bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase II Study Of Aprepitant As Anti-Emetic Prophylaxis In Patients Receiving Induction Chemotherapy For AML
Authors: Brandwein Joseph , Yee Karen W.L. WL , Schuh Andre C , Gupta Vikas , Seki Jack T 
Published: October 2019

Abstract

Background
Standard AML induction chemotherapy includes an anthracycline plus cytarabine (3+7); the former is considered moderately emetogenic. Such patients typically received anti-emetic prophylaxis using a 5-HT3 antagonist; however, many patients continue to experience chemotherapy-induced nausea and vomiting (CINV) requiring additional therapy. Aprepitant is a neurokinin inhibitor with documented efficacy against CINV, but has not been evaluated to date in the setting of AML induction therapy.

Patients and Methods
Patients with previously untreated AML, receiving induction chemotherapy with daunorubicin 60 mg/m2 IV daily on Days 1-3 plus cytarabine 200 mg/m2 IV daily (100 mg/m2 for patients age 60 and over) as a continuous IV infusion x 7 days, were enrolled in a Phase II single arm open label study. All patients received 5-HT3 antagonist prophylaxis using either granisetron 1 mg IV daily or ondansetron 8 mg IV q12h on the 3 daunorubicin dosing days. In addition, patients received aprepitant 125 mg PO on Day 1 followed by 80 mg PO daily on Days 2-5. No corticosteroids were used. Additional anti-emetic therapy was given as needed, at the discretion of the medical staff, for any nausea or vomiting. The primary endpoint was any vomiting or retching, while secondary endpoints included nausea requiring supplemental anti-emetics. Results were compared to a retrospective cohort of 40 patients who had received the same AML induction chemotherapy and 5-HT3 antagonist prophylaxis, but without aprepitant.

Results
At a pre-planned interim analysis, 27 patients receiving aprepitant on study were evaluated. By the end of Day 5, 3/27 patients (11%) had experienced at least one episode of vomiting or retching, while by the end of Day 8 four additional patients had experienced vomiting/retching, for a cumulative incidence of 26%. In comparison, the cumulative incidence of vomiting or retching by the end of Day 5 in the retrospective cohort was 50% (20/40), and 53% by Day 8. The proportion of patients experiencing vomiting was below 8% per day on aprepitant dosing days, but increased to11% on Day 6. The cumulative incidence of nausea and/or vomiting in the aprepitant group was 52% by the end of Day 5 and 60% at the end of Day 8, as compared to 78% at both time points in the retrospective cohort. There were no toxicities attributable to aprepitant.

Conclusion
The results indicate that aprepitant is highly effective, when combined with a 5-HT3 antagonist, in preventing vomiting in patients receiving AML induction chemotherapy with 3+7. The combination appears less effective in controlling nausea. The results warrant further evaluation in a Phase III randomized placebo controlled study.

Disclosures:
Brandwein: Merck: Honoraria, Research Funding. Off Label Use: Aprepitant as anti-emetic prophylaxis for AML induction. Seki:Merck: Honoraria.
Fast Detection Of MYD88-L265P Mutation By PCR-RFLP In Chronic Lymphoproliferative Disorders
Authors: Argentou Nikoletta , Vassilopoulos George , Ioannou Maria , Germenis Anastasios , Speletas Matthaios 
Published: October 2019

Abstract

Introduction
Waldenstrom’s macroglobulinemia (WΜ) is an incurable disorder characterized by bone marrow infiltration from neoplastic lymphoplasmacytic B-lymphocytes and monoclonal IgM production. Recent data suggest a possible causal relationship of MYD88-L265P mutation with the pathogenesis of the disease (Treon Sp et al. N Eng J Med 2012;367:826-33). Additional studies have conformed that MYD88-L265P is characteristic of WΜ, but it is also rarely present in other chronic lymphoproliferative disorders (LPDs) (Jiménez C et al. Leukemia 2013,doi: 10.1038/leu.2013.62; Varettoni M et al. Blood 2013;121:2522-8). The purpose of this study was to analyse the prevalence of the aforementioned mutation in patients with WM and other LPDs, using a fast and reliable polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol.

Methods
Genomic DNA was extracted from the bone marrow of 11 patients with WΜ, 12 patients with B-cell chronic lymphocytic leukemia (CLL), 8 with splenic lymphoma with villous lymphocytes (SLVL). Furthermore, consecutive samples of peripheral blood and bone marrow isolated CD19+ cells, derived from a patient with monoclonal IgM gammopathy of undetermined significance (MGUS-IgM), were also retrospectively analysed for the presence of MYD88-L265P defect. The detection of the mutation was performed by PCR amplification of the MYD88 exon 5 region, followed by RFLP analysis, since the presence of the mutation results in the generation of BsiEI restriction enzyme site. PCR-RFLP results were also confirmed by direct sequencing of purified CD19+cells.

Results
The MYD88-L265P mutation was detected in 10 patients with WΜ (90.9%), in 1 patient with SLVL with markers of lymphoplasmatocytoid differentiation (12.5%) and was absent in all CLL patients. Interestingly, our PCR-RFLP protocol exhibited a greater sensitivity than direct sequencing, when applied to total bone marrow cells (12.5% vs 25%). Moreover, the patient with MGUS-IgM displayed the MYD88-L265P mutation in isolated CD19+cells of both bone marrow and peripheral blood in all consecutive samples and remains in a stable condition for the last 7 years.

Conclusion
PCR-RFLP is a rapid, sensitive and reliable technique for the detection of MYD88-L265P mutation in patients with WM and lymphomas with lymphoplasmatocytoid differentiation. Additionally, the presence of MYD88-L265P mutation in MGUS-IgM in the absence of disease progression for many years, suggests that this genetic defect alone is not sufficient to lead to overt neoplastic disease.

Disclosures:
No relevant conflicts of interest to declare.
Prognostic Role Of Monoclonal and Polyclonal Gammopathy Measured By Serum Free Light Chain and Immunofixation In Diffuse Large B-Cell Lymphoma
Authors: Kim Yu Ri , Kim Soo Jeong , Kim Yundeok , Hwang Doh Yu , Jang Ji Eun , Hyun Shin Young , Cheong June-Won , Min Yoo Hong , Kim Jin Seok 
Published: October 2019

Abstract

Background
Serum free light chain (FLC) assay has been used to evaluate the prognosis of several hematologic malignancies. We evaluated the prognostic role of monoclonal gammopathy (MG) and polyclonal gammopathy (PG) measured by serum FLC and immunofixation (IF) in DLBCL.

Patients and methods
We retrospectively reviewed 115 patients with DLBCL who treated with rituximab containing chemotherapy. MG was defined as elevated kappa (κ) or lambda (λ) FLC with abnormal κ to λ ratio or positive IF and PG was defined as elevated κ and/or λ FLC with normal κ to λ ratio and negative IF.

Results
Fifty-six (48.7%) patients had an elevated FLC. Twenty (17.4%) patients had MG and 39 (33.9%) patients accompanied by a PG. Two-year overall survival (OS) was 89.2%, and 2-year event-free survival (EFS) was 88.4%. Elevated FLC was associated with inferior OS and EFS (p=0.013, p=0.012). Patients with MG had an inferior OS and EFS compared to patients with normal FLC (p=0.006, p=0.011). In multivariate analysis, both elevated FLC and MG showed the significance for OS (HR 4.57, 95% CI 1.43-14.60, p=0.001 and HR 5.63, 95% CI 1.50-21.09, p=0.010). Elevated FLC did not show the significantly shorter OS or EFS in non-germinal center B-cell (GCB) type according to the Han’s criteria. However, MG was a significant prognostic factor for OS and EFS in non-GCB type (HR 6.28, 95% CI 1.21-32.62, p=0.029, HR 6.38, 95% CI 1.58-25.74, p=0.009).

Conclusion
It important to evaluate the associated MG and PG using serum FLC and IF for predicting the prognosis of DLBCL, especially in non-GCB subtype.

Disclosures:
No relevant conflicts of interest to declare.
Demographic Analysis Of 90 Polycythemia Vera Egyptian Cases : An Egyptian Reference Center Experience
Authors: Mattar Mervat , Tawfik Nihad , Elhosseiny Noha , Morad Mohamed 
Published: October 2019

Abstract

Objective
We report 90 cases of Polycythemia Vera ( PV )during the period between 2003 and 2013 followed up in an adult Cairo hematology reference center

Results
Among 90 PV cases registered between 2003 and 2013, sixty eight cases (75.6%) of whompresented in the last three years alone. The age range was between 19 and 72 years with a mean of 53.5 years and 25 cases ( 27.78%) presented in the age group between 50-55 years. Male : female ratio was 1.3:1.Fifty per cent of patients were urban while 50% lived in the country.
Symptoms included headache (24 cases) (26.67%), tinnitus (7 cases) (7.78%), fatigue (14 cases) (15.56%), weight loss (5 cases)(5.56%), fever and sweating( 7 cases)( 7.78%) , bone or joint pains (22 cases)(24.44%), parasthesias (13 cases)(14.44%), pruritis(7 cases) (7.78%) or abdominal discomfort (16 cases)(17.78% (Fig 1)
Figure (1) : Incidence Of Symptoms Among 90 Egyptian PV Cases
Severity of symptoms was assessed by a simple score of zero (none), +1 (mild),+ 2 (moderate) and +3 (severe) (table1)
Nine cases (10%) presented by venous thrombosis , 4 of whom had portal vein thrombosis (4.44%) Cerebro-vascular strokes were noted in 5 cases (5.56%) and acute myocardial infarction in 2 cases (2.22%).
Splenomegaly was noted in 29 cases (32.22%) of cases and hepatomegaly in 13 cases (14.44%).
Associated conditions included hypertension in 24 cases (26.67%), gastrointestinal symptoms in 16 cases(17.78%) Diabetes mellitus in 15 cases (16.67%),Hepatitis C virus infection in 6 cases ( 6.67%), Hepatitis B in 2 cases ( 2.26%), coronory heart disease in 5 cases (5 .56%) and renal problems in 3 cases ( 3.33%). Bleeding episodes included 6 (6.67%) GI and 3(3.33%) gum bleeds.
Familial MPN, Cancer prostate, intestinal Schistosomiasis and post-liver transplant done post- hepatitis C virus cirrhosis were reported in one case each.
Twenty two cases(24.44%) were controlled on Hydroxyuria only,16 cases 17.78%) on venesection plus hydroxyuria,16 cases(17.78%) on venesection only. Progression was noted in 13 cases (14.44%) with marrow fibrosis in five cases (5.56%) and 14 cases (15.56%) were lost to follow-up. Mortality was seen in 10% (nine cases).

Conclusion
PV among Egyptians may have distinct presentations regarding incidence, age and presentation.Simpler methods of symptom severity assessments may be more suitable for Egyptian patients.

Disclosures:
Mattar: Novartis, BMS, Amgen: Honoraria.
Protein Methyltransferase Inhibitors as Personalized Cancer Therapeutics
Authors: Copeland Robert A. 
Published: October 2019

Abstract
The protein methyltransferases (PMTs) constitute a class of enzymes that catalyze the methylation of lysine or arginine residues on histones and other proteins. A number of PMTs have been shown to be genetically altered in cancers through, for example: gene amplification, chromosomal translocations, point mutations, and synthetic lethal relationships [Copeland et al. (2013) Oncogene 32: 939-946]. The enzymes DOT1L and EZH2 provide two representative examples of altered PMTs that act as genetic drivers of specific human cancers. The enzymatic activity of DOT1L is associated with a chromosomal translocation that is universally found in patients with MLL-rearranged leukemia [Daigle et al. (2011) Cancer Cell 20: 53-65; Daigle et al. Blood, prepublished June 25, 2013; doi:10.1182/blood-2013-04-497644]. Point mutations at Y641 of EZH2 are found in a subset of non-Hodgkin lymphoma patients; the enzymatic activity of both wild-type and mutant EZH2 are required for pathogenesis in these patients [Sneeringer et al. (2010) Proc. Natl. Acad. Sci. USA 107: 20980-20985; Knutson et al. (2012) Nature Chem. Biol. 8: 890-896]. Also, deletion of the SMARCB1 subunit of the SWI/SNF chromatin-remodeling complex occurs in nearly all malignant rhabdoid tumors (MRTs), a childhood cancer with a particularly poor prognosis. An antagonistic relationship has been demonstrated between the biochemical action on chromatin of the SWI/SNF complex and EZH2 (in the context of the polycomb repressive complex 2), that is relieved in MRTs due to the SMARCB1 deletion. MRTs therefore demonstrate increased reliance on the enzymatic activity of EZH2 for proliferation and we have shown that MRT cells deficient in SMARCB1 are selectively killed by inhibition of EZH2 in cell culture and in mouse xenograft models [Knutson et al. (2013) Proc. Natl. Acad. Sci. USA 110: 7922-7927]. Drug discovery efforts have yielded potent, selective inhibitors of each of these targets that have now transitioned into phase I clinical trials. These inhibitors affect the appropriate histone methyl marks in cells, lead to selective cell killing that is dependent on genetic alteration of the target enzyme, and effect tumor growth inhibition in xenograft models. These data portend the effective use of selective PMT inhibitors as a novel modality for future personalized cancer therapeutics.

Disclosures:
Copeland: Epizyme: Employment, Equity Ownership.
Matters of Life and Death: Give and Take in the Bcl-2 Family
Authors: Green Douglas R. 
Published: October 2019

Abstract
The mitochondrial pathway of apoptosis, a major mode of cell death in vertebrate animals, is characterized by the process of mitochondrial outer membrane permeabilization (MOMP), in which proteins of the mitochondrial inter-membrane space gain access to the cytosol, thereby triggering caspases and apoptosis. This life-or-death decision is controlled by the proteins of the Bcl-2 family. These include the pro-apoptotic Bcl-2 effector proteins, Bax and Bak, that cause the permeabilization event, and the anti-apoptotic proteins, e.g., Bcl-2, Bcl-xL, Mcl-1, which prevent it. A third sub-family, the BH3-only proteins, which include Bid, Bim, Bad, Puma, and Noxa (among others), regulate the other two sub-families, promoting the activation of the effectors or blocking the activity of the anti-apoptotic proteins (or both). Structural studies have led to a greater understanding of these complex interactions and have provided the basis for the development of BH3-mimetics that show promise for cancer therapies. New structural studies have begun to elucidate the mechanisms whereby Bax and Bak become activated, opening new avenues towards promoting or inhibiting the mitochondrial pathway of apoptosis. A proposed “hit and run” model of effector activation, whereby a BH3-only protein engages Bak or Bax and then must be displaced as the effector proteins associate, was validated in these structural studies. Additional, emerging insights will be discussed in the context of a unified model of Bcl-2 protein interactions.

Disclosures:
No relevant conflicts of interest to declare.
Inherited and Acquired RUNX1 Mutations in Hematologic Disorders
Authors: Speck Nancy A. , Cai Xiongwei , Ge Jingping , Mason Philip J. 
Published: October 2019

Abstract
RUNX1, a DNA binding subunit of core binding factors, is frequently mutated or rearranged in hematopoietic malignancies, including acute myelogenous leukemia (AML), chronic myelomonocytic leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome (MDS). Mutations in RUNX1 can be early events in leukemia, and generate a long-lived pre-leukemic stem cell (pre-LSC). Additionally, it has been reported that loss of function RUNX1 mutations are particularly frequent in radiation-associated MDS and AML, suggesting that pre-existing RUNX1 mutations in a pre-LSC may predispose patients to MDS/AML following DNA damage. Discussion will focus on the phenotypic properties of Runx1-deficient pre-LSCs, and the mechanisms by which Runx1 deficiency contributes to these phenotypes. Pan-hematopoietic Runx1 loss in mice causes a G1 to S-cell cycle delay and decreases apoptosis of pre-LSCs. Runx1-deficient pre-LSCs are radiation- and chemotherapy-resistant, and this correlates with decreased p53 protein levels and an attenuated p53 pathway response. Both p53 protein levels and apoptosis are increased following treatment with Nutlin-3. Runx1-deficient pre-LSCs are smaller, consume less glucose, and produce less ATP than normal hematopoietic stem cells (HSCs). Runx1-deficient stem and progenitor cells have lower overall ribosomal content and skewing in the relative amounts of rRNA and mRNA encoding ribosomal proteins. Analysis of AKT pathway components suggests that the decreased ribosome biogenesis is unlikely to be primarily caused by lower AKT signaling. We hypothesize that one or more of the above-mentioned properties (low p53 levels, decreased metabolism) render Runx1-deficient pre-LSCs less sensitive to genotoxic stress than normal HSCs, allowing a Runx1-deficient pre-LSC population to both perdure and expand in the bone marrow.

Disclosures:
No relevant conflicts of interest to declare.
Oral Administration of Ibrutinib Is Ineffective at Preventing Scleroderma in Chronic Gvhd in Two Preclinical Mouse Models
Authors: Xu Yajing , Johnston Heather F , Forman Stephen J. , Zeng Defu 
Published: October 2019

Abstract
We have established two mouse models of chronic graft versus host disease (cGVHD): one is an MHC-matched DBA/2 donor to BALB/c recipient, and this model amplifies the role of CD4+ T and B cells in transplants; the other model is an MHC-mismatched C57BL/6 donor to BALB/c recipient, and this model amplifies the role of de novo-developed CD4+ T and B cells. BALB/c recipients in both models started to develop scleroderma ~35 days after transplantation of donor spleen and bone marrow cells and this peaked ~50 days after transplantation. BALB/c recipients given DBA/2 transplants also developed proteinuria due to IgG anti-dsDNA autoantibody deposition in the glomeruli. We have reported that donor CD4+ T and B cells play critical roles in the pathogenesis of chronic GVHD (J. Immunol 2012 and 2013). Administration by I.V. injection of depleting anti-CD20 prevented induction of chronic GVHD in both models (Biol. Blood and Marrow Transplant 2014). In the current studies, using these two models, we tested whether oral administration of Ibrutinib could prevent induction of cGVHD. Ibrutinib was gavaged at 12.5 mg/kg/day from day 0 to day 30 or given in drinking water at 35 mg/kg/day (0.16 mg/ml) from day 0 to day 50. We found that administration of Ibrutinib significantly delayed the onset of proteinuria in the model of DBA/2 donor to BALB/c recipient, but accelerated the onset and increased the severity of scleroderma in 20/20 recipients given DBA/2 transplants and 9/9 recipients given C57BL/6 transplants as measured by a clinical score system. Administration of Ibrutinib significantly reduced CD138+B220lo plasma cells but not CD138-B220+ B cells in the spleen and peripheral lymph nodes of both recipients. Administration of Ibrutinib slightly reduced CD4+ T cell numbers in the spleen but significantly increased CD4+ T cell numbers in the peripheral lymph nodes, although there was no significant impact on CD4+ T cell expression of IFN-g and TNF-α in both recipients. These results indicate that, although oral administration of Ibrutinib is able to reduce B cell activation and differentiation into plasma cells, it is ineffective at inhibiting the CD4+ T cell expansion that mediates scleroderma in the models of DBA/2 donor to MHC-matched BALB/c recipient and C57BL/6 donor to MHC-mismatched BALB/c recipient. Our result is in contrast to a previous report showing that oral administration of Ibrutinib prevented induction of chronic GVHD with bronchiolitis obliterans in a mouse model and reversed scleroderma in another mouse model (Poster 2591, AACR 2014, San Diego). Further discussion about the differences is warranted. (This work was supported by Nesvig Lymphoma Foundation).

Disclosures
No relevant conflicts of interest to declare.
Stimulation of Nitric Oxide Synthase Activity By Plasma Apolipoproteins: a Biomarker of Endothelial Function in Adults with Sickle Cell Disease
Authors: Wang Xunde , Mendelsohn Laurel , Freeman Lita , Vaisman Boris , Remaley Alan , Kato Gregory J. 
Published: October 2019

Abstract
Nitric oxide (NO) plays a critical role in maintaining basal vascular tone and regulating blood flow. Many factors, including shear stress and endogenous ligands such as vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF1), stimulate the activity of endothelial nitric oxide synthase (eNOS). We have developed a bioassay that measures stimulation of NOS activity by soluble factors in unfractionated human plasma in cultured human endothelial cells using a sensitive NOS activity assay with radiolabeled substrate.
The addition of 1% human plasma to the culture medium stimulates NOS activity 1.5-fold over background, with a linear response up to 10% plasma, which activates NOS 5.5-fold. We have concluded from several lines of evidence that this NOS-inducing activity in human plasma comes from high-density lipoprotein (HDL): The activity is heat-labile and sensitive to reducing agents; it is precipitable by ammonium sulfate and elutes as a broad peak on molecular exclusion and anion exchange columns; by immunoblot, the active fractions have large amounts of apolipoproteins apoA-I, apoE and paroxonase-1. We find that plasma from an apoA-I null mouse shows less stimulation of NOS activity in our bioassay than plasma from a wild type mouse and apoA-I transgenic mouse (p=0.06, Brown-Forsythe test; p=0.04, post-test for linear trend; see figure). Purified HDL fractions stimulate NOS activity four-fold, equivalent to unfractionated plasma, but further subfractionation of HDL components extinguishes its ability to activate NOS.
Remarkably, higher than median NOS-stimulating activity in our bioassay was associated with endothelial-dependent blood flow, detected by venous occlusion strain gauge plethysmography measurement of forearm blood flow induced by graded infusions of acetylcholine into the brachial artery in adults with sickle cell anemia (p=0.0013, two-way ANOVA, see figure). The NOS-stimulating activity in patient plasma also correlated with the plasma apoA-I level (Spearman r=0.64, p=0.0012).
In summary, our results suggest that circulating functional apoA-I and possibly other apolipoproteins, regulate NO production and endothelial function in adults with sickle cell disease, which is consistent with previous lines of evidence published by other investigators in subjects without sickle cell disease. Most strikingly, our plasma NOS stimulation assay appears to provide a useful research biomarker for endothelial function, applicable to frozen archived plasma biospecimens.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.