bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib Demonstrates Superior Efficacy to High-Dose Dexamethasone in Relapsed Multiple Myeloma: Final Report of the APEX Study.
Authors: Richardson Paul , Sonneveld P. , Schuster M. , Irwin D. , Stadtmauer E. , Facon T. , Harousseau J. , Ben-Yehuda D. , Lonial S. , Goldschmidt H. , Reece D. , Miguel J. San , Blade J. , Boccadoro M. , Cavenagh J. , Dalton W. , Boral A. , Schenkein D. , Anderson K. 
Published: October 2019

Abstract
Introduction/Methods: This international phase 3 study conducted at 93 sites is the largest randomized study to date in relapsed multiple myeloma (MM). Patients (pts) had to have received 1–3 prior therapies and those with dexamethasone (Dex) refractory disease were excluded. Pts were randomized to bortezomib (VELCADE®) 1.3 mg/m2 IV d 1, 4, 8, 11 q3wk for 8 cycles followed by 3 cycles on d 1, 8, 15, 22 q5wk, or Dex 40 mg PO d 1–4, 9–12, 17–20 q5wk for 4 cycles followed by 5 cycles on d 1–4 every 28 d. The 1° endpoint was time to progression (TTP); 2° endpoints included survival, response rate (CR+PR) using EBMT criteria, duration of response, time to response (TTR), time to skeletal events, infections ≥gr 3 and safety; exploratory endpoints included pharmacogenomics and quality of life. Pts with progressive disease on Dex were eligible to crossover to bortezomib in a companion study.
Results: 669 pts were randomized and baseline characteristics were balanced in both arms. Based on a median follow-up of 8.3 mo, bortezomib demonstrated a 78% improvement in median TTP (hazard ratio 0.55, P<0.0001) and a significant 1-y and overall survival benefit over Dex (hazard ratio 0.53, P=0.0005; hazard ratio 0.57, P=0.0013, respectively). The response rate (CR+PR) was significantly higher (P<0.0001) with CR/nCR rates of 13% for bortezomib vs 2% for Dex. 132 (40%) and 119 (35%) pts received bortezomib or Dex 2nd line, respectively. Importantly, in 2nd-line bortezomib vs Dex, median TTP was 7.0 v 5.6 mo, 1-y survival was 89% vs 72%, and CR+PR rate was 45% vs 26%, respectively. The incidence of ≥ gr 3 adverse events and the discontinuation rate were similar across treatments in all pts.
Conclusion: This is the first and largest randomized study demonstrating a survival advantage in relapsed MM, with single-agent bortezomib proving superior to Dex based on TTP, survival, and response. Superiority was also observed in 2nd line and later salvage therapy. The safety profiles of bortezomib and Dex were predictable and toxicities were manageable.
Efficacy Bortezomib Dex P (n=333) (n=336) NC = not calculated. Median TTP, mo 6.2 3.5 <0.0001 1 prior line 7.0 (n=132) 5.6 (n=119) 0.0021 > 1 prior line 4.9 (n=200) 2.9 (n=217) <0.0001 1-year survival, % 80 66 0.0005 1 prior line 89 72 0.0098 > 1 prior line 73 62 0.0109 CR, % (n/N) 6 (20/315) 1 (2/312) 0.0001 1 prior line 6 (8/128) 2 (2/110) 0.0842 > 1 prior line 6 (12/187) 0 (0/202) 0.0002 CR/PR, % (n/N) 38 (121/315) 18 (56/312) <0.0001 1 prior line 45 (57/128) 26 (29/110) 0.0035 > 1 prior line 34 (64/187) 13 (27/202) <0.0001 Median TTR (CR/PR), d 43 43 NC
Treatment with Pegylated Interferon α (PegIntron) for High-Risk Essential Thrombocythemia: Results of a Phase II Study.
Authors: Langer Christian , Lengfelder Eva , Thiele Jurgen , Kvasnika Hans M. , Pahl Heike , Matzdorff Axel , Stade Barbara , Schauer Stefanie , Gisslinger Heinz , Dohner Hartmut , Griesshammer Martin 
Published: October 2019

Abstract
In high risk Essential Thrombocythemia (ET) there is a indication for cytoreductive therapy. However, especially in younger patients long-term use of alkylating agents or hydroxyurea is a matter of concern. Modification of the pharmacokinetic profile of interferon α, a non-leukemogenic agent, through addition of a polyethylenglicol (pegylation) has resulted in slower absorption and lower elimination rate, thus enabling a weekly application with potentially increased compliance compared to conventional interferon α.
In this phase II study we evaluate the safety, tolerability and efficacy of pegylated Interferon α (PegIntron, Essex Pharma) in high risk essential thrombocythemia. PegIntron is administered subcutaneously at a starting dose of 50 μg weekly. In patients not achieving a platelet count < 500 G/l after 8–12 weeks, the dosages can be increased by 25 μg/week up to 150 μg/week. Between 12/01 and 09/03 a total of 36 high risk ET patients (either platelet > 1500 G/l, or age> 60 years, or previous ET related complications) were enrolled by a total of 16 centers (16 male and 20 female patients, median platelet count at diagnosis 900 G/l, median age at diagnosis 54 years [range: 24–72 years]). Treatment was indicated because of at least one of the following reasons: Age > 60 years (38%), platelet count > 1500 G/l (36%) or previous ET related complications (50%). 10 patients (28%) were previously treated (hydroxyurea: 8 patients, anagrelide: 2 patients).
In this analysis there are 35 of 36 patients evaluable, 1 patient was lost to follow-up. Of these 35 patients, 24 (69%) are still on therapy with PegIntron after a median observation time of 18 months. The individual dosages of PegIntron are shown in table 1. A platelet count < 500 G/l was achieved in 57% of the patients after 3 months and in 75% and 89% after 6 and 12 months, respectively.
In 9 patients (26%) therapy was stopped because of drug related side effects (alopecia: 2 patients, arthralgia: 2 patients, flu-like symptoms: 2 patients, psoriasis: 1 patient, depression: 1 patient, diarrhea: 1 patient). In one patient an alternative cytoreductive therapy was initiated because of an insufficient platelet control. One patient suffered from a cerebral stroke and subsequently was taken off PegIntron application. After a median observation time of 18 months, we observed one potentially ET related complication (stroke) during PegIntron therapy so far.
These preliminary data indicate the efficacy of PegIntron in the treatment of high risk ET at relatively low doses and reasonable toxicity and safety compared to conventional interferon α.
A New Model to Evaluate Signaling of Raf in Hematopoietic Cells.
Authors: Okuda Keiko , Sonoda Yoshiaki , Griffin James D. 
Published: October 2019

Abstract
The Raf/MEK/ERK pathway is thought to be critical in mediating cell survival and proliferation by cytokine receptors. However, the exact contribution of Raf is complex and not well understood. A better understanding of Raf signaling is important because of the recent observation that B-Raf is frequently mutated in various human cancers. We have generated a new model system that activates Raf directly by linking the extracytoplasmic and transmembrane domains of the erythropoietin receptor (EPOR) with the catalytic domain of Raf (CR3). This synthetic oncogene in which dimerization can be controlled by an exogenous ligand, is fixed at the cellular membrane, while the endogenous Raf is normally activated by binding with Ras. The chimeric receptor (EPOR/CR3) was stably expressed in Ba/F3 cells which lack EPO receptors, and eight independent sublines were established. Although the lines remained dependent on IL-3 for proliferation, EPO treatment reduced the rate of cell death in the absence of IL-3. Also, EPO was synergistic with sub-optimal concentrations of IL-3 in inducing long-term cell proliferation, but did not augment proliferation of cells cultured with full concentrations of IL-3. EPO induced a rapid activation of ERK and also phosphorylation of endogenous Raf. It also induced tyrosine phosphorylation of several cellular proteins, estimated molecular masses of 150, 130, 110, 95, 60 and 42 kD. Many of the prominent targets of the wild type IL-3 or EPO receptors, such as Shc, Stat1, Stat3 and Stat5 were not tyrosine phosphorylated by the EPOR/CR3 receptor. The MEK1 inhibitor PD98059 reduced EPO-induced tyrosine phosphorylation, suggesting these substrates are downstream of MEK kinase. Interestingly, PD98059 also reduced the phosphorylation of endogenous Raf, indicating there is a positive feedback mechanism in Raf activation. We conclude that Raf can be activated by a mechanism that induces clustering at the cell membrane, and that this leads directly to activation of MEK and ERK. This is insufficient to induce proliferation by itself, but can add to sub-optimal growth signals from another receptor. This EPOR/CR3 system may serve as a useful model to evaluate the effects of signal transduction inhibitors for Raf as a target.
COAT Platelet Formation Is P2Y12-Dependent.
Authors: Kempton Christine L. , Hoffman Maureane , Lenkowski Angie , Roberts Harold R. , Monroe Dougald M. 
Published: October 2019

Abstract
Inhibition of the platelet ADP receptor, P2Y12, has been shown to reduce thrombin-stimulated exposure of platelet phosphatidylserine and tissue factor (TF)-dependent thrombin generation in human platelet rich plasma (ATVB2003;23(10):1941–1947). Platelets stimulated by the combination of convulxin (Cvx) and thrombin develop two populations of platelets, one with low coagulation factor binding and a second with high levels of coagulation factor binding (Blood2000;95(5):1694–1702). Platelets in the population with increased coagulation factor binding have been termed COAT platelets. Previously we have demonstrated that the percentage of COAT platelets correlates with increased thrombin generation on Cvx plus thrombin-stimulated platelets compared to platelets stimulated with thrombin alone (Blood2003; 102(11): 293a). In this study we investigated whether inhibition of the platelet P2Y12 receptor reduced the development of the COAT platelets in addition to reducing thrombin generation.
METHOD: A well established cell-based model of hemostasis was used. Components included: LPS-stimulated monocytes expressing TF, coagulation factors (II, V, VII, VIII, IX, X, XI) at plasma concentrations, coagulation inhibitors (AT, TFPI) at plasma concentrations, platelets from normal donors, and calcium chloride. Thrombin generation in the system was measured by cleavage of a chromogenic substrate and compared to a standard curve. Model systems without the addition of Cvx (20 ng/ml) were compared to model system with the addition of Cvx with and without a 2-methylthiol AMP (2MeSAMP, an inhibitor of the P2Y12 receptor). To determine the percentage of COAT platelets formed, samples were removed at 9.5 minutes after the model system was initiated, fixed in 1% paraformaldehyde, and analyzed on FACScan flow cytometer for binding of factor V using a polyclonal primary and secondary.
RESULTS: In the absence of 2MeSAMP approximately 30% of Cvx plus thrombin-stimulated platelets were COAT platelets. In the presence of 2MeSAMP, none of the platelets were COAT platelets. 2MeSAMP led to a significant reduction in the peak and rate of thrombin generation in the presence of Cvx but no change in the total amount of thrombin generated as measure by the area under the curve.
CONCLUSIONS: Inhibition of the platelet P2Y12 receptor prevents COAT platelet formation. The absence of COAT platelet formation correlates with a reduction in both the rate of thrombin generation and the peak of thrombin generated. COAT platelet formation and up-regulated thrombin generation induced by the combination thrombin plus moderate concentrations of Cvx are P2Y12-dependent.
The Addition of Rituximab to Combination Chemotherapy with CHOP Has a Long Lasting Impact on Subsequent Treatment in Remission in Follicular Lymhoma but Not in Mantle Cell Lymphoma: Results of Two Prospective Randomized Studies of the German Low Grade Lymphoma Study Group (GLSG).
Authors: Hiddemann Wolfgang , Forstpointner Roswitha , Kneba Michael , Schmitz Norbert , Schmits Rudolf , Metzner Bernd , Reiser Marcel , Lengfelder Eva , Woermann Bernhard , Harder Hariett , Hegewisch-Becker Susanna , Berdel Wolfgang , Hess Georg , Eimermacher Hartmut , Aldaoud Ali , Planker Manfred , Parwaresch Reza , Dreyling Martin , Unterhalt Michael 
Published: October 2019

Abstract
The addition of Rituximab (R) to combination chemotherapy has been shown to increase the remission rate (RR) and to prolong the time to treatment failure (TTF) both in follicular lymphoma (FL) and mantle cell lymphoma (MCL). The impact of the R-chemo combination on subsequent therapy in remission, however, remains unclear. The GLSG embarked on two parallel studies in FL and MCL comprizing a prospective randomized comparison of R-CHOP versus CHOP alone followed by a second randomization in remission for Interferon alpha maintenance (IFN) versus myeloablative radio-chemotherapy with subsequent stem cell transplantation (PBCT) in patients < 60 yrs. of age while all older pts. received IFN maintenance. In 428 pts. with FL R-CHOP revealed a significantly higher RR (96% vs. 90%, p = 0.011) and a longer TTF (median not reached vs. 2.6 yrs, p<0.0001). From 347 patients evaluable for subsequent treatment in remission 79 younger patients (35 after CHOP and 44 after R-CHOP) received PBCT. 52 younger patients after CHOP and 69 after R-CHOP received IFN maintenance. 122 older cases received IFN (59 after CHOP and 63 after R-CHOP). For IFN treated pts. a significantly longer progression free survival (PFS) was observed after initial therapy with R-CHOP (estimated 2 yrs - PFS: 63% vs. 84%, p = 0.0004) while no differences were encountered at the time of this analysis after PBCT (estimated 2 yrs - PFS for the whole group: 86%). Hence, in FL initial therapy with R-CHOP appears to have a long lasting beneficial effect on PFS which may be in the range that has previously only been achieved by chemotherapy followed by PBCT. Similar to FL a significantly higher RR (94% vs. 75%, p = 0.005) and a longer TTF (median 14 months vs. 21 months, p = 0.0131) was observed in 122 pts. with MCL undergoing the same randomized comparison. In contrast to FL, however, no differences were revealed for the PFS after R-CHOP versus CHOP and subsequent therapy with IFN or PBCT. These data show a differential effect of adding R to CHOP for initial therapy in FL and MCL. In FL the addition of R to CHOP has a long lasting beneficial effect with a substantial impact on subsequent treatment in remission while in MCL the benefit of R seems restricted to the remission induction period only.
Mabthera (Rituximab) in the Treatment of 34 Adult Patients with Refractory Autoimmune Hemolytic Anemia (AIHA).
Authors: Cabrera JRafael , Penalver F. Javier , Millan Isabel , Alvarez-Larran Alberto , Diez-Martin Jose L. , Gallur Laura , Jarque Isidro ,   other 13 participants in the multicentric retrospective Spanish Study on use of Rituximab in refractory AIHA
Published: October 2019

Abstract
Objectives: Rituximab (RB) is an anti-CD20 murine/human chimeric antibody that has been used in the treatment of auto-immune diseases. RB has shown to be effective in childhood AIHA but data on adults are lacking. The effectiveness of RB in the treatment of adult patients with AIHA has been evaluated.
Patients and methods: A multicentric retrospective study of patients with AIHA treated with RB has been carried out. A questionnaire about clinical characteristics and response to RB was sent to the participating centers. These questionnaires were filled out by the physician in charge of each patient. We received questionnaires from 20 centers (34 patients). Response criteria were defined as follows: Complete Response (CR): Hb >10 g/dl or Hb increase >1.5 g/dl; Partial Response (PR): Hb > 9 g/dl or Hb increase of 1–1.5 g/dl. Median age was 64 years (20–86), 62% were women. 13 cases were idiopathic and the remaining 20 were associated with chronic lymphoproliferative syndromes (CLS) (14), connective tissue diseases (2), allogeneic hematopoietic stem cell transplantation (2), liver transplant (1), amiloidosis (1) and MGUS (1). In 6 cases the immune hemolysis was due to cold-reactive antibodies. Before RB they have received several treatment schemes, 12 patients were splenectomized and only 6 (17.6%) had not been transfused. Median Hb before the treatment with RB was 6.9 g/dl (3.3–12.7). 27 patients received 4 doses of RB (1–6), 24 received it in association with other treatments, mainly steroids.
Results: 19 patients obtained CR (63%) and 4 patients obtained PR (13%). In 50 % of the cases the Coombs antiglobulin test became negative. The majority of the responses took place in 3 weeks (1–8) and maximum responses in 10 weeks (1–35). 15 out of the 19 patients that obtained CR, reached it from the beginning of the response. 82% (9/11) of the patients with AIHA associated to CLS obtained CR, 58% (7/12) of the patients with idiopathic AIHA obtained CR and 17% (2/12) PR. 50% (3/6) of the patients with immuno-hemolytic anemia due to cold-reactive antibodies obtained CR. There were no differences in the response between splenectomized and not splenectomized patients. Median increase in Hb level was 5.9 g/dl (1.2–9.8) with a monitoring median of 8.7 months (1–48). There were no significant toxicities.
Conclusions: These results suggest that RB can be effective in the treatment of adult patients with AIHA, both idiopathic and associated with CLS, with a very low toxicity profile.
Manipulation and Visualization of the Erythroid Lineage - In Vivo Models for Erythroid Disorders.
Authors: Heinrich Achim C. , Pelanda Roberta , Klingmueller Ursula 
Published: October 2019

Abstract
Red blood cells have a short half-life and are continuously renewed in a tightly controlled growth process. Dysregulation of erythropoiesis results in erythroleukemias or more frequently in anemias. To elucidate molecular mechanisms regulating red cell production in an animal model, we generated a mouse line (ErGFPcre) that simultaneously facilitates erythroid specific gene manipulation via the CreloxP recombination system and visualization of erythroid progenitor cells. To avoid site of integration effects frequently observed for randomly integrated transgenes, we used a knock-in strategy targeting the genomic EpoR locus that ensures a reliable EpoR promoter controlled transgene expression of our GFPcre fusion protein.
The flow cytometric analysis of GFP fluorescence in different hematopoietic subpopulations of adult and embryonic ErGFPcre mice revealed a strictly erythroid-specific expression pattern for GFPcre. Further studies on GFP positive erythroid progenitor cells indicated a developmental switch in lineage progression from the hematopoietic stem cell compartment to early erythroid progenitor cells that are Sca-1 negative and c-kit high. To monitor previous and persistent GFPcre expression during development and to determine the efficiency of Cre-mediated recombination in our mouse model, we crossed the ErGFPcre mouse line with the LacZ reporter strain R26R. The spatial and temporal analysis of GFPcre-mediated LacZ expression confirmed that within the hematopoietic system GFPcre expression is limited to the erythroid lineage. Surprisingly, non-hematopoietic expression of GFPcre is restricted to the vascular system. It is possible that the observed differential transcriptional activity of the knock-in and the wild-type allele is linked to the absence of intron 2 to 7 in the knock-in locus. The quantitative analysis of the recombination frequency confirmed that GFPcre-mediated recombination is limited to erythroid progenitor cells and showed that it occurs in the adult bone marrow at a frequency of up to 80% and in the fetal liver with an efficiency close to 100%.
Thus, our ErGFPcre mouse model offers the possibility to study regulatory mechanisms in erythroid progenitor cells and facilitates the establishment of mouse models for erythroid disorders.
Comparison of Conventional Versus Lineage-Specific Chimerism Analysis for Detection of Minimal Residual Disease or Relapse in Myeloid Malignancies after Myeloablative Allogeneic Hematopoietic Cell Transplantation with Respect to Clinical Follow-Up.
Authors: Zeiser Robert , Spyridonidis Alexandros , Waesch Ralph , Ihorst Gabriele , Grullich Carsten , Hartmut Bertz , Jurgen Finke 
Published: October 2019

Abstract
In order to detect minimal residual disease (MRD) or relapse after allogeneic hematopoietic cell transplantation (aHCT) the immunophenotype of the original leukemic clone can be used for separation of distinct cell populations, expected to harbor malignant cells.
Since conventional (CCA) and lineage-specific (LCA) chimerism analysis as diagnostic means have potential pitfalls, the present study assesses the results of both methods, to determine how predictive the evaluations prior to a hematological relapse were with respect to the risk that the patient would develop a relapse during the course of his disease.
118 individuals with acute myeloid leukemia (n=98) and myelodysplastic syndrome (n=20), investigated with CCA and LCA, were evaluated with a median follow-up of 26.6 months (range: 8–47).
Subset chimerism samples were cell-separated by using immunomagnetic beads with respect to the patient’s leukemia phenotype, expressed at diagnosis. Mean purity of the positive-selected CD34 fractions were 97% (93–99%). PCR products were analyzed and quantified by capillary electrophoresis. 33 patients experienced a clinical relapse after aHCT. CCA and LCA detected a mixed chimerism (MC) in 27/118 and 25/118 patients, respectively. MC was detected at a median of 27 (12–54) and 34 (10–71) days before clinical relapse by CCA and LCA, respectively. LCA reached a significantly higher sensitivitiy than CCA with 91% (CI:54–98%) as compared to 83% (CI: 69–91%) and was also more sensitive as compared to bone marrow morphology examination (BME) (61%; CI:44–75%). Specificity was also higher with LCA (98%, CI: 89–100%) as compared to CCA (92%; CI: 75–99%) and BME (91%; CI: 82–96%).
Our data suggest a higher sensitivity and specificity of LCA as compared to CCA and BME with respect to the clinical follow-up. We conclude from these data that due to the high predictive value subset chimerism monitoring may be employed for clinical decision making concerning adoptive immunotherapy after myeloablative aHCT for patients with AML and MDS, especially when lacking other molecular markers for detection of MRD.
Differential accuracy of Lineage-specific versus Conventional Chimerism analysis
Lineage-specific Chimerism analysis (LCA) Conventional Chimerism analysis (CCA) Bone marrow examination (BME) Sensitivity and specificity of lineage specific (LCA), conventional (CCA) chimerism analysis and bone marrow examination (BME) with respect to the event that the patient would develop a relapse in the clinical follow-up. Sensitivity in % (Confidence interval) 91 (54–98) 83 (69–91) 61 (44–75) Specificity in %(Confidence interval) 98 (89–100) 92 (75–99) 91 (82–96)