bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monoclonal Gammopathy of Undetermined Significance (MGUS): Predictors of Outcome and Recognition of an Evolving Type.
Authors: Rosiñol Laura , Bladé Joan , Cibeira Ma Teresa , Montoto Silvia , Esteve Jordi , Rozman Maria , Fililla Xabier , Montserrat Emili 
Published: October 2019

Abstract
MGUS occurs in up to 3% of persons older than 50 years and the probability of malignant evolution is 1% per year. The risk of progression from MGUS to a symptomatic monoclonal gammopathy has been investigated in a number of series. However, only the presenting features have been considered while the evolutive pattern during the first years of follow-up has not been taken into account. The aim of our study was to investigate the predictors of outcome considering both the initial features and the pattern of evolution of the M-protein size during the first three years in a large series of patients with MGUS with long follow-up. Three-hundred and fifty nine patients (160 M, 199 F; median age 66 yrs) diagnosed with MGUS at a single institution were included in the study. Patients who showed an inequivocal increase in their M-protein size at the serum electrophoresis during the first three years of follow-up were considered as evolving while the remainders were considered as non-evolving. In the overall series the median values for serum M-protein level and for the proportion of bone marrow plasma cells (BMPC) were 14.8 g/L and 4%, respectively. Three hundred an thirty patients had a non-evolving MGUS while 29 fulfilled the criteria for the evolving type. The M-protein size and the proportion of BMPC at diagnosis were similar in both types of MGUS. The IgG type was more frequent in the non-evolving (65% vs. 45%, p=0.005) whereas the IgA and IgM type were more frequent in the evolving type (55% vs. 32%, p=0.04). Overall, 32 patients developed malignant transformation after a median follow-up of 93 months. Fourteen of the 29 (48%) evolving patients developed symptomatic multiple myeloma while only 18 out of the 330 (5%) remaining patients with non-evolving MGUS progressed to a malignant condition. The progression rate at 10 and 20 years of follow-up for the evolving and the non-evolving types was 55% vs. 10% and 80% vs. 13%, respectively. No patient in the non-evolving type evolved to a malignant condition after the first 12 years of follow-up. The predictors for malignant transformation at the univariate analysis were: the type of MGUS (evolving vs. non-evolving, p<0.001), a proportion of BMPC higher than 5% (p=0.001), the immunoglobulin isotype (IgA vs. IgG, p=0.007) and the M-protein size greater than 15 g/L (p=0.05). At the multivariate analysis the features significantly associated to a higher risk of progression were: the evolving type (RR 12.1, p<0.001,), the IgA type (RR 2.9, p=0.006) and the M-protein concentration (RR 2.2, p=0.044).
Conclusions: The evolutive pattern of the serum M-protein during the first years of follow-up is the most important risk factor for progression in patients with MGUS.
Anti-Thymocyte Globulin (ATG) Induces Apoptosis in Myeloma Cells: A Basis for Myeloma Sero-Therapy?.
Authors: Ayuk Francis A. , Zander Axel R. , Kroeger Nicolaus 
Published: October 2019

Abstract
Allogeneic stem cell transplantation is a potentially curative therapy for patients with multiple myeloma. Polyclonal ATG is included in conditioning regimens to enhance engraftment and reduce the risk of severe graft-versus-host disease. Since ATG has been reported to induce depletion of T-, B- and dendritic cells, we sought to investigate its cytotoxic activity on myeloma cells. Complement-mediated and complement-independent activity of ATG-Fresenius was investigated on 4 myeloma cell lines (RPMI-8226, U266, KMS-12-BM and EJM) and bone marrow samples from 6 myeloma patients. Cytotoxicity was determined by staining with annexin V-FITC and 7AAD followed by flow cytometry. ATG at clinically relevant concentrations induced up to 100% and 85% complement-dependent killing of myeloma cell lines and primary myeloma samples respectively. In the absence of complement ATG still induced up to 50% and 80% apoptosis in myeloma cell lines and primary myeloma samples respectively. Preincubation of myeloma cells with a general caspase inhibitor (ZVAD-fmk) abrogated ATG-induced complement-independent cell death. Absorption assays indicate that ATG induced cytotoxicity is mediated by specific antibodies and antigens whose further elucidation may pave the way for antibody-based myeloma therapy.
BCR-ABL1 Disrupts SDF-1-Dependent Hematopoietic Cell Migration and Adhesion through the LFA-1 Integrin-Mediated Mechanism.
Authors: Chen Ying-Yu , Malik Mobeen , Tomkowicz Brian E. , Collman Ronald G. , Ptasznik Andrzej 
Published: October 2019

Abstract
Stromal-derived factor-1 (SDF-1) and its receptor, CXCR4, are essential for normal stem/progenitor cell movement, adherence, and retention within the bone marrow environment. Two mechanisms through which BCR-ABL1 are thought to disrupt CXCR4-mediated chemotactic responses have been described in leukemia:
the inhibition of CXCR4 expression (Geay et al. 2005, Cancer Res.) and intra-cellular signaling defects without modification of CXCR4 expression (Salgia et al. 1999, Blood; Ptasznik et al. 2002, J. Exp. Med.).
These opposing mechanisms suggest that the actual situation is more complex and that new signaling paradigms are needed. To address this, we studied the effects of BCR-ABL1 on SDF-1-dependent, integrin-mediated, migration and adhesion of hematopoietic precursors. Stimulation of BCR-ABL1(−) hematopoietic cells with SDF-1 showed reduced cell adherence to surfaces coated with ICAM-1 (a ligand for the LFA-1 integrin), which was associated with down-regulated expression of activation-dependent epitopes of the β2 integrin, LFA-1, on hematopoietic cells. Inhibition of Lyn expression with siRNA prevented the SDF-1-triggered down-regulation of LFA-1 and cell adherence, indicating that CXCR4 inhibited the function of LFA-1 through Lyn. Expression of BCR-ABL1 in these cells resulted in increased expression of activation-dependent epitopes of LFA-1 and prevented SDF-1-dependent regulatory effects on both LFA-1 affinity and ICAM-1 adherence. Also, expression of BCR-ABL1 prevented Lyn-mediated regulation of cell adhesion to ICAM-1 as well as Lyn-mediated regulation of LFA-1 affinity. These results indicate that BCR-ABL1 constitutively increases the affinity of the LFA-1 integrin to its ligand ICAM-1, locking the integrin into an “active” conformation. The net result is the loss of responsiveness of LFA-1 to SDF-1-induced ‘inside-out’ signaling involving CXCR4 and Lyn kinase. Because in our experiments BCR-ABL1 had no significant effect on the expression of CXCR4 in Mo7e cells, transfected with low and high amounts of p210-BCR-ABL, or in primary BCR-ABL(+) cells from CML blast crisis patients (n=3), we conclude that BCR-ABL1 inhibits CXCR4-triggered ‘inside-out’ integrin signaling rather than CXCR4 expression. Taken together, we propose that BCR-ABL1 disrupts the signaling link between the chemokine receptor, CXCR4 and the β2 integrin LFA-1 so as to inhibit normal SDF-1-mediated chemotaxis and adhesion in hematopoietic cells.
Gain-of-Function Mutations of GATA-2 in Acute Myeloid Transformation of Chronic Myeloid Leukemia.
Authors: Zhang Su-Jiang , Ma Li-Yuan , Huang Qiu-Hua , Li Guo , Gu Bai-Wei , Gao Xiao-Dong , Shi Jing-Yi , Wang Yue-Ying , Gao Li , Cai Xun , Ren Rui-Bao , Chen Zhu , Chen Sai-Juan 
Published: October 2019

Abstract
Acquisition of additional genetic and/or epigenetic abnormalities other than BCR/ABL fusion gene is believed to cause disease progression in chronic myeloid leukemia (CML) from chronic phase to blast phase. To gain insights into the underlying mechanisms, we screened DNA samples from CML patients during acute transformation for alterations in a number of transcription factor genes crucial to myeloid-lymphoid development. In 85 cases of CML blast transformation, we identified two new mutations in the coding region of GATA-2, a negative regulator of hematopoietic stem/progenitor cell differentiation. L359V within zinc finger domain (ZF) 2 of GATA-2 was found in 8 cases with myelo-monoblastic features, while an in-frame deletion of six amino acids (D341–346) across the border of ZF1 was detected in 1 patient at blast crisis with eosinophilia. Further studies showed that L359V not only increased transactivation activity, but also enhanced inhibitory effects on the major myelopoietic regulator PU.1. Consistent with the myelo-monoblastic features of CML patients with GATA-2 L359V mutant, transduction of GATA-2 L359V mutant into HL-60 cells or BCR/ABL-harboring mouse model disturbed myelo-monocytic differentiation/proliferation in vitro and in vivo, respectively. These data suggest that GATA-2 mutations may be involved in acute myeloid transformation in some CML patients.
The Plk-1 Inhibitor BI 2536 Counteracts Proliferation and Viability of CML Cells and Synergizes with Imatinib and Nilotinib (AMN107) in Producing Growth Inhibition.
Authors: Gleixner Karoline V. , Ferenc Veronika , Gruze Alexander , Kneidinger Michael , Baumgartner Christian , Mayerhofer Matthias , Pickl Winfried F. , Sillaber Christian , Valent Peter 
Published: October 2019

Abstract
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease in which BCR/ABL enhances growth and survival of leukemic cells. In most patients, the disease can be kept under control by the BCR/ABL tyrosine kinase inhibitor imatinib (STI571; Novartis Basel, Switzerland). However, resistance or intolerance against imatinib may occur during therapy. Therefore, current research is focusing on novel targets and targeted drugs in CML. Polo-like kinase 1 (Plk-1) is a serine/threonine kinase that plays an essential role in mitosis and is expressed in activated/phosphorylated form in various malignancies including acute myeloid leukemia (AML). BI 2536 (Boehringer Ingelheim GmbH, Germany) is a novel selective inhibitor of Plk-1, that is currently tested in AML-trials. In this study, we have evaluated expression and the potential role of Plk-1 as a novel target in CML cells. As assessed by PCR, Plk-1 mRNA was found to be expressed abundantly in primary CML cells and in the CML cell line K562, whereas normal peripheral blood cells did not express detectable levels of Plk-1 mRNA. The Plk-1 protein was detected in primary CML cells and K562 cells by immunocytochemistry. In consecutive experiments, we were able to show that CML cells display phosphorylated Plk-1. As assessed by 3H-thymidine-uptake experiments, BI 2536 was found to inhibit the proliferation of K562 cells in a dose-dependent manner (IC50 5–15 nM). Moreover, BI 2536 was found to inhibit the proliferation of both imatinib-naive (n=6) and imatinib-resistant (n=3) primary CML cells (IC50: 1–15 nM). The growth-inhibitory effect of BI 2536 on CML cells was found to be associated with mitotic arrest, a G2-M cell cycle arrest, and consecutive apoptosis. In normal bone marrow or peripheral blood mononuclear cells, neither mitotic cell arrest nor apoptosis were observed after exposure to BI 2536. In further experiments, primary CML cells were coincubated with BI 2536 plus imatinib or with BI 2536 plus nilotinib (AMN107; Novartis) at fixed ratio of drug concentrations. In these experiments, BI 2536 was found to synergize with both tyrosine kinase inhibitors in counteracting the proliferation of CML cells. In conclusion, our data show that Plk-1 is expressed in activated form in CML cells and plays a role in cell cycle progression and cell viability. Targeting Plk-1 with BI 2536 leads to mitotic arrest, growth inhibition, and apoptosis in imatinib-naive and imatinib-resistant leukemic cells. Moreover, BI 2536 synergizes with imatinib and nilotinib in counteracting the growth of neoplastic cells in CML. Targeting of Plk-1 may be a novel interesting pharmacologic approach to counteract growth of CML cells.
Reduced Incidence of Severe Acute GVHD in Patients Transplanted from Donors with IL23R (Arg381Gln) Gene Variant.
Authors: Elmaagacli Ahmet H. , Koldehoff Michael , Steckel Nina K. , Beelen Dietrich 
Published: October 2019

Abstract
Background. Recently, a gene polymorphism of the IL23R gene (Arg381Gln), which is a subunit of the receptor of the pro-inflammatory cytokine interleukin-23, was found to be strongly associated with Crohn’s disease (Duerr et al.Science 2006). The exchange of arginine with glutamine at position 381 of IL23R causes a blockade of the IL-23 signaling pathway, which confers strong protection against Crohn’s disease. Because IL-23 activity is participated in autoimmune diseases, we hypothesized that it might also be important in the development of GVHD reaction post allogeneic transplantation.
Methods .Here we evaluated 401 patients with their donors for the occurrence of the IL23R gene variant (Arg381Gln, 1142 G>A) by real-time PCR who underwent allogeneic transplantation.
Results. We analyzed the IL23 gene variant 1142 G>A in a cohort of 221 transplant recipients and their HLA-identical sibling donors and in a second cohort of 186 transplant recipients and their HLA- identical unrelated donors. A heterozygous Arg381Gln gene variant was found in 13,1% of patients and in 11,3% of donors. The donor’s IL-23R genotype was significantly associated with a reduced risk of severe acute GVHD in both cohorts for patients after transplant. Analysis of all 407 transplant recipients showed that IL-23R (1142G>A, Arg381Gln) genotype of the donor were associated with a decreased risk of grade II-IV acute GVHD (31.6% compared to 51.0%, p=0.02) and severe acute GVHD III or IV (3.91% compared 23.4%, p=0.003). Death in remission was significantly lower in patients transplanted from donors with variante of IL23-R (11.7% versus 27.7%, p=0.028), whereas overall survival or relapse rates were not influenced significantly by the IL-23R genotype. The multivariate analysis including factors which influence the occurrence of severe acute GVHD as disease stage, age of patients (>or <40 years, gender constellation of recipient and donor, graft source, HLA-status (HLA-identical versus non-identical), donor constellation (sibling versus unrelated) confirmed that the gene variant of IL23R at the donor site confers protection against the occurrence of acute GVHD grade II-IV or severe acute GVHD grade III-IV. The association of IL23R mutation to GVHD was stronger than NOD2 mutations.
Conclusions. The results presented here suggest that IL-23 signaling pathway may play an important role in development of acute GVHD after transplant. Blockade of IL-23 signaling could be a rational therapeutic strategy for GVHD.
Impact of Conditioning on the Outcome of Allografting in Myelofibrosis with Myeloid Metaplasia: Better Survival with Reduced Intensity Approach in Patients ≥50 Years.
Authors: Gupta Vikas , Kroger Nicolaus , Aschan Johan , Leber Brian , Dalley Christopher , Sabloff Mitchell , Lipton Jeffrey H. , Messner Hans , Xu Wei , Brune Mats 
Published: October 2019

Abstract
We analyzed the impact of intensity of conditioning therapy on the outcomes of allogeneic blood or marrow transplantation (BMT) in patients (pts) with myelofibrosis with myeloid metaplasia (MMM). The study included 46 consecutive patients treated at 7 transplant centers between 1998 and 2005. The indications for BMT were intermediate/high risk disease (n=41) or low risk disease with constitutional symptoms (n=5). Donors were matched sibling/family donor (n=25); mismatched family donor, 2; and unrelated, 19. Twenty-three pts received conventional myeloablative (MY) conditioning: Cy/TBI (n=22); Bu/Cy (n=1), and 23 received non-myeloablative (NMA) conditioning [fludarabine (Flu)/PO or IV Bu (n=16); Flu/TBI 200cGy (n=6); others(n=1)]. Median age at BMT of the MY and NMA group was 47 (31–60) and 54 (38–74) years, respectively. NMA group had a higher proportion of pts ≥50 years (74% vs 30%, p=0.003), a longer interval from diagnosis to BMT (p=0.05) and more transplants using blood stem cells (p=0.0002). At a median follow-up of 31 (1–89) months, 8 and 16 patients were alive in MY and NMA groups, respectively. The transplant related outcomes of the two groups are summarized in the table. Serial pre and post BMT bone marrow biopsy results were available in 24 patients. Median days to resolution of fibrosis were 167 and 363 in the MY and NMA groups (p=0.16). In a multivariate analysis, after adjusting for age the survival was better for pts ≥50 years treated with NMA approach (hazard ratio 2.98, 95% CI 1.09–8.12, p=0.03). In conclusion, both MY and NMA approaches have curative potential for pts with MMM. NMA approach is particularly promising in pts ≥50 years.
Table: Comparison of BMT related outcomes for MY and NMA conditioning for MMM Outcomes MY Group (95% C.I.) NMA Group (95% C.I.) P value Neutrophil engraftment (days) 21 (13–46) 18 (1–30) 0.01 Cumulative incidence of graft failure (primary and secondary) at 2-years % 30 (16–58) 23 (10–50) 0.51 Median number of hospital days (Day 0 to +100) 41 (26–85) 27 (8–58) 0.0006 Cumulative incidence of acute GvHD grade II–IV (%) 78 (62–98) 18 (7–45) 0.0002 Cumulative incidence of chronic GVHD at 2-years % 94 (79–100) 45 (27–74) 0.0009 Cumulative incidence of TRM at 2-years % 43 (27–70) 27 (14–55) 0.08 Progression free survival at 2-years % 48 (27–66) 64 (40–80) 0.11 Overall survival at 2-years % 57 (34–74) 68 (45–83) 0.08
A European Phase II Study (BIOV-111) of Clofarabine (Evoltra®) in Refractory and Relapsed Childhood Acute Lymphoblastic Leukemia: Final Results.
Authors: Kearns Pamela , Michel Gerard , Nelken Brigitte , Joel Simon , Al-Ghazaly Essam , Beishuizen Auke , Conter Valentino , Henze Gunter , Baruchel Andre , Saha Vaskar 
Published: October 2019

Abstract
The BIOV-111 study was a European multicentre phase II non-randomised, open-label study of the novel purine nucleoside analogue, clofarabine (Evoltra ®). The study recruited patients ≤ 21 years old at initial diagnosis with primary refractory or relapsed/refractory acute lymphoblastic leukemia (ALL). The dose of clofarabine was 52mg/m2 daily x 5 days, every 28–42 days. Patients were evaluable after one complete course. The primary endpoint was overall response rate (OR) defined as either a complete response (CR) or CR without platelet recovery (CRp). Pharmacokinetic parameters and molecular responses were assessed in a sub-group of cases. The study enrolled a total of 74 patients. 65 were evaluable for response. We report the final efficacy and safety data on these evaluable patients. In total 120 courses of clofarabine were administered to 65 patients from 25 centres. The median age was 10 yrs (range 0.5–23 yrs). The median number of prior treatments was 2 (range 1–5) and 22 patients (34%) had been previously transplanted. The OR was 26% (6 CR, 11 CRp). In addition 1 PR was observed. 11/18 (61%) responders had a prior transplant and 3 of these patients received a further transplant post clofarabine. Of the 7 patients proceeding to transplant post-clofarabine; 3 patients had achieved a CR and 4 achieved a CRp. The updated median duration of response and survival will be presented. The pharamockinetic analyses showed plasma clofarabine concentration did not correlate with treatment outcome, however the ratio of day2/day 1 end of infusion intracellular clofarabine triphosphate (cloTP) levels were higher in responding pts. Serious adverse events included febrile neutropenia 50.8%, hepatic events (raised bilirubin, raised ALT/AST) 6.2%, renal failure 6.2%, palmar-plantar erythrodysaesthesia 4.6% and bone pain 4.6%, seizures 7.7% and cardiac failure 1%. In conclusion, this study demonstrated that clofarabine can achieve significant, durable response rates in heavily pre-treated paediatric patients with relapsed/refractory ALL and intracellular cloTP accumulation may be predictive of response. The response rates in this study are consistent with a previous clofarabine study (CLO-212) in relapsed/refractory pediatric ALL, however in BIOV-111 a lower incidence of adverse events was observed, including hepatic and renal adverse events, possibly attributable to fewer prior treatments compared to CLO-212 (median 2 vs 3 respectively). The reported episodes of seizure and cardiac failure were associated with pre-existing co-morbidities and/or sepsis in the majority of cases. The safety profile of clofarabine was manageable and acceptable and does not preclude subsequent HSCT.
Nasal Epithelial Cells of Donor Origin after Allogeneic HCT.
Authors: Khan Faisal , Lee Robyn , Storek Jan 
Published: October 2019

Abstract
Allogeneic HCT leads to hematolymphatic chimeras. Multiple studies in recent years have reported that stem cells can differentiate into muscle, skin, liver, lung, neurons and epithelium of GI tract after HCT. These studies were performed on recipients of sex-mismatched HCT using XY FISH and are often subject to criticism as XY discrimination may lead to overestimation or underestimation of donor cells due to reasons ranging from fetomaternal chimerism; male blood transfusions and loss of Y chromosome. Moreover, most recipients in these studies were ≤ 1 year post HCT. In the present investigation we determined whether donor epithelial nasal cells can be detected in patients ≥ 5 years post HCT. To avoid above limitations, we used the combination of immunocytochemistry, Laser capture microscopy (LCM) and STR based automated DNA fragment analysis for chimerism quantitation. We collected nasal scrapings and whole blood from 12 allo-HCT survivors (5–22 yrs after HCT; median = 10 yrs). Nasal cells were cytospinned; stained with cytokeratin (CK) and CD45 antibodies and true epithelial cells (CK+CD45−) were laser captured. DNA extracted from the captured cells and blood leukocytes was PCR amplified for a panel of 16 STR markers (ABI-Identifiler™). Genescan analysis of the amplicons was done to quantify chimerism. In all 12 recipients, epithelial cells of donor origin were identified accounting for 3.8% to 12.20% (mean = 7.25%) of the nasal epithelial cells. In conclusion, even with a method obviating the artifacts of XY based differentiation; donor origin epithelial cells were identified. We cannot conclude, whether these cells originate from
hematopoietic stem cells, or epithelial cell precursors transferred with the graft, or recipient epithelial cell fused with donor hematolymphatic cells.
However, as we found only up to 12.20% donor epithelial cells at 5–22 yrs post HCT, it is likely that none of the three mechanisms contribute to the generation of epithelial cells significantly.