwat Akmal , Specht Lena , Hansen Flemming , Hansen Mads , Jurlander Jesper , d’Amore Francesco 
Published: April 2020

Abstract
Background: To further improve the results achieved by adding Rituximab (R) and shortening chemotherapy interval in elderly patients, an effective but relatively non-toxic treatment modality is needed. We tested therefore the addition of low dose total body irradiation (LTBI) of 1,6 Gy given after chemo-immunotherapy.
Methods: A multicenter, phase II trial including patients &gt;60 yrs with stage II-IV, CD20-positive DLBCL was performed between 2003 and 2007. Patients received 6x R-CHOP-14 + 2x R alone followed by LTBI given as 2 courses of 4 daily fractions of 0,2 Gy separated by 2 weeks of rest. Radiotherapy to sites of bulky (&gt;7.5 cm) disease was given according to the local guidelines of the participating centres.
Results: Forty two patients were included. Observation time ranged from 3 to 47 months with median follow up of 24 months. The median age was 67 years; 62% had stage III or IV; 48% had B symptoms and 36% had bulky (&gt; 7.5 cm) disease; 50% had ECOG score ≥ 1; 76% had elevated LDH and 57% had IPI of &gt;2. Twenty four patients (57%) achieved a CR or CRu at the end of chemotherapy, while 12 (28.5%) were in PR. One of the 12 PR patients refused LTBI. Of the remaining 11 PR patients who received LTBI, 8 (82%) achieved CR in the first follow up after LTBI while the remaining 3 patients had initially stable disease but progressed shortly after. One patient (2%) progressed under chemotherapy while seven patients (17%) relapsed after achieving CR. Six of these refractory/relapsed cases presented with IPI ≥ 3. The 3-yr event-free and progression-free survival values were 64.8% (SE: 8.7%) and 73.5% (SE: 8.9%), respectively, while the 3-yr overall survival was 85.4% (SE: 5.5%). There were 3 toxic deaths (7.1%) due to sepsis occurring during chemotherapy. Ninteen of 235 cycles of CHOP (8%) were given at reduced dose levels in 3 patients (7%), while 3 cycles (1.3%) were delayed but given at 100% dose level. None of the 305 injections of Rituximab were dose reduced. Only one of 31 patients (3%) got his second LTBI cycle at 75% of the planned dose because of thrombocytopenia. CTC Gr 3–4 neutropenia occurred following 50 of 250 R-CHOP-14 cycles (20%). CTC Gr. 3–4 thrombocytopenia was seen in 8 pts (22%) following LTBI.
Conclusions: Despite the high risk profile of the patient cohort enrolled in this trial, the 3-yr outcome values match the results of the best performing recent phase III clinical trials designed for elderly patients with DLBCL. Adding LTBI to 6 cycles of R-CHOP-14 was well tolerated and effective in converting the majority of PRs into CRs. Therefore, it may provide survival benefit and should be tested in a randomised setting.
The Pattern of KIR Ligands in Adult Patients with AML Is Associated with Various Post-Transplant Complications, Including GvHD after HLA-Matched Sibling or Unrelated Donor Transplantation
Authors: Kim Heeje , Min Woo-Sung , Cho Byung-Sik , Kim Yoo-Jin , Lee Seok , Min Chang-Ki , Cho Seok-Goo , Lee Jung-Lim , Lee Jong-Wook , Kim Chun-Choo 
Published: April 2020

Abstract
The function of natural killer (NK) cells in allogeneic stem cell transplantation (allo-SCT) is known. HLA-Cw is predominantly involved in inhibiting and activating human NK cells. Many pilot studies have examined the treatment of high-risk AML patients in terms of killer cell immunoglobulin-like receptor (KIR) disparity. NK alloreactivity may be determined by KIR and their ligands. We evaluated 370 adult AML patients scheduled for allo-SCT from family or unrelated donors. All but 41 patients in this study were in first complete remission (CR), as assessed just before the elective SCT. The HLA data for each transplant pair and clinical outcome were analyzed to study the impact of KIR ligands, especially on graft-versus-host disease (GvHD). High-resolution HLA typing was performed in 185 cases and serological data were used for the others. SCT was from an unrelated donor in 113 patients. Interestingly, we found a predominant pattern of group 1 (C1 epitope) HLA-Cw antigen in Korean acute myelogenous leukemia (AML). Only 3% of the pairs studied were C2 homozygotes. Heterozygosity of HLA-Cw C1 or C2 in either donors or recipients was closely related to the development of acute GvHD (P=0.006) and a lower rate of relapse (P=0.015). As in previous studies, we found discrepant results between the ligand-ligand model and the receptor-ligand model in the context of GvHD directed by allogeneic NK cells. We suggest that KIR ligands in allo-SCT, even in HLA-matched siblings or unrelated donors, are unique and a stable parameter to be considered in association with various post-transplant complications. According to the HLA immunogenetic background, KIR ligands are responsible for GvHD. Further investigations with longer follow-up are needed to verify the role of KIR receptor-ligand balance.
Peptide Multimers for Binding of Factor VIII Inhibitors.
Authors: Kessel Christoph , Kreuz Wolfhart , Klich Katharina , Vorpahl Frank , Becker-Peters Karin , Dietrich Ursula , Klingebiel Thomas , Königs Christoph 
Published: April 2020

Abstract
Hemophilia A is an X-chromosome linked bleeding disorder resulting from the absence or nonfunctional expression of coagulation factor VIII (FVIII). About 30% of severe hemophiliacs develop neutralizing antibodies (inhibitors) to FVIII upon treatment with exogenous factor preparations. Specificity of these antibodies is often restricted to functional determinants in the A2 and C2 domain. Phage displayed random peptide libraries were screened with various plasma samples of high titer inhibitor patients and inhibitor specific peptide ligands were selected. In silco mapping of consensus amino acid motifs among peptides revealed conformational epitopes in A2 and C2. Selected ligands partially restored FVIII activity. Equimolar combination of these ligands enhanced blocking of inhibitors in autologous and heterologous patients’ plasma. Peptide ligands were fused to the C-terminal multimerization domain of the C4bp alpha-chain and expressed as multimers in 293T cells. Peptide multimers revealed improved binding of anti-FVIII IgG and prolonged in vitro half-life in comparison to single synthetic peptides. Selected peptide ligands were combined in heteromultimers by co-transfection of respective vectors, resulting in molecules binding both A2- and C2- specific IgG and blocking up to 100% of antibody binding to FVIII. Those molecules could provide a basis for the generation of novel peptide-based therapeutic approaches.