bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neither Serum Ferritin Nor Number of Red Blood Cell Transfusions Affect Overall Survival in Refractory Anemia with Ringed Sideroblasts.
Authors: Chee Cheng E. , Steensma David P. , Hanson Curtis A. , Tefferi Ayalew 
Published: April 2020

Abstract
Background: Most experts agree that iron chelation therapy is unlikely to benefit myelodysplastic syndrome (MDS) patients with a bone marrow (BM) blast percentage of ≥ 5% because of the associated short life expectancy. In contrast, using a serum ferritin of 1,000 ng/mL as a surrogate for iron overload, a recent study suggested a negative impact of iron overload on overall survival in MDS patients with &lt; 5% BM blasts including those with refractory anemia with ringed sideroblasts (RARS) (Malcovati et al. JCO2005:23:7594). In the current retrospective study, we examined the validity of this observation in a large group of RARS patients seen at a single institution.
Methods: The diagnosis of RARS was based on the French-American-British cooperative group criteria. Serum ferritin levels obtained both at diagnosis and during follow-up as well as total number of packed red blood cells transfused were recorded. Standard statistical methods were used for survival and other analyses.
Results: A total of 126 RARS patients (median age 73 years, range 44-90; 67% males) were seen at our institution over the last several years. At diagnosis, median (range) values were 9.4 g/dL (5.7-13.4) for hemoglobin (Hgb), 2.8 × 109/L (0.3-13.7) for absolute neutrophil count (ANC) and 214× 109/L (22-819) for platelet count; 38% of the patients had received red blood cell (RBC) transfusions at the time of initial diagnosis. International Prognostic Scoring System (IPSS) risk distributions in evaluable patients were 66% for low, 28% for intermediate-1 and 6% for intermediate-2 risk. Median follow-up was 36 months and during this time 83 patients (66%) had died and leukemic transformation was documented antemortem in 8 patients (6%). As expected, IPSS was highly predictive of survival outcome (p&lt;0.0001). In addition, history of RBC transfusions at diagnosis (p=0.001) but not the total number of RBC transfusions received during the entire disease course (p=0.17) carried an independent prognostic value for inferior survival. There were no significant correlations between overall survival and serum ferritin level at either diagnosis (median 567 ng/mL, range 16-3,475; p=0.24) or the maximum value during follow-up (median 1,108 ng/mL; range 238-43,500; p=0.72). Similarly, Kaplan-Meier plots of 77 evaluable patients stratified by serum ferritin levels of &lt; or ≥1000 ng/mL at diagnosis or 107 evaluable patients stratified by maximal serum ferritin levels of &lt; 1000, 1000-5000, or &gt; 5000 ng/mL during follow-up revealed similar curves (Figure).
Conclusions: The current study suggests no significant association between transfusional hemosiderosis and survival even in good risk patients with MDS. The study also undermines the utility of serum ferritin as a surrogate for assessing the value of therapeutic iron chelation.
Figure Figure Figure Figure
Monoclonal Gammopathy of Undetermined Significance: Estimated Incidence and Duration Prior to Recognition.
Authors: Kyle Robert A. , Therneau Terry M. , Melton Lee J. , Dispenzieri Angela , Larson Dirk R. , Benson Joanne T. , Katzmann Jerry A. , Rajkumar S. Vincent 
Published: April 2020

Abstract
Background: Monoclonal gammopathy of undetermined significance (MGUS) is defined by a monoclonal protein concentration in serum of 3 g/dL or less and a proportion of plasma cells in the bone marrow of 10% or less, absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the proliferation of the monoclonal plasma cells. Two major questions remain unanswered:
What proportion of patients with MGUS in the population is unrecognized clinically? What is the likely duration of MGUS at the time of its discovery?
Methods: We examined the serum of 21,463 (77%) of the 28,038 enumerated residents of Olmsted County, Minnesota, in a population-based screening study and found that MGUS was present in 1.3% of persons 50 years of age and 3.8% of those 70 years of age. The risk of progression of MGUS to multiple myeloma (MM), primary amyloidosis (AL), Waldenstrom’s macroglobulinemia (WM), or related plasma cell disorders was 1% per year.
Results: By age 70, only 21% of Olmsted County residents with MGUS, as determined by the prevalence study, had been recognized by routine clinical practice (Fig. 1). This is probably higher in Olmsted County than elsewhere because serum protein electrophoresis is frequently ordered on Mayo Clinic patients. The incidence of MGUS, estimated from the prevalence data, indicates onset of the condition long before clinical recognition. The duration of MGUS prior to detection at age 70 is shown in Fig. 2. Thus, 30% of patients recognized to have MGUS at age 70 probably had MGUS onset before age 50 and 55% had a prior (unrecognized) MGUS already by age 60. The median duration of MGUS prior to its recognition on the basis of clinical practice is 11 years (median). Linear extrapolation of the incidence curve implies a first appearance of MGUS around 30 years of age.
Figure 1 Figure 1 Figure 2 Figure 2
MicroRNA Expression Analysis in Multiple Myeloma Plasma Cells and Cell Lines by a Quantitative Real-Time PCR Approach.
Authors: Bakkus Marleen , Dujardin Sylvie , Van Riet Ivan , De Waele Marc 
Published: April 2020

Abstract
MicroRNAs (miRNAs) are small RNA molecules that negatively regulate gene expression at the post transcriptional level. Over the past few years, these miRNAs have been shown to be widely involved in diverse biological processes, like apoptosis, cell metabolism and cancer. The aim of this study was to compare the miRNA expression in multiple myeloma plasma cells to that in their normal counterparts. A subset of ten miRNAs was chosen based upon evidence in the literature for their role in tumorigenesis with special emphasis on B cell malignancies. The expression of mature miRNAs was examined with quantitative real-time reverse transcription based polymerase chain reaction (TaqMan®MicroRNA assay) in 7 human multiple myeloma (MM) cell lines, in purified bone marrow derived plasma cells from 4 MM patients, one MGUS patient and 3 healthy adults. The plasma cells from patients and controls were positively selected using CD138-coated microbeads. Our results showed that miR-15a and miR-21 were equally expressed in cell lines, patients and healthy controls. Therefore, these 2 miRNAs were used for normalization. All data were compared with the data derived from normal plasma cells. Higher expression was seen for let-7a, miR-16 and 2 members of the miR-17 cluster (miR-17-5p and miR-19b) both in MM patients and cell lines. Expression of miR-16 was much higher in the MM plasma cells than in the MGUS plasma cells (only one sample). The miR-181a showed a heterogeneous expression in cell lines but was normally expressed in patients. The miR-372 expression was below the level of accurate quantification in all samples. There was a dramatic difference between the stroma dependent (MM5.1) and the stroma independent cell line (MM5.2) in miR-155 expression. The miR-143 was less abundant in all cell lines and in one MM sample that contained more than 90% plasma cells. Interestingly, the MM5.2 cell line, which is stroma independent, reflecting a more aggressive MM stage, showed also a much lower expression for miR-143 than the stroma dependent counterpart (MM5.1). In summary, the results of this study show that there is a difference in miRNA expression between MM plasma cells and their healthy counterparts and also between more and less aggressive MM plasma cells, suggesting that miRNAs could play a role in disease onset and progression.
Dexamethasone Induced Apoptotic Mechanisms in Myeloma Cells by Analysis of Mutant Glucocorticoid Receptors.
Authors: Sharma Sanjai , Lichtenstein Alan 
Published: April 2020

Abstract
Although glucocorticoids (GC) like dexamethasone (dex) are very effective in Multiple myeloma (MM), it is still unknown how they induce MM cell apoptosis. To investigate this issue, we studied the MM1S and MM1R cell lines. The MM1S cells are sensitive to dex-mediated apoptosis, while the MM1R cells are resistant due to lack of expression of the glucocorticoid receptor (GR). The latter resistant cells were exploited by the stable lentiviral-mediated expression of wild type (wt) or mutant GRs. Initial experiments demonstrated that infection of the MM1R cells with wt GR lentiviral vector resulted in stable expression of the wt GR and GC-induced reporter expression through the GR response element (GRE). These infected cells were now sensitive to GC-mediated apoptosis, although slightly less than MM1S cells. Nevertheless, this indicated that GR expressing MM1R cells could be used as a model to study the effectors of dex mediated apoptosis. MM1R cells were also similarly infected with lentiviral vectors expressing four different mutant GRs, that are either deficient in mediating GC-induced transactivation through the GRE or deficient in the ability to transrepress NF-KB activity. A GR mutant that transactivated through the GRE but was deficient in NF-KB transrepression did not induce apoptosis indicating that GRE transactivation was not sufficient for apoptosis. Further support for this notion was found when MM1S cells were treated with a concentration of cycloheximide which prevented GRE reporter expression but did not induce apoptosis by itself. This concentration did not affect GC-induced apoptosis supporting the finding that GC-induced transactivation is not required for apoptosis. In contrast, there was a correlation between the ability of mutant GRs to transrepress NF-KB and induce apoptosis. To test if GC-induced transactivation could participate in apoptosis in the setting of NF-KB transrepression, MM1R cells expressing a mutant GR which activates through GRE but does not transrepress NF-KB and is deficient in GC-induced apoptosis was infected with an adenoviral vector expressing the IKB super repressor to inhibit NF-KB. With abrogation of NF-KB, these cells underwent apoptosis at a higher level as compared to infection with a control adenoviral vector. Also, the addition of dex to these cells expressing IKB super repressor significantly enhanced apoptosis suggesting that transactivation through GRE can participate in apoptosis if the NF-KB survival factor is paralyzed.
IL-6-Induced C-MYC Down-Regulates the Expression of CD33 in CD33(+) Myeloma Cell Lines.
Authors: Shamsasenjan Karim , Otsuyama Ken-ichiro , Iqbal Mohd S. , Abroun Saeid , Amin Jakia , Islam Abul , Kawano Michio M. 
Published: April 2020

Abstract
Since human myeloma cells specifically lose the expression of PAX-5 gene, the master gene of B cell lineage, we frequently detect the ectopic expressions of non-B cell lineage markers such as CD56 and CD33. As for the expression of CD33, we confirmed that CD33 expression was found in primary myeloma cells from about 12% of 120 cases with overt myeloma and also in 2 myeloma cell lines (ILKM8 and Liu01 (a subclone of U266)) in the protein and mRNA levels. In primary myeloma cells as well as CD33(–) myeloma cell lines, DMSO treatment could induce the expression of CD33 in the in vitro culture. In these CD33(+) myeloma cell lines and DMSO-induced myeloma cells, we found that expressions of C/EBPα and PU.1 were markedly increased by gene expression profiling. On the other hand, IL-6 down-regulated the expression of CD33 in CD33(+) myeloma cell lines accompanying with down-regulation of C/EBPα and PU.1 expressions. Also, we found that IL-6 up-regulated the expression of C-MYC and the increased C-MYC bound to the promoter region of C/EBPα gene followed by the down-regulation of C/EBPα expression. It was confirmed that introduction of sh-RNA for C-MYC to two CD33(+) myeloma cell lines blocked the IL-6-induced down-regulation of CD33 and C/EBPα expression. Therefore, these results indicate that IL-6 can reverse the ectopic expression of non-B cell lineage markers by up-regulating C-MYC followed by its down-regulation of C/EBPα expression and also suggest that constitutive activation of STAT3 by IL-6 may keep PAX-5(–) myeloma cells being uncommitted cells to any lineage; myeloma cells could be one of stem cell-like cancer cells.
Phase 1/2 Study of AMG 531 in Thrombocytopenic Patients (pts) with Low-Risk Myelodysplastic Syndrome (MDS): Update Including Extended Treatment.
Authors: Kantarjian Hagop , Fenaux Pierre , Sekeres Mikkael A. , Becker Pamela , Boruchov Adam , Bowen David , Larson Richard , Lyons Roger , Muus Petra , Shammo Jamile , Ehrman Michael , Hu Kuolung , Nichol Janet 
Published: April 2020

Abstract
Background: AMG 531 is a novel thrombopoiesis-stimulating peptibody that is being studied for its ability to increase platelet production by stimulating the thrombopoietin receptor. This report updates outcomes in Part A of the study as of May 2007 on pts who continued into the extension phase of this ongoing phase 1/2, open-label, sequential-cohort, dose-escalation study to evaluate the safety and efficacy of AMG 531 in low risk MDS pts with severe thrombocytopenia (Kantarjian et al., ASCO, 2007).
Methods: Pts with low- risk MDS (IPSS Low or Intermediate-1, excluding CMML), a mean baseline platelet count ≤50×109/L, and only receiving supportive care were eligible to enter this study. Pts were enrolled into sequential cohorts of 300, 700, 1000, and 1500μg, receiving 3 weekly subcutaneous injections of AMG 531. After evaluation of platelet response at week 4, pts could continue AMG 531 in an optional treatment extension at their assigned dose or dose adjust to achieve or maintain a response.
Results: The mean duration of exposure to AMG 531 was 23±15.5 (SD) weeks. Of 44 pts enrolled, 40 continued into the extension phase; 16 pts remain on treatment. Eighteen pts (41%) achieved a durable platelet response (per IWG 2006 criteria for at least 8 consecutive weeks). Evaluation of durable responses based on baseline platelet count showed that responses occurred in 12/29 (41%) pts with a baseline count of ≥20×109/L, and in 6/15 (40%) pts with a baseline count of &lt;20×109/L. The mean duration of the platelet response was 22.8±13.3 (SD) weeks. A total of 104 platelet transfusions were given to 17/44 (39%) pts during this study; of these transfusions, 7 were given in 3/18 (17%) pts who achieved a durable response. Treatment-related AEs were reported in 17 pts. There were 3 deaths unrelated to treatment. Two confirmed cases of transformation to AML were reported. These two pts received maximum doses of 300 and 1000μg. Six pts were confirmed to have temporary blast cell increases, three of whom had increases above 20%. Of the 6, 4 were receiving 1500μg and 2 were receiving 1000μg. In all 6 pts, blast cell counts were observed to have fallen upon follow-up assessments within 7 weeks after treatment discontinuation. In one case, treatment was reinitiated at 700μg.
Conclusions: In this study, AMG 531 appeared to be well-tolerated in severely thrombocytopenic low-risk MDS pts, and resulted in increased and sustained platelet counts in the responding pts. AMG 531 may have a role in the treatment of low-risk MDS pts who are thrombocytopenic or have a history of bleeding. These data suggest that further exploration is merited in this pt population. Pt recruitment is ongoing until reaching the planned 84 pts.
Allogeneic Stem Cell Transplantation for Therapy-Related Myelodysplastic Syndrome (t-MDS) and Acute Myeloid Leukemia. A Report from the MDS Subcommittee of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).
Authors: Kroeger Nicolaus , Brand Ronald , van Biezen Anja , Niederwieser Dietger , de Witte Theo 
Published: April 2020

Abstract
Background: With the prolonged survival and increasing cure rate for some malignancies there appears to be an increasing incidence of therapy related MDS or AML.
Methods: Between 1981 and 2006, 486 patients (pts) with t-MDS or t-AML underwent allogeneic stem cell transplantation (SCT) and were reported to the EBMT registry. The median age of the pts was 40 years (r., 3–69) and primary disease were solid tumor (n=167), malignant lymphoma (n=141), myeloproliferative syndrome (n=12), acute leukaemia (n=32), aplastic anemia (n=16) and autoimmune disease (n=1). The median time from primary diagnosis to t-MDS/t-AML was 54 months (r., 1–416). Diagnosis were: RA/RARS (n=28), RAEB (n=49), RAEB-T (n=44) and t-AML (n=308). At time of transplantation, 268 pts were in complete and 186 pts not in complete remission (CR). Cytogenetic abnormalities were found in 262 pts.
Results: For the entire study population the cumulative incidence of non-relapse mortality (NRM) and relapse at 3 years was 37% and 34%. In a multivariate analysis significant factors for higher incidence of relapse were “non CR” at SCT (HR:2.20; 95% CI: 1.44–3.36, p&lt;0.001) and abnormal cytogenetic (HR: 1.78; 95% CI: 1.03–3.07; p=0.04), while higher NRM was noted for higher pts age: 40–50 years (HR: 2.25; 95%CI: 1.46–3.46, p&lt;0.001) and older than 50 years (HR: 2.67; 95% CI: 1.68–4.25, p&lt;0.001). Furthermore, there was a marked reduction in NRM per calendar year during the study period (HR: 0.93; 95% CI: 0.90–0.96, p&lt;0.001). The 3 year event-free (EFS) and overall survival (OS) was 31% and 34%. In a multivariate analysis EFS was negatively influenced by higher age: 40–50 years (HR: 1.91; 95% CI: 1.39–2.61, p&lt;0.001) and age &gt; 50 years (HR: 1.95; 95% CI: 1.36–2.78, p&lt;0.001), abnormal cytogenetic (HR: 1.41; 95% CI: 1.01–1.99; p=0.05), “non CR” at SCT (HR: 1.78; 95% CI 1.34–2.36; p&lt;0.001) and disease status RAEB-T (HR:2.23; 95% CI: 1.20–4.13; p=0.01) and t-AML (HR: 2.00; 95% CI; 1.13–3.52, p=0.02). A significant higher EFS and OS was seen per calendar year (HR: 0.96:; 95% CI: 0.94–0.98, p=0.004) and (HR: 0.95:; 95% CI: 0.93–0.98, p=0.001). OS was further influenced by higher age: 40–50 years (HR: 1.93; 95%CI: 1.61–2.68, p&lt;0.001) and age &gt; 50 years (HR: 2.13; 95% CI: 1.47–3.08, p&lt;0.001), “non CR” at SCT (HR: 1.57; 95% CI 1.18–2.09; p&lt;0.001) and disease status RAEB-T (HR:2.44; 95% CI: 1.27–4.66; p=0.007) and t-AML (HR: 2.26; 95% CI; 1.19–3.92, p=0.02).
Conclusion: Allogeneic SCT can cure pts with therapy related MDS or AML. During study period a better EFS and OS could be seen per calendar year due to a marked reduction in non-relapse mortality. Advanced disease-status, abnormal cytogenetics and higher age of the pts are the most significant factors for survival.
Inhibition of Hsp90 Targets Multiple Myeloma Cell Growth, Angiogenesis, and Osteoclastogenesis in the BM Microenvironment.
Authors: Okawa Yutaka , Hideshima Teru , Ikeda Hiroshi , Vallet Sonia , Kiziltepe Tanyel , Raje Noopur , Yasui Hiroshi , Enatsu Sotaro , Pozzi Samantha , Breitkreutz Iris , Podar Klaus , Richardson Paul G. , Anderson Kenneth C. 
Published: April 2020

Abstract
Heat-shock protein 90 (hsp90) is a important molecular chaperone required for protein folding, assembly, and maintenance of conformational integrity of several client proteins regulating cell survival, proliferation, and apoptosis. In this study, we investigate whether targeting hsp90 induces cytotoxicity of multiple myeloma (MM) cells in the bone marrow (BM) microenvironment using the small molecule hsp90 inhibitor SNX-2112. SNX-2112 induces growth inhibition in both MM cell lines and patient MM cells resistant to conventional therapeutic agents, with IC50 of 0.019-7.339 uM. Interestingly, SNX-2112 is more potent against all MM cell lines than 17-allylamino-17-demethoxy-geldanamycin (17-AAG) and orally bioavailable. These data suggest its potential utility to overcome conventional drug resistance in MM. MM cell apoptosis triggered by SNX-2112 is mediated via caspase-8,-9,-3 and PARP cleavage. In addition, SNX-2112 significantly inhibits Akt and extracellular signal-related kinase (ERK) signaling pathways induced by interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1), which mediate cell proliferation and survival in MM cells, both known client proteins of hsp90. Moreover, SNX-2112 overcomes the survival and growth advantages conferred by IL-6, IGF-1 and bone marrow stromal cells (BMSC). Importantly, SNX-2112 inhibits in vitro capillary-like tube formation by human umbilical vein endothelial cells (HUVEC) via abrogation of endothelial nitric oxide (eNOS)/Akt pathway which is essential cascade in angiogenesis. It also markedly inhibits osteoclast formation associated with downregulation of ERK/c-fos, p38MAPK, and PU.1 pathways, which mediate osteoclastogenesis. Furthermore SNX-5422, a prodrug of SNX-2112, significantly inhibits MM tumor growth and prolongs survival in vivo in a xenograft murine model. We also confirm that SNX-5422 triggers MM cell apoptosis in vivo by TUNEL assay, associated with an inhibitory effect on microvessel density (MVD), evidenced by immunohistochemical analysis for CD34 expression. Therefore, targeting hsp90 by novel small molecule inhibitor SNX-2112 not only inhibits MM cell growth, but also acts in the BM microenvironment to block angiogenesis and osteoclast formation associated with downregulation of Akt and ERK signaling. Taken together, our data provide the preclinical rationale for clinical evaluation of SNX-2112 to improve patient outcome in MM.