bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using Multiparametric Flow Cytometry to Analysis the Immunophenotypic Abnormalities of Bone Marrow Cells in Patients with MDS-RAEB.
Authors: Huang Jing , Du Xin , Geng Suxia , Zhou Maohua , Weng Jianyu , Wu Suijing , Guo Rong , Lu Zesheng , She Miaorong 
Published: October 2019

Abstract
Abstract 4856

Objective
The multiparametric flow cytometry is becoming a very useful tool of the diagnosis and prognostication for patients with Myelodysplastic Syndrome(MDS). This study was aimed at using multiparametric flow cytometry to explore the immunophenotypic abnormalities of bone marrow cells from patients with RAEB.

Methods
We collected BM samples from 12 MDS-RAEB patients (6 male, 6 female, Median Age 67.5) and 20 non-MDS patients (11 male, 9 female, median age 32.5, 7 AA, 5 PNH, 3 IDA, 1 ALL, 2 CML, 2 MM). The multiparametric flow cytometric analysis was performed using an extensive panel of monoclonal antibodies. We used the conventional and secondary gating strategies to analysis the BM cells compartments such as the percents of blast cells and the expression of lineage and maturation-associated antigens of BM hemopoietic cells quantified.

Results
Compared with the non-MDS group, the proportion of blast cells increased significantly in the MDS-RAEB group (P=0.001), but the percentages of nucleated erythrocyte, lymphocyte, monocyte and granulocyte were no significant difference (P=0.954, P=0.893, P=0.730 and P=0.182). As the percentage of blasts cells increasing, the survival time became shorter (13 ± 6 vs 35 ± 15 months; P=0.02). The expressions of haemopoietic stem/progenitor cell surface marker CD34+ and T lymphocyte surface marker CD7+ on blast cells were much higher by secondary gating method than non-MDS group (P=0.009, P=0.002, respectively), while no significant difference of the expression of CD56 (P=0.375). The expressions of CD7+ and CD56+ on lymphocyte were no significant difference between the two groups (P=0.195, P=0.369, respectively), however the expression of CD19+ may be different (P=0.039). The expressions of CD33+ and CD13+ on granulocyte were no significant difference between the two groups (P=0.289, P=0.744, respectively). However, the expression levels of CD15+CD11b+, CD15+CD11b-, CD10+, HLA-DR, CD56+ in the MDS-RAEB group were significantly higher than those in the non-MDS group, specially, the levels of CD10+, HLA-DR and CD56+ were much higher (P=0.016, P=0.011, P=0.005, P=0.005 and P=0.005, respectively) and these patients showed a shorter median overall survival (15 ± 5 vs 36 ± 10 months; p = 0.03).

Conclusions
The percentage of blast cells increased in MDS-RAEB patients and the expressions of CD34+, CD7+ on blast cells and the expressions of CD10+, HLA-DR and CD56+ on granulocyte is higher than non-MDS group. It will be necessary to increase the number of cases (MDS-RAEB) to confirm our findings. Using multiparametric flow cytometry can find the immunophenotypic abnormalities more sensitively, accurately and objectively, and this new approach could provide much more useful information in the diagnosis and prognosis of MDS-RAEB patients.

Disclosures
No relevant conflicts of interest to declare.
The Epitope Targeted by Apoptosis-Inducing ICAM-1 Antibody B11 Is Highly Expressed in Multiple Myeloma.
Authors: Hansson Markus , Veitonmäki Niina , Lindblom Anders , Frendéus Björn 
Published: October 2019

Abstract
Abstract 4897
Complex adhesive and non-cognate interactions participate in multiple myeloma disease progression, resistance to apoptosis, and development of drug resistance. In spite of significant recent attempts to develop new drug classes targeting both myeloma and its microenvironment, multiple myeloma remains an incurable disease warranting development of more effective therapies. Applying novel combined target and drug discovery methodology we isolated a human tumor cell apoptosis-inducing antibody (IgG B11) targeting ICAM-1, as previously described. ICAM-1 is a cell adhesion molecule strongly implicated in myeloma pathophysiology, both regarding bone marrow stromal cell mediated disease progression and cell adhesion mediated drug resistance. We here characterize B11 epitope expression by multicolor FACS analysis in 25 patients investigated for multiple myeloma referred to Department of Hematology, Lund University Hospital, Lund, Sweden and 5 healthy controls. The B11 epitope was highly expressed in plasma cells in 5 of 5 patients with myeloma and in 1 of 1 patient with AL (light chain) amyloidosis. A comprehensive preclinical program assessing IgG B11 anti-myeloma activity and evaluating IgG B11 safety has been conducted. Based on these studies, and having received an investigational new drug (IND) approval from the U.S. Food and Drug Administration (FDA), clinical phase I trials with IgG B11 will soon commence.

Disclosures
Veitonmäki: BioInvent International: Employment. Lindblom:BioInvent International: Employment, Equity Ownership. Frendéus:BioInvent International AB: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
Fluorescent in Situ Hybridization Analysis at Bone Marrow Biopsy Section in Multiple Myeloma.
Authors: Hae Cho Eun , Lee Sang-Mi , Eom Hyeon-Seok , Kim In-Suk , Lee Gyeong-Won , Kong Sun-Young 
Published: October 2019

Abstract
Abstract 4898

Introduction
The technique of fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms has recently been introduced to detect molecular cytogenetic abnormalities in plasma cell myeloma of bone marrow (BM) aspirate. However, in case of sub-optimal BM aspirate or the focal distribution of myeloma in the BM, the plasma cells are significantly lower in the BM aspirate than those of biopsy section. Therefore, we have developed a sensitive fluorescence in situ hybridization (FISH) technique which is combined with immunochemistry and is applicable to BM biopsy section for molecular cytogenetic study of plasma cell neoplasms.

Patients and Methods
Conventional cytogenetic analysis and FISH results of BM samples of 35 multiple myeloma (MM) patients at the time of diagnosis have been evaluated. The probe for IgH rearrangement has been used for hybridization with myeloma cells coupled with CD138 immunostain at BM biopsy section.

Results
Nineteen patients (54.3%) had abnormal FISH IgH results in biopsy section, whereas seven (20%) cases had abnormal findings in BM aspirate. FISH IgH analysis at biopsy section revealed various signal patterns and proportions (range 6-87%) of cells with atypical signals out of CD138 positive cells. Among five cases with <10% of plasma cells at BM aspirate, four (80%) had abnormal FISH results at biopsy section, whereas one (20%) had abnormal signals at aspirate. There is no correlation between the proportions of cells with atypical signal corrected by the plasma cell count at BM aspirate and the proportions of cells with atypical signal at biopsy section.

Conclusions
FISH analysis combined with immunostain which is applied at biopsy section is a highly sensitive and convenient technique to detect and quantify monoclonal plasma cells. It could be used for molecular cytogenetic study in plasma cell neoplasms even though there are less than 10% of plasma cells at BM aspirate and the monitoring of residual disease.

Disclosures
Kong: National cancer center, Korea: Research Funding.
The Prognostic Impact of Fluorescent-in Situ Hybridization (FISH) and Conventional Karyotying in Korean Multiple Myeloma Patients: A Retrospective Multicenter Study.
Authors: Kim Min Jae , Oh Suk Joong , Min Chang Ki , Park Chong Won , Yoon Hwi-Joong , Do Young Rok , Kim Byung Soo , Kim Yang Soo , Eom Hyeon Seok , Ryoo Hun-Mo , Kim Sung Hyun , Shin Ho Jin , Bang Soo-Mee , Kim Seok Jin , Yoon Sung-Soo , Lee Dong Soon , Suh Cheolwon , Kim Jin Seok , Won Jong Ho , Park Seongkyu , Kim Min Kyoung , Shim Hyeok , Kang Hye Jin , Kim Chul Soo , Lee Je-Jung , Kwak Jae-Yong , Jo Deog Yeon , Lee Jae Hoon ,   Korean Multiple Myeloma Working Party
Published: October 2019

Abstract
Abstract 4902

Introduction
Cytogenetics and fluorescent-in situ hybridization (FISH) are important outcome predictors in multiple myeloma (MM). There were only few small studies that investigated prognostic implication of FISH and/or conventional karyotyping in Korean MM patients. We investigated the incidences and prognostic significances of chromosomal abnormalities detected by FISH and/or conventional karyotyping among Korean MM patients.

Patients and Methods
We collected data of patients from Korean Myeloma Registry and performed retrospective analysis. We compared the survival of patients with chromosomal abnormalities and other clinical findings.

Results
From 2000 to 2009, total of 801 newly diagnosed myeloma patients were enrolled in this study. Median age of patients was 62 years. Median overall survival was 82 months, and median follow up of time was 92 months. Among the patients who had conventional karyotype analysis, 17.1% were complex karyotype, followed by del13q (7.4%), hyperdiploidy (7.6%), hypodiploidy (3.0%), and t(11;14) (3.9%). Among the patients who had FISH analysis, 22.8% were del 13q, followed by t(11;14) (18.2%), t(4;14) (13.7%), del17p (11.8%) and t(14;16) (5.9%). Univariate analyses revealed that complex karyotype (p<0.01), hypodiploidy (p=0.01), del13q (p<0.01) by conventional karyotyping, and t(4;14) (p=0.04) by FISH negatively impacted the overall survival. Other genomic aberrations did not affect the overall survival. Clinical parameters that impact on overall survival were percentage of plasma cells in bone marrow, serum beta2-microglobulin, creatinine, low hemoglobin, and low albumin levels. On multivariate analysis, percentage of plasma cells in bone marrow (p<0.01) and low serum albumin level (p<0.01) were independent risk factors for overall survival.

Conclusions
Our results showed that complex karyotype, hypodiploidy, t(4;14), and del13q by FISH and/or conventional karyotyping were negative prognostic factors for overall survival in univariate analyses. On multivariate analysis, low serum albumin level and percentage of plasma cells in bone marrow were independent risk factors for overall survival. In future, prospective trial with laboratory standardization is warranted for more reliable results from FISH and/or conventional karyotyping in MM patients.

Disclosures
Suh: Janssen Korea: Research Funding.
The Presence of Multinuceated Plasma Cells in Bone Marrow Aspirates Has No Clinical Significance.
Authors: Shumate Mark , Whitehead Cecille 
Published: October 2019

Abstract
Abstract 4904
There is no published literature on the clinical significance of multinucleated plasma cells in bone marrow aspirates. The few references in the literature that mention multinucleated plasma cells imply that their presence is pathologic. We decided to investigate the clinical significance of these cells. All bone marrow aspirates done at the Atlanta VAMC from 1/1/99 until 8/1/99 were examined by a skilled hematopathology technician for 2 minutes. The presence of multinucleated plasma cells were recorded if they were identified. We then determined clinical characteristics of the patients and compared the characteristics of those with multinucleated plasma cells and those without. RESULTS. There were a total of 61 aspirates for review. 34 of these had identified multinucleated plasma cells MNPCs. The average age of the group with MNPC was 58.7 years (SD 15.4) and the group without MNPC was 61.6 (SD 12.4). 11 of the 27 patients without MNPC were alive at 10 years (41%) while 14 of the 34 patients with MNPC were alive at 10 years (also 41%). Among the group with MNPC who were still alive at 10 years the average change in serum creatinine over the 10 year period was .23 mg/dl. Among the group without MNPCs the average change in serum creatinine over the 10 year period was .26 mg/dl. Finally, 12 of the 34 patients (35%)with MNPCs were found to have a clonal lymphoid disorder sometime over the 10 year period after their aspirate, while 10 of the 27 patients (37%, a nonsignificant difference)without MNPCs were found to have a clonal lymphoid disorder.

CONCLUSION
MNPC have no impact on survival or changes in renal function over a 10 year period. Furthermore, their incidence is not impacted by age. Finally, they do not predict the occurrence of clonal lymphoid disorders. We conclude that MNPC are likely a normal variant of plasma cells

Disclosures
No relevant conflicts of interest to declare.
Inhibition of Constitutively Activated JAK/STAT3 Pathway in Multiple Myeloma Cells Leads to Induction of Protective Autophagy.
Authors: Ma Huihui , Lu Caisheng , Ziegler Judith , Feng Rentian , Lentzsch Suzanne , Mapara Markus Y. 
Published: October 2019

Abstract
Abstract 4914
Constitutive activation of Janus Kinase-2 (JAK-2)/signal transducer and activator of transcription-3 (STAT3) has been implicated to play a crucial role in the pathogenesis of Multiple Myeloma (MM). Therefore, targeted inhibition of STAT3 is an attractive therapy for MM patients. JSI-124 is a natural product isolated from various plant families and has been recently described as a specific inhibitor of JAK2/STAT3. It has been shown to exert strong apoptosis-inducing effects against STAT3+ tumor cell lines in vitro and in vivo. However, there is little information available about the anti-tumor effects of JSI-124 on myeloma cells. We therefore tested the role of JSI-124 as a potential novel anti-MM compound and were able to determine that JSI-124 has potent anti-myeloma properties against human MM cell lines. Our results revealed that JSI-124 could inhibit both constitutively expressed and IL-6 induced phosphorylation of Tyr705 STAT3 as well as other important cell signal pathways that regulate cell proliferation in MM cell lines. However, the anti-myeloma effects were not restricted to STAT3+ MM cells. In STAT3+ cells JSI-124 induced cell death, which was predominantly caspase dependent. In contrast, JSI-124 induced both caspase-dependent and caspase-independent cell death in STAT3-MM cells. Furthermore, JSI-124 induced DNA damage only in STAT3- MM cells. Surprisingly, STAT3- cell lines were more sensitive to JSI-124-induced growth inhibition and induction of cell death than STAT3+ MM cell lines. Further analysis revealed that JSI-124 led to induction of autophagy only in STAT3+ MM cells as determined by upregulation of LC3B. A dramatic increase of JSI-124-dependent apoptosis was observed when the autophagy pathway was blocked by Chloroquine suggesting that STAT3-inhibition in STAT3+ MM cells leads to protective autophagy, which can be overcome by Chlorquine treatment. Interestingly, inhibition of autophagy by Chloroquine or 3-mA in STAT3+ cell lines U266 or ARH 77 resulted in AIF release and well as caspase-independent cell death. The results in this study suggest that JSI-124 could be an effective anti-myeloma agent regardless of STAT3 activation status and that combination with Chloroquine may enhance its anti-MM effect.

Disclosures
Lentzsch: celgene: Consultancy, Honoraria, Research Funding; cephalon: Consultancy, Research Funding. Mapara:Resolvyx: Consultancy, Honoraria, Research Funding; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; GENTIUM: STOCK OWNERSHIP.
CC102528: A Novel Histone Deacetylase Inhibitor in the Hydroxamate Family Demonstrates Potent Anti-Myeloma Activity.
Authors: Li Zhi-Wei , Leung Crystal , Hu Mengyin , Xiang Jinbao , Jiang Chao , Steinberg Jeffrey A , Shen Jing , Li Mingjie , Wang Cathy S , Sanchez Eric , Bonavida Benjamin , Chen Haiming , Bai Xu , Berenson James R. 
Published: October 2019

Abstract
Abstract 4927
Despite advances in the treatment of multiple myeloma (MM), the disease remains incurable. Thus, there is a need for the development of new drugs to improve the outcome for patients with this common B-cell malignancy. Histone acetylation, which is controlled by the balanced activities between histone acetyltransferase (HAT) and histone deacetylase (HDAC), is a major epigenetic modification that may contribute to tumorigenesis. Through inhibition of HDAC activity, HDAC inhibitors (HDACis) increase acetylation level of histones as well as other tumor suppressor gene products; and, therefore, are potential anti-cancer agents. Based on the structures, currently available HDAC inhibitors can be divided into four groups, including hydroxamates, cyclic peptides, aliphatic acids, and benzamides. We have screened a library of combined compounds and identified two potential novel HDACis (CC102528 and CC102598) that demonstrate potent anti-MM effects in vitro. Both compounds are hydroxamate derivatives with IC50 below 5 μM in the MM cell line RPMI8226 as determined with the MTS assay. These compounds induce apoptotic cell death and inhibit HDAC activity in MM cells as determined with Annexin V staining followed by flow cytometric analysis and acetylation status of histones, respectively. Interestingly, only CC102528, but not CC102598, caused death of nearly all MM cells when used at 10 μM or 20 μM. These results suggest that CC102528 blocks HDACs more efficiently than CC102598, or CC102528 targets additional intracellular molecules that are also responsible for its greater anti-MM activity. These results suggest that CC102528 could be a potential novel agent for the treatment of MM. We are currently evaluating the anti-MM effects of this compound in combination with other currently available agents for the treatment of MM including bortezomib, melphalan, dexamethasone, and doxorubicin. We are also determining the effects of this drug alone and in these combinations on normal peripheral blood and bone marrow mononuclear cells. In addition, modifications of CC102528 are being made, and we will determine if these newer analogs improve upon the anti-MM effects of the parent compound. Updated data from these additional studies will be reported at the meeting.

Disclosures
No relevant conflicts of interest to declare.
Thalidomide-Dexamethasone as Induction Therapy Prior to Autologous Stem-Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma and Renal Failure.
Authors: Tosi Patrizia , Zamagni Elena , Tacchetti Paola , Ceccolini Michela , Perrone Giulia , Brioli Annamaria , Pantani Lucia , Petrucci Alessandro , Baccarani Michele , Cavo Michele 
Published: October 2019

Abstract
Abstract 4934
Multiple myeloma (MM) patients presenting with renal feature at disease onset should not be excluded from high-dose therapy programs; seeking novel effective and non-nephrotoxic induction regimens is thus mandatory in order to maximize the reduction of tumor burden prior to transplant.
From May 2002 to February 2008, 31 newly diagnosed MM patients (18 male, 13 female, median age 60 years) with symptomatic MM and renal failure, defined as creatinine clearance '50ml/min, were enrolled in a clinical trial aimed at evaluating the efficacy and the feasibility of a thalidomide-based regimen as induction therapy in preparation to autologous stem cell transplantation. Sixteen patients had a more severe renal impairment (creatinine clearance '30ml/min) and 7 of them were in chronic hemodyalisis. After informed consent, patients received four months of combined oral thalidomide (thal) (100mg/day for two weeks and 200mg/day thereafter) and dexamethasone (dex) (40mg/day on day 1-4, 9-11, 17-20/28 days on odd cycles and on day 1-4 on even cycles); peripheral blood stem cell collection was thus to be performed after priming with high-dose cyclophosphamide + G-CSF or G-CSF alone; a single or double autologous stem cell transplantation was then to follow, upon preparation with high-dose melphalan. After induction, a PR or better was obtained in 23 patients (74%), with 8 patients (26%) achieving a VGPR or better. No difference in response rate was observed in patients with a baseline creatinine clearance ≥30ml/min (86%) or < 30ml/min (62%). An improvement in renal function was more frequently observed in patients achieving ≥ PR (82% vs. 37% in patients obtaining < PR, p =0.04). Twenty-six patients underwent peripheral blood stem cell mobilization; in 17 of them (65%) the procedure was successful resulting in the collection of > 4 × 106 CD34+ cells/kg. Fifteen patients received a double autologous stem cell transplantation while a single transplant was performed in four patients. Overall, median event-free survival was 30 months, and median survival has not been reached, upon 32 months median follow-up. Toxicity profile of thal-dex was comparable to that observed in patients with a normal renal function. In conclusion, our data show that thal-dex can be safely administered in patients with newly diagnosed MM and renal failure. given the relationship between recovery of renal function and response to induction treatment, more intensive thal + bortezomib-including regimens could be potentially useful in order to rescue a higher number of patients.

Disclosures
Off Label Use: Thalidomide plus dexamethasone in newly diagnosed multiple myeloma.
Successful Bortezomib-Based Therapy in POEMS Syndrome.
Authors: Tang Xiaowen , Shi Xiaolan , Sun Aining , Qiu Huiying , Gu Bin , Zhou Huifen , Xue Shengli , Liu Yuejun , Ruan Changgeng , Depei Wu 
Published: October 2019

Abstract
Abstract 4966
POEMS syndrome is a rare multisystem disease characterized by polyneuropathy (P), organomegaly (O), endocrinopathy (E), serum M-protein (M), and skin changes (S). Owing to the fairly little refined mechanisms underlying the pathogenesis of POEMS syndrome, standard and general-accepted regimens have not been established to date. Recently, we successfully treated a POEMS syndrome patient who was unresponsive to conventional therapies by using bortezomib-based regimen. This 37-year-old patient represented a number of typical manifestations including: 1) paresthesia, 2) increased level of IgA » type of M protein, 3) elevated concentration of serum VEGF (vascular endothelial growth factor), 4) splenomegaly, gynaecomastia, limbs edema, hydropericardium, hydrothorax, and plethora. According to the latest Mayo Clinic criteria, the diagnosis of POEMS syndrome could thus be comfirmed. After several courses of classical regimens [VAD (Vincristine, doxorubicin, dexamethasone), CMP (cyclophosphamide, melphalan and prednisone) and AD (doxorubicin and dexamethasone)], the patient poorly responded with only slight improvement and failed to achieve remission. Following the patient's informed consent and Ethics Committee approval, a tentative VDD regimen was carried out. The details were as follows: Bortezomib, at a dose of 1.3-1.6 mg/m2 (initial cycle: 1.3 mg/m2 in the first week, 1.6 mg/m2/w in following three weeks; next three cycles: 1.6 mg/m2/w×4 weeks in each cycle); 40 mg of Liposomal doxorubicin on the fourth day of the first week; and 10 mg of dexamethasone during the initial 4 days of first cycle. Each course was at 21 days interval. Following four cycles of VDD, the patient acquired remarkable improvement (concerning neurological disease, skin changes, clonal plasmacytosis, and organomegaly) and finally achieved complete remission. To our knowledge, It should be the first time in the world that the bortezomib-based new strategy could be applied effectively against the POEMS syndrome. Further, we could speculate that the VDD regimen would be a potent candidate in the treatment of POEMS syndrome, at least in the conventional therapy-resistant condition.

Disclosures
No relevant conflicts of interest to declare.