bluuebunny/crossref_metadata_2025_split huggingface dataset:
Limited Efficacy of BMS-911543 in a Murine Model of JAK2V617F Myeloproliferative Neoplasm
Authors: Pomicter Anthony D. , Eiring Anna M. , Senina Anna V. , Marvin James E , Prchal Josef T. , O'Hare Thomas , Deininger Michael W. 
Published: October 2019

Abstract
Activation of JAK2, frequently as a result of the JAK2V617F mutation, is a characteristic feature of the classical myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia and myelofibrosis and thought to be responsible for the constitutional symptoms associated with these diseases. BMS-911543 is a JAK2 selective inhibitor that induces apoptosis in JAK2-dependent cell lines and inhibits the growth of CD34+ progenitor cells from patients with V617F+ MPN. To explore the clinical potential of this inhibitor, we tested BMS-911543 in a murine retroviral transduction – transplantation model of JAK2V617F MPN. Treatment was initiated at two dose levels (3 mg/kg and 10 mg/kg) when the hematocrit exceeded 70%. Following the first week, white blood cell counts were reduced to normal in the high dose group and were maintained well below the vehicle-treated mice throughout the study. However, BMS-911543 had no effect on red cell parameters. After 42 days of treatment, the proportion of JAK2V617F - positive cells in hematopoietic tissues was identical to controls or slightly increased compared to controls. Plasma concentrations of IL-6, IL-15, and TNFα were elevated in MPN mice and reduced in the high dose treatment group, while other cytokines were unchanged. Collectively, these results show that BMS-911543 has limited activity in this murine model of JAK2V617F – driven MPN and suggest that targeting JAK2 alone may be insufficient to achieve effective disease control.

Disclosures
Deininger: BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMA, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy.
Comparison of DNA Methyltransferase Inhibitors in Patients with Myelodysplastic Syndrome
Authors: Avsar Esin , Salim Ozan , Toptas Tayfur , Deveci Burak , Kurtoglu Erdal , Tombak Anil , Tiftik Eyup Naci , Undar Levent 
Published: October 2019

Abstract
The aim of this retrospective study was to compare the response rates (RR), overall survival (OS), time–to–acute myeloid leukemia–transformation (TTAMLT), hematologic toxicity and transfusion requirement of azacitidine and decitabine in patients with Myelodysplastic Syndrome Refractory Anemia with Excess Blasts (MDS RAEB) types 1 and 2. A total of 51 patients (35 male, 16 female, median age (years): 67) diagnosed with MDS RAEB-1 and RAEB-2 treated with azacitidine (n=31) or decitabine (n=20) in three Turkish institutes were evaluated . Response to treatment was classified according to International Working Group response criterias. Competing risk analysis was used to compare TTAMLT. There was no significant difference between the two groups in terms of age, gender, performance score, diagnosis, etiology, treatment cycles, bone marrow cellularity and blast percentage. Most patients received at least 4 cycles of azacitidine or decitabine. Patients who received azacitidine or decitabine had comparable response rates (58.1% vs 66.7%, respectively, p= 0.55). There was no difference in terms of red blood cell and platelet transfusion requirement and febrile neutropenia episodes (p= 0.46, p= 0.27, p= 0.19, respectively). Median follow–up was 31 months for azacitidine and 20 months for decitabine. Median OS was 18.4 months for azacitidine and 13.4 months for decitabine (p= 0.16). Only predictor of OS was at least 4-cycle treatment with any DNA methyltransferase inhibitors. 1–year risk of AML transformation was comparable across the groups (26% vs 33%, p= 0.55). In conclusion, both azacitidine and decitabine have similar efficacy and toxicity profiles in the treatment of MDS RAEB-1 and RAEB-2. Until a head–to–head comparison in prospective, randomized studies are conducted, the current source of available data will derive from meta–analyses that consist of the indirect comparison of treatment arms, or retrospective analyses with inevitable biases.

Disclosures
No relevant conflicts of interest to declare.
Cryptic Unbalanced Chromosomal Changes in a Case of Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL) Identified By Single Nucleotide Polymorphism (SNP) Microarray, but Not By Conventional Karyotyping
Authors: Kurniali Peter C. , Al-Janadi Anas , Chai Hongyan , Wei Sainan 
Published: October 2019

Abstract
Genomic abnormalities have been widely used to diagnose and provide prognostic significance in many hematologic malignancies (HM). The use of conventional G-banded chromosome and fluorescence in situ hybridization (FISH) analyses sometimes fail to detect genomic abnormalities due to the need for actively dividing cells and lower resolution of chromosome analysis (G-banded), as well as the inability to detect copy number of neutral loss of heterozygocity (G-banded and FISH). The addition of single nucleotide polymorphism (SNP) microarray has been shown to increase the detection rate of genomic abnormalities in HM.
We report a 62-year-old Caucasian woman with a diagnosis of chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL). Cytogenetic studies done at the time when she required initial treatment in 2011 showed a balanced translocation between chromosomes 6 and 13 {46,XX,t(6;13)(p10;q10)[10]/46,XX[10]}. She was treated with bendamustine plus rituximab and achieved complete response. In 2013, she developed worsening of anemia and marked lymphocytosis. Blood and bone marrow examination showed polymphocytic transformation. G-banded cytogenetic studies again showed a balanced translocation between chromosomes 6 and 13 (same as in 2011). However, FISH analysis detected a deletion of 13q. G-banded cytogenetic study was re-examined and showed balanced translocation: 46,XX,t(6;13)(p10;q10)[10]/46,XX[10]. Re-analysis of bone marrow cytogenetic from 2011 also suggested possible deletion of 13q, but the resolution was poor. Cytogenetic microarray validation was performed and revealed not only deletions of 13q14.2q14.3, but also 6p21.1p21.1. Karyotypic changes of chromosome 6 have been associated with prolymphocytic transformation in CLL/SLL.
Deletion of 13q14.3 usually carries good prognosis in CLL/SLL. However, additional abnormalities and deletions of different sizes of 13q reportedly cooperate to change its favorable value. An accurate cytogenetic analysis may be useful in aiding in diagnosis, prognosis, and possibly therapy. Our findings suggest that microarray analysis is a suitable companion test to G-banded chromosome and FISH analyses, especially in CLL/SLL.

Disclosures
No relevant conflicts of interest to declare.
Differences in the Original Diagnostic Markers Including the "CRAB" Criteria in Multiple Myeloma Patients from Different Ethnicities: A Single Center Experience
Authors: Mattour Ahmad Hatem , Vollstaedt Joshua , Kuriakose Philip 
Published: October 2019

Abstract
LEARNING OBJECTIVES:
Determine if there are any differences in the original diagnostic markers, including the “CRAB” criteria, in Multiple Myeloma patients from different ethnicities.
BACKGROUND:
About 24,050 new cases of Multiple Myeloma are expected to be diagnosed in 2014. In a metropolitan institution, such as Henry Ford Hospital, newly diagnosed patients are drawn from multiple ethnic backgrounds. While several epidemiological studies have demonstrated a positive correlation between race and values of several diagnostic markers (such as hemoglobin, creatinine and albumin), most of the research focused on molecular and genetic, as opposed to clinical, differences in patients from multiple ethnicities.
Our study, therefore attempted to offer a more customized diagnostic approach to patients with newly diagnosed Multiple myeloma, based on their ethnicity, and to determine if there was a correlation between the patients' races and common diagnostic elements, including the CRAB criteria, at time of diagnosis.
METHODS:
We conducted a retrospective study. Data from 300 patients over 5 years (2007-2012) with newly diagnosed with Multiple myeloma was collected. Only 197 patients fulfilled the diagnostic criteria and were included in the final analysis. The following data was extracted: Age at diagnosis, gender, diagnostic elements according to the CRAB criteria (serum Calcium, serum Creatinine, Anemia, Bone lytic lesions) at date of diagnosis, serum beta-2-microglobulin level, M-protein serum concentration, and whether Urine monoclonal protein excretion was present. The patients were divided into two groups by race: African American and Caucasian. An overall score was created by summing the incidence of each diagnostic marker.
RESULTS:
Categorical data was compared between the two groups using chi-square tests, and CRAB score was compared using a Wilcoxon rank-sum test due to its ordinal nature. Our study demonstrated that there were no statistically significant differences between the two groups in any of the components collected, or in the final total score
CONCLUSIONS: Our study demonstrated that there was no statistically significant difference in the original diagnostic markers, including the CRAB criteria, in Multiple Myeloma Patients from Different Ethnicities presenting to our Institution.The effect of baseline cytogenetic characteristics on the diagnostic markers between multiple myeloma patients from different ethnicities is still not fully understood, and might be a factor that needs to be studied further.

Disclosures
No relevant conflicts of interest to declare.
Exomic microRNA Profiling of Bone Marrow Aspirate Plasma and Comparison with mRNA Profiles Used in the Clinical Management of Multiple Myeloma
Authors: Van Laar Ryan K , Flinchum Rachel , Nathan Brown , Ramsey Joseph , Shaughnessy John , Epstein Joshua , Heuck Christoph , Barlogie Bart 
Published: October 2019

Abstract
Exosome-mediated processes are increasingly being implicated in the pathobiology of many forms of solid tumors and hematologic malignancies. In the case of blood cancers, an oncogenic role for exosomes has been demonstrated for multiple myeloma (MM). An increased understanding of the abundance and disease association of extra-cellular microRNAs in particular, may lead to opportinities to improve early detection and management of MM and precursor conditions.
We performed microRNA profiling of cell-free bone marrow aspirate plasma on a series of 100 patients with diagnoses of MGUS, active multiple myeloma or relapsed multiple myeloma. The microRNA profiles were compared between disease status groups and also individually with each patient’s routine MyPRS results (ie. GEP70 high/low risk and molecular subtype gene signatures), generated from their malignant CD138+ plasma cells1. MicroRNAs with patterns of expression associated with these clinically validated genomic (mRNA) signatures were investigated to determine if they (i) were known regulators of the genes used in MyPRS and (ii) in a cross-validated analysis, were able to predict the patients MyPRS risk group and molecular subtype.
An additional series of paired peripheral blood and bone marrow aspirates (isolated CD138+ plasma cells) were also microRNA and MyPRS profiled, to further investigate the role and potential clinical utility of extracellular microRNAs in multiple myeloma. Results will be presented which describe the abundance of individual microRNA's in realtion to disease status, including microRNA's previously linked to the regulation of mRNA's contained in the GEP70 signature.
The ability to predict MGUS progression risk or active myeloma prognosis using molecular signatures in peripheral blood may increase access to, and adoption of, genomic technologies in the diagnosis and management of these related conditions.
Reference:
[1] van Laar R, Flinchum R, Brown N, et al. Translating a gene expression signature for multiple myeloma prognosis into a robust high-throughput assay for clinical use. BMC Medical Genomics. 2014;7(1):25.

Disclosures
Van Laar: Signal Genetics: Employment, Equity Ownership. Flinchum:Signal Genetics: Employment. Nathan:Signal Genetics: Employment. Ramsey:Signal Genetics: Employment. Shaughnessy:Signal Genetics: Consultancy.
Oxymatrine Induces Apoptosis in Human Myeloma Cells By Cell Cycle Arrest and Activation of Caspase-Dependent Apoptosis
Authors: Wu Wenjun , Wu Cai , Zi Fuming , Li Yi , Yang Li , He Jingsong , He Donghua , Yang Yang , Zhao Yi , Han Xiaoyan , Zheng Gaofeng , Huang He , Cai Zhen 
Published: October 2019

Abstract
Background : Multiple myeloma (MM) is a B cell malignant hematologic cancer. Despite the introduction of new drugs and improvement of chemotherapy, MM is still an incurable disease. Oxymatrine (OMT), the active ingredients of traditional Chinese herbal medicine sophora, has been reported to have antitumor activity. This study was to estimate the therapeutic efficacy of OMT in MM.
Methods: The growth inhibition of myeloma cell lines (RPMI8226, U266, ARP-1) or primary cells by OMT was assessed by MTT assay. Apoptosis of MM cells was examined by annexin V-FITC using flow cytometry analysis. DNA content was analyzed by flow cytometry. RT-PCR and western-blot analysis were used to assess the expression of Bcl-2 family proteins and the IAP family proteins. Western blotting was also used to elucidate the signaling pathway that may mediate OMT-induced apoptosis of MM cells.
Results: OMT treatment resulted in cell growth inhibition and apoptosis in primary MM cells and all tested MM cell lines in a dose-dependent manner (P <0.05). To elucidate OMT -induced MM cell apoptosis, MM cell lines were treated with or without OMT for 24h and assessed for caspase activation and signaling pathway by Western blotting. The results showed the cleavage of PARP, caspase-3, and caspase-9, and p-AKT were down-regulated after OMT treatment. The mRNA expression of survivin and HIAP by RT-PCR was down-regulated. OMT treatment at 5mM for 48h resulted in increased G-phase cells and decreased S-phase cells in MM cell lines (P <0.05). Cell cycle repressor P21 protein was up-regulated while CDK4, CDK6 and CyclinD1 expression was down-regulated. Our finding also showed a synergistic anti-MM activity of OMT and dexamethasone or adriamycin at a low does (CI<1). In addition, LC3-II expression was significantly increased both in RPMI8226 and U266 cells after treatment with OMT. However, treatment with different doses of OMT and 5 mM autophagy inhibitor 3-MA, significant increased cell apoptosis (P <0.05).
Conclusion: Our findings demonstrate the anti-MM activity of OMT and indicate that OMT alone or together with other MM chemotherapeutics may be a prospective treatment for MM.

Disclosures
No relevant conflicts of interest to declare.
Ocular Complications of Bortezomib Therapy in Multiple Myeloma
Authors: Puri Sonam , Joshi Jitesh , Derman Olga , Kornblum Noah , Verma Amit , Braunschweig Ira , Battini Ramakrishna 
Published: October 2019

Abstract
Introduction:
Bortezomib (Velcade¨; V), a proteasome inhibitor, is currently FDA (Food and Drug Administration) approved for the treatment of multiple myeloma (MM) and relapsed mantle cell lymphoma. Common side effects reported with its use include thrombocytopenia, fatigue, peripheral neuropathy and neutropenia. Ocular complications associated with bortezomib are less well described. We describe 6 patients with multiple myeloma who developed meibomitis, multiple chalazions and blepharitis after treatment with bortezomib containing regimens, resulting in delay and in some cases termination of the therapy.
Methods:
We reviewed the charts of forty patients who received induction chemotherapy for multiple myeloma between June 2013-June 2014 at Montefiore Medical Center, New York. Charts were reviewed for data pertaining to demographics, chemotherapy regimen and schedule as well as follow up of ocular symptoms.
Results:
Six of these forty (15%) patients complained about bilateral eye soreness, itching and redness. They did not have any evidence of viral or upper respiratory infections. Ophthalmology evaluation showed blepharitis, meibomitis and multiple chalazion. Majority of the patients were 60 years or greater, with 50% African-Americans. Half of the cases had stage 3 MM with a median duration of chemotherapy 8 weeks prior to onset of ocular symptoms. 4 of these 6 patients received VCD regimen (Bortezomib via subcutaneous route and Cyclophosphamide/ Dexamethasone as tablets) while the remaining 2 patients received VD and VCD-R (addition of Lenalidomide) via intravenous and subcutaneous route respectively. Ocular symptoms led to a 1-3 week delay in the next cycle of chemotherapy. These symptoms promptly responded to withdrawal of chemotherapy and other conservative measures. Chemotherapy was resumed in 4 out of 6 patients, with recurrence of chalazion in two patients within 3 weeks of starting Bortezomib.
Conclusions:
Ocular symptoms are commonly seen but rarely reported with bortezomib therapy. They can adversely affect patient's quality of life as well as lead to interruption in chemotherapy. Although these symptoms respond well to withdrawal of chemotherapy and conservative measures, the rate of recurrence is high once bortezomib is resumed. Awareness of these complications and early intervention can potentially avoid treatment delay.
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Severe Diffuse Alveolar Hemorrhage Associated with Bortezomib Administration in Patients with Multiple Myeloma
Authors: Ayed Ayed O , Moreb Jan S , Hsu Jack W. , Hiemenz John W , Wingard John R , Norkin Maxim 
Published: October 2019

Abstract
Background: Bortezomib, a proteasome inhibitor, is frequently used in treatment of patients with multiple myeloma (MM). Bortezomib is generally well tolerated with gastrointestinal symptoms and peripheral neuropathy being the most common adverse effects. Here we report cases of severe diffuse alveolar hemorrhage (DAH) associated with bortezomib administration.
Methods and Results: We identified 3 cases of severe DAH that were associated with bortezomib administration in MM patients treated at our institution between 2010 and 2014 (Table 1). All 3 patients presented with fever and worsening hypoxia shortly after initiation of bortezomib therapy and later developed progressive respiratory failure due to DAH. None of 3 patients had any respiratory symptoms or preexisting pulmonary conditions prior to bortezomib initiation. In one patient respiratory symptoms developed after 4 doses of bortezomib, improved off therapy, however rapidly progressed to a respiratory failure with a subsequent bortezomib treatment. Imaging studies showed diffuse areas of ground-glass opacities, apparent prominence of segmental and subsegmental bronchi and interlobular septal thickening. Infectious workup, which included bronchoscopy with bronchoalveolar lavage and respiratory viral studies, was completely negative in all 3 patients. All patients received supportive care, empiric broad-spectrum antimicrobial therapy and high-dose glucocorticoids, which were started within 4 days of hospital admission. Two patients died from complications of DAH and 1 patient recovered without pulmonary sequelae.
Conclusion: Bortezomib-associated DAH is a rare, but serious and potentially fatal adverse event. Pathogenesis remains unclear and is likely related to impaired regulation of the inflammatory response. Early recognition of bortezomib associated DAH is essential for immediate discontinuation of the drug and prompt initiation of high dose steroids. More reports are needed to provide further insights about the pathogenesis and most optimal management of bortezomib induced DAH.
Abstract 5761. Table 1: Patients who developed DAH after bortezomib administration Pt Age/ Gender/Race Smoker Sx Bor dose Bor schedule # of Bor doses Time of onset after last bor dose (days) Platelet count at the onset (103/mm3) Imaging/BAL findings Time to initiation of high dose steroids Outcome 1 67/M/C Never SOB, fever 1.3 mg/m2 IV/2Xwk 8 5 157 Bilateral infiltrates and GGO/DAH 2 Death 2 72/M/C Yes Fever, cough 1.3 mg/m2 IV/2Xwk 2 3 108 Bilateral infiltrates/DAH 4 Recovery 3 55/M/C Yes Fever, chills 1.5 mg/m2 IV/2Xwk 1 2 144 Bilateral diffuse airspace disease/DAH 4 Death
Abbreviations: Pt, patient; M, male; C, Caucasian; Sx, symptoms; Bor, bortezomib; BAL, broncho-alveolar lavage; GGO, ground-glass opacities.

Disclosures
No relevant conflicts of interest to declare.
Survival Outcomes of Double and Triple-Only Combination Anti-Myeloma Chemotherapeutic Regimens on 26 Multiple Myeloma Patients Seen in a Sub-Saharan African Country
Authors: Nwabuko Ogbonna Collins , Nnoli Martin Anazodo , Igbigbi Elizabeth Eneikido , Okoh Dorathy Adaunwa , Chukwuonye Ijezie Innocent 
Published: October 2019

Abstract
Backgound: Multiple myeloma (MM) is one of the commonest haematological malignancies of public health importance in low-income countries of sub-Saharan Africa. Though primarily a disease of the bone marrow, it often poses a diagnostic dilemma for the orthopaedic surgeons because of the frequent skeletal manifestations. Consequently, misdiagnosis and late presentation are often common contributory factors to the poor prognosis and survival of victims in this environment. This retrospective study aimed at finding out the therapeutic challenges of MM in developing countries such as Nigeria.
Methodology: A-10-year multi-centered retrospective analysis of 26 patients diagnosed and managed in three major centers between 2003 and 2013. Informations on the clinical, laboratory, radiological datas and therapeutic interventions were obtained at presentation until patients were lost to follow-up.
Result: The median age of diagnosis was 60.6 years with M:F ratio of 2.3:1.(p<0.05). 61.5%, 30.8% and 7.7% presented in Durie Salmon (DS) stages III, II and I diseases respectively. The mean survival interval was 39.2 months (95% CI, 32.0-47.2 months). 84.5% and 8% were on Melphalan plus Prednisolone (MP) and Cyclophosphamide plus prednisolone (CP) combination chemotherapies respectively. The longest survival interval of 80 months was recorded by MP plus Bortezomib (V) triple regimen.There was no significant difference between the outcome of MP and VMP (p=0.33).
Conclusion: Triple combination regimens (i.e,VMP, MPT) are superior to standard MP in terms of overall survival (OS),and quality of life of MM patients in developing countries, although this is not statistically significant.

Disclosures
No relevant conflicts of interest to declare.