bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Transfusion-Dependency on the Outcome of Patients with Myelodysplastic Syndromes (MDS) Receiving Allogeneic Peripheral Blood Stem Cell Transplantation after Myeloablative Conditioning.
Authors: Platzbecker Uwe , Germing Ulrich , Stumpf Julian , Kröger Nikolaus , Böhm Anne , Valent Peter , Schwerdtfeger Rainer , Krieger Otto , Kobbe Guido , Ehninger Gerhard , Bornhäuser Martin
Published: April 2020

Introduction: The majority of MDS patients become red blood cell transfusion-dependent during their clinical course. In fact, the presence or absence as well the extent of red blood cell transfusion-dependency (RBC-TD) has been recently shown to add significant prognostic information for an individual MDS patient treated with supportive care (BSC) only. Given the fact that allogeneic hematopoietic cell transplantation (HCT) is the only curative option for MDS patients, the aim of this study was to elucidate the role of RBC-TD on patient outcome.

Methods: We report results of a retrospective multicenter German-Austrian study investigating 100 patients with MDS (RA(RS) n=33, RAEB n=33, RAEB-t n=19, CMMOL n=11, MDS/AML n=4) with either IPPS LOW (n=2), INT-1 (n=31), INT-2 (n=37) or HIGH (n=30) undergoing allogeneic myeloablative conditioning followed by peripheral blood stem cells (PBSC) from related (n=39) or unrelated donors (n=61). The median age of the patients was 50 years (range 18–68).

Results: With a median follow-up of 32 months the 2-year overall survival (OS) was 48% for all patients and 64%, 50% and 34% for patients according to IPSS INT-1, INT-2 or HIGH, respectively (p=0.03 for INT-1 vs. HIGH). The 2-year OS of all patients was not different when comparing 68 patients displaying vs. 24 not displaying RBC-TD prior to PBSCT (46% vs. 55%, p=0.67). This holds also true when analyzing INT-1/INT-2 (n=62) as well as HIGH (n=27) patients separately. In a multivariate analysis only FAB classification (p=0.03) but not prior induction chemotherapy (n=18), presence of fibrosis (n=18), IPSS LOW/INT-1 vs. INT-2/HIGH, RBC-TD as well as ferritin level lower or above the median 973 μg/l (range 19–7000) had an impact on OS.

Conclusion: These data suggest that the negative prognostic impact of RBC-TD in MDS patients receiving BSC can be overcome by myeloablative allogeneic PBSCT.
Methylation Profiles of p16, p15 and p14 Genes in Korean Patients with Multiple Myeloma.
Authors: Kang Seong-Ho , Lee Dong Soon , Kim Tae Young , Min Hyun Jung , Oh Bo Ra , Cho Han-Ik , Yoon Sung-Soo ,   the Korean Multiple Myeloma Working Party
Published: April 2020

Dysruption of cell cycle control genes (p16, p15 and p14) is known to be involved in the tumorigenesis of multiple myeloma (MM). We investigated the inactivation status of p16, p15 and p14 genes using promoter methylation study and fluorescent in situ hybridization (FISH) study in patients with MM and analyzed the association of inactivation of those genes and clinical prognosis.MM Promoter methylation study of p16, p14 and p15 gene was done with newly diagnosed 52 patients with by bisulfite modification and methylation specific PCR. Two sets of primers were used for p16 methylation study and one set of primer was used for p15, p14 methylation study. Deletion of p16, p14 and p15 gene was detected by dual color FISH (Vysis, Downers GroveIL, USA). Overall survival was analyzed by Kaplan Meier Method and Cox’s proportional hazard model. Methylation of p16, p15 and p14 promotor was detected in 36/52 (69.2%), 15/52(28.8%) and 7/52 (13.5%) patients with MM, respectively. Methylation of any of p16, p15 or p14 promotor was observed in 44/52 (84.6%) of MM patients Deletion of p16, p15 and p14 was detected in only one of the patients with MM. Of note, in the cases (15/52, 28.8%) showing that in cases with two positive methylation specific PCR of the p16 promotor with two sets of primers, significant lower overall survival rate (p<0.036) were observed compared with only one positive methylation specific PCR. Heavy methylation of p16 protomor was a independent predictive variable for overall survival [Hazard Ratio, 3.74; 95% CI, 1.44–9.68, P = 0.007]. Other adverse prognostic factors by univariate analysis were old age (p=0.014), β2-microglobuline (p=0.026), high serum creatinine levels (≥2.0 mg/dL, p=0.014). More than 80% of MM patients showed the methylation of any of p16, p15 or p14 promotor, which suggest the potential applicability of hypomethlyating agents to MM. The promoter methylation of p16, p14 or p15 was a major contributor to the disruption of cell cycle regulation in MM, whereas both the deletion and/or the promoter methylation of p16, p14, and p15 contributed to the disruption of cell cycle regulation in ALL. In our study, methylation of two positive methylation specific PCR of the p16 promotor was an independent adverse prognostic factor in MM. We infer that quantitative methylation study for p16 promotor is helpful for the evaluation of prognosis.

Figure 1. Overall survival analysis of patients with according to p16 methylation amount (P = 0.036) Figure 1. Overall survival analysis of patients with according to p16 methylation amount (P = 0.036)
FIP1L1/PDGFRa Synergizes with SCF/c-Kit Signaling To Induce Systemic Mastocytosis in a Chronic Eosinophilic Leukemia Murine Model
Authors: Yamada Yoshiyuki , Cancelas Jose A. , Brandt Eric B. , Sanchez-Aguilera Abel , McBride Melissa , Al-Moamen Nabel J.H. , Finkelman Fred , Williams David A. , Rothenberg Marc E.
Published: April 2020

Systemic mastocytosis (SM) associated with chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES) is a result of expression of the Fip1-like1 (FIP1L1)/platelet-derived growth factor receptor alpha (PDGFRa) (F/P) fusion gene. We have previously described a murine CEL/HES model (CEL-like mice) induced by F/P fusion gene transduction and T-cell overexpression of IL-5 (Yamada Y et al., Blood 2006). We have now validated a preclinical murine model of F/P-induced SM/CEL and analyzed the pathogenesis of SM in this model. F/P+ mast cells (MC, defined as EGFP+/c-kit+/FceRI+) were significantly increased in the small intestine, bone marrow (BM) and spleen of CEL-like mice compared to wild-type mice (Table). CEL-like mice also developed cutaneous MC infiltration. In addition, mMCP-1 serum levels, which correlate well with MC expansion and activation in vivo, were significantly higher in CEL-like mice than in wild-type mice (64,000 ± 23,800 and 38 ± 41.4 pg/ml, respectively). F/P induces increased expansion of BM-derived MC in vitro (∼2,000-fold) and F/P+ BM-derived MC survive longer than wild-type MC in cytokine-deprived medium (28.0 ± 2.3% vs. 8.7 ± 3.1% 7AAD−/Annexin V− cells after 48 hours). This correlated with increased Akt phosphorylation in the F/P+ MC. Since c-kit mutations are the most frequent cause of SM, we analyzed the possible synergistic role of SCF and F/P signaling. F/P and SCF/c-kit signaling indeed synergize in the development of BM-derived MC (16-fold greater expansion than in the absence of SCF) and F/P+ BM-derived MC showed a 3.7-fold greater migratory response to SCF than wild-type BM-derived MC. In order to determine the role of SCF/c-kit signaling in F/P+ MC development, activation and tissue infiltration in vivo,these responses were evaluated in mice that were treated with a blocking anti-c-kit blocking antibody, ACK-2, or an isotype-matched control antibody. ACK-2 treatment suppressed intestinal MC infiltration and elevated plasma levels of mMCP-1 induced by F/P expression by 95 ± 6.0% and 98 ± 0.76%, respectively, whereas MC and plasma mMCP-1 were completely undetectable in wild-type mice treated with ACK2. This suggests that SCF/c-kit interactions may synergize with F/P to induce SM. In summary, mice with CEL-like disease also develop SM. F/P-induced SM is a result of increased in vivo MC proliferation, survival, activation and tissue infiltration. SCF/c-kit signaling synergizes with F/P in vivo and in vitro to promote mast cell development, activation and survival.

EGFP+/c-kit+/FcεRI+ cell frequency in tissues of control and CEL-like mice (%) Control mice CEL-like mice Small intestine 1.0±0.95 47±21.4* Bone marrow 0.2±0.14 3±1.9* Spleen 0.05±0.01 3±0.8*
Anti-Tumor Effect of INNO-406, a Novel Bcr-Abl Inhibitor in Combination with Cyclosporin A Against the Murine Central Nervous System and Systemic Leukemia Model.
Authors: Yokota Asumi , Kimura Shinya , Masuda Satohiro , Ashihara Eishi , Urasaki Yoshimasa , Terui Yasuhito , Ruthardt Martin , Ueda Takanori , Hatake Kiyohiko , Inui Ken-ichi , Maekawa Taira
Published: April 2020

Central nervous system (CNS) is one of the major cites for extramedullary relapse of Ph+ leukemias, which have been treated with imatinib mesylate (IM). The reason for this is that IM is a substrate for P-glycoprotein (P-gp) at the blood brain barrier and effluxed by it. We have already shown in the last annual meeting that INNO-406 had much stronger anti-tumor effects against the murine CNS leukemia model compared with IM, and INNO-406 is also effluxed from the murine CNS by P-gp. In this study, we investigated the combination effect of INNO-406 and P-gp inhibitors, verapamil or cyclosporin-A (CsA). First, we examined the growth-suppressive effect of INNO-406 and the combination with the P-gp inhibitors against the BCR-ABL positive leukemic cell line, K562 and the P-gp-overexpressing K562, K562/D1-9 cell line. K562/D1-9 showed 10 times higher resistant to both IM and INNO-406 compared with K562. Furthermore, both verapamil and CsA synergistically augmented the effect of INNO-406. Next, we investigated the pharmacokinetics of INNO-406 when orally administrated with CsA to mice. Mice were administrated p.o. with 50mg/kg of CsA 2 hours before INNO-406. We found that the concentration of INNO-406 in the CNS elevated by 2 times when combined with CsA, while the plasma concentration was decreased to two thirds of that when singly administrated with INNO-406. It was suggested that the decreased plasma concentration of INNO-406 seen here resulted from the increased uptake into the CNS by CsA inhibiting P-gp at the blood brain barrier. These changes of the drug distribution to the murine tissues may alter the anti-leukemic effect of INNO-406, thus we planned to investigate the combination effect of INNO-406 and CsA in the murine models of both CNS and systemic leukemia. We found that CsA significantly augmented the anti-tumor effect of INNO-406 in the CNS leukemia model. Moreover, in spite of the decreased plasma concentration of INNO-406, the combination with CsA also prolonged the survival phase of the mice in the systemic leukemia model, more significantly than single treatment of INNO-406 (Figure). This may be explained by which CsA increased the intracellular uptake of INNO-406, resulted from the direct inhibition of drug efflux via P-gp expressed in the leukemic cells. Phase I clinical study on INNO-406 is now underway in MD Anderson Cancer Center and in Frankfurt University. From the results of this study, we expected the effective application of INNO-406 in combination with P-gp inhibitor to the patients suffering from refractory Ph+ leukemia as well as CNS relapse.

Figure Figure