bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Prognostic Scoring System for Patients with Multiple Myeloma Who Were Classified Stage II By Revised International Staging System
Authors: Jung Sung-Hoon , Kim Kihyun , Kim Jin Seok , Kim Seok Jin , Cheong June-Won , Kim Soo-Jeoong , Ahn Jae-Sook , Ahn Seo-Yeon , Yang Deok-Hwan , Kim Hyeoung-Joon , Lee Je-Jung 
Published: October 2019

Abstract
Background: Revised International Staging System (R-ISS) is recently proposed risk stratification algorism based on ISS, cytogenetic risk, and lactate dehydrogenase in multiple myeloma (MM). Although R-ISS had an improved prognostic power compared to ISS, there is a problem that patients with stage II increase to 1.7 times. In this study, we evaluated survival outcomes and a new prognostic tool for MM patients classified as R-ISS II.
Methods: Retrospective data from 441 patients who were initially treated with a novel agent-containing regimens were analyzed.
Results: R-ISS staging system could discriminate survival outcome more clearly compared to ISS in patients treated with novel-agents [median overall survival (OS) times of R-ISS I vs. II. Vs. III was 76.3 vs. 51.3 vs. 30.3 months, P < 0.001]. By applying R-ISS, 6.2% of patients with ISS I, and 24.3% with ISS III were reclassified into R-ISS II. Overall, 290 patients (66%) was classified into R-ISS II and had wide range of survival outcomes (0.7-114.5 months). In multivariate analysis, poor performance status (PS) (HR 1.657, 95% CI 1.159-2.370, P =0.006), del (17p13) (HR 2.227, 95% CI 1.174-4.223), P = 0.014), and thrombocytopenia (HR 1.533, 95% CI 1.033-2.276, P = 0.034) were significantly associated with OS in patients with R-ISS II. Based on this analysis, we constructed a new prognostic model consisted of poor PS (1 point), del(17p13) (2 point), and thrombocytopenia (1point). Among the 290 patients, 152 patients (52.4%) were classified as low-risk (score 0), 109 (37.5%) as intermediate risk (score 1), and 29 (10%) as high risk (scores 2 or more). The median OS times for the corresponding risk groups was 57.5 months (95% CI 40.4-74.5), 30.2 months (95% CI 20.7-39.7), and 20.9 months (95% CI 6.4-35.3) (P <0.001).
Conclusion: R-ISS is an excellent prognostic tool in MM in the novel-agent era, but there is a limitation that most of patients were classified into R-ISS II. A new prognostic model for patients with R-ISS II is needed, and prognostic scoring system based on poor PS, del(17p13), and thrombocytopenia may be useful to distinguishing survival outcomes of patients with R-ISS II.
Figure Figure.

Disclosures
No relevant conflicts of interest to declare.
Concomitant Suppression of IKZF1, IRF4 and MYC Contribute to the Anti-Tumor Activity of the BET Inhibitor, Cpi-0610, in Disease Models of Multiple Myeloma
Authors: Siu Ka Tat , Ramachandran Janani , Yee Andrew J. , Eda Homare , Santo Loredana , O'Donnell Elizabeth K. , Panaroni Cristina , Mertz Jennifer , Sims Robert J. , Cooper Michael , Raje Noopur 
Published: October 2019

Abstract
Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic malignancies. Previous studies suggest that BET inhibitors constrain tumor cell proliferation and survival mainly through suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the anti-tumor activity of BET inhibitors but is less well understood.
Here we investigated the therapeutic potential of CPI-0610, a novel BET inhibitor that is currently in a phase I clinical trial in relapsed multiple myeloma (MM) (ClinicalTrials.gov Identifier: NCT02157636). CPI-0610 displays potent in vitro cytotoxicity against MM cell lines and patient-derived MM cells by inducing G1 cell cycle arrest and caspase-dependent apoptosis. Furthermore, CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse model. CPI-0610 significantly delayed tumor growth and increased the survival of MM-bearing SCID mice.
Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC. These findings indicate that BET inhibition not only results in a robust reduction of MYC transcription and activity but also suppresses the expression of IKZF1 and IRF4 in MM. Given that immunomodulatory drugs stabilize cereblon and facilitate Ikaros degradation in MM cells, we combined it with CPI-0610. Combination studies of CPI-0610 with lenalidomide or pomalidomide show in vitro synergism, in part due to concomitant suppression of IKZF1, IRF4, and MYC, providing a rationale for clinical testing of this drug combination in MM patients.

Disclosures
Mertz: Constellation Pharmaceuticals, Inc.: Employment, Equity Ownership. Sims:Constellation Pharmaceuticals, Inc.: Employment, Equity Ownership. Cooper:Constellation Pharmaceuticals, Inc.: Employment, Equity Ownership. Raje:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding.
Polymorphisms of CTLA-4 Are Associated with Treatment Outcome in Multiple Myeloma Patients Receiving Bortezomib-Based Regimens
Authors: Qin Xiao-Ying , Lu Jin , Li Guo-Xuan , Wen Lei , Xu Lan-Ping , Chang Ying-Jun , Liu Kai-Yan , Jiang Zheng-Fan , Huang Xiao-Jun 
Published: October 2019

Abstract
Objectives: SNPs of CTLA-4 have been shown to be important risk factors associated with autoimmune disease and malignancy , the objectives of this study were to explore the association of CTLA-4 SNPs with the development of myeloma and to evaluate the outcome of patients receiving bortezomib-based regimens in relation to CTLA-4 SNPs.
Methods: Peripheral blood samples from 86 MM patients and 154 controls were obtained for the investigation of CTLA4 polymorphisms, The five SNP genotypes of CTLA-4, namely, -1772(rs733618),-1661 (rs4553808), -318 (rs5742909), CT60 (rs3087243), and +49 (rs231775), were determined by TaqMan SNP genotyping assays (Applied Biosystems) ,
Results: Some of the CTLA-4 polymorphisms display frequencies that are different among the different ethnic groups. The Kaplan-Meier analysis revealed that patients with rs733618 GG showed a significantly lower DFS (0% vs. 57.4%, P = 0.020) and OS (46.3% vs. 83.3%, P = 0.026) than those with GA+AA in MM patients after Botizomib based therapy. Multivariate analyses showed that rs733618 GG were risk factor for OS (HR= 0.025; 95% CI= 0.004-0.161;P=0.000). The incidence of nonhematologic grade 3/4 adverse events was significantly increased in the rs 4553808 GA+GG group compared to AA group(P=0.036).
Conclusion: In summary, CTLA-4 rs733618 GG reduced the progression-free survival and overall survival in MM patients after Botizomib based therapy,knowledge of the CTLA-4 polymorphism and haplotype may provide useful information for MM therapy. The exact effect of the CTLA-4 polymorphism and haplotype on MM therapy outcome should be determined in different cohorts with substantially larger number of subjects.
Correspondence: Professor X-J Huang, Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking-Tsinghua Center for Life Sciences, 11 Xizhimen South Street, Beijing 100044, P.R. China. E-mail: huangxiaojun@bjmu.edu.cn
The first 2 authors contributed equally to this work.

Disclosures
No relevant conflicts of interest to declare.
Functional and Pain Score Improvement with Vertebroplasty in De Novo Multiple Myeloma in a Public Institution in Mexico
Authors: Torres Jorge Carlos , Espinoza Ramiro , Alarcon Silvia , Zapata Nidia , Cervera Eduardo , Sosa Alejandro , Vieyra Magnolia , Espinoza Javier , Sosa Luis , Oñate Luis , Lahuerta Juan José , Aguilar Manuel 
Published: October 2019

Abstract
Multiple myeloma a plasmatic cell disorder, characterized by bone marrow infiltration of clonal plasmatic cells, monoclonal immunoglobulin production and end stage organ damage. This disease has a wide range of clinical manifestations, including solitary disease or plasmacytoma. It´s the second most common hematologic disease just behind Non Hodgkin Lymphoma. More than 60% of de novo MM patients present vertebral involvement.
80% of MM patients refer pain as the first symptom of the disease, and this often leads to opioid abuse and adverse effects related to pain medication. Plasmocytoma is one of the three neoplastic lesions of the vertebra that can be susceptible of percutaneous vertebroplasty.
The preferred method of treatment is a percutaneous vertebroplasty (PV), a radiologic invasive treatment that can treat multiple pathologies, and is now widely used for treatment of osteoporosis vertebral fractures.
For the purpose of the study we aimed to assess functional status and reincorporation to daily living, we used the Karnofsky Performance Status; and the Barthel index. For pain improvement we used the Visual Analog Scale. The Likert satisfaction scale (introduced in 1932) measures patient satisfaction in an analog scale.
The main objective of the study was to assess the repercussion of the PV in pain score modification and improvement of functional scores in patients with MM at the Pain Clinic of the Instituto Nacional de Cancerología (INCan) in Mexico City.
We carried out the study between January 2004 and October 2015. We compared VP treatment to bisphosphonate (BP) and radiotherapy (RT) according to the visual analog scale; and according to Karnofsky and Barthel scales, we determined the reincorporation to daily activities.
We included 119 new cases con MM, of this only 64 were included in the study. Of this 54 were female, and 65 were male with a mean age of 59 years (28-87). 88% of patients referred pain as their main symptom, and 70% presented with a vertebral fracture. 26.9% had an ECOG of 3 or more. 96% (114) received RT and 99% (118) BP.
64 (54%) of patients were treated with VP. Of this, 67% referred a VAS of 4 or more (moderate to severe pain). And 92% of the patients achieved a VAS of 4 or less. As for the Karnofsky we assessed an improvement of 50/80 points pre VP to 80/90 post VP. The same result was assessed in the Barthel scale, with an improvement of 50/80 points pre VP to 80/100 post VP.
This data provides solid evidence of the importance of multidisciplinary approach, and that VP is a safe and effective treatment, coupled of course with BP and RT.

Disclosures
No relevant conflicts of interest to declare.
Basal CD34+ Cell Count Predicts Peripheral Blood Hematopoietic Progenitor Cells Mobilization in Healthy Donors after Administration of G-CSF
Authors: Martino Massimo , Gori Mercedes , Pitino Annalisa , Dattola Antonella , Fedele Roberta , Gallo Giuseppe Alberto , Barillà Santina , Pontari Antonella , Irrera Giuseppe , Messina Giuseppe , Moscato Tiziana , Console Giuseppe , Morabito Fortunato , Tripepi Giovanni 
Published: October 2019

Abstract
BACKGROUND: Peripheral blood (PB) hematopoietic progenitor cells (HPC) mobilized with G-CSF are the first-choice source for allogeneic stem cell transplantation. We carried out a prospective study on healthy donors (HDs), to identify donor characteristics that could influence the effectiveness of mobilization.
STUDY DESIGN AND METHODS: PB-HPC allogeneic donations from sibling HDs were analyzed. We tested somatic variables (sex, age, weight, height, volemia) and blood counts (WBC, platelets, hemoglobin, CD34+ cell count). Two different determinations of CD34+ cells were done in each HD: baseline (before G-CSF administration) and in PB on the morning of the fifth day (after G-CSF administration). HDs received G-CSF subcutaneously at a dose of 10 µg/kg per day.
RESULTS: 128 consecutive HDs (66 males) with a median age of 43 years were enrolled. The mean value of CD34+ on day 5 was 90.8 cells/µL, 84.2 cells/µL in females and 97.2 cells/µL in males. The median values of CD34+ on day 5 were 75.5 cells/µL for the overall sample, 74 cells/µL in females and 80 cells/µL in males. On univariate correlation analysis, donor weight r=0.19, P<0.05, height (r=0.20, P<0.05), volemia (r=0.18, P<0.05) and baseline CD34+ (r=0.38, P<0.001) were significant predictors of CD34+ on day 5. Data analysis by gender showed that CD34+ on day 5 were predicted by age (r=-0.30, P<0.05), baseline WBC (r=0.25, P<0.05), baseline CD34+ (r=0.31, P<0.05) in males and by baseline CD34+ (r=0.45, P<0.001) in females. We performed two multivariate analyses either by using ordinary regression (to predict the mean value of CD34+ on day 5) or median regression (to predict the median value of CD34+ on day 5) according to the values of CD34+ at baseline (see table) in the whole study population and separately in females. These results indicate that in the whole study population and by using ordinary regression, a baseline value of CD34+ ranging from 0.5 to 2 cells/µL predicts a mean CD34+ value of 75.7 cells/µL at 5 days whereas a baseline value of CD34+ ≥3 cells/µL predicts a mean CD34+ value of 107.5 cells/µL at 5 days. Furthermore, in the whole study population but by using the median regression, a baseline value of CD34+ ranging from 0.5 to 2 cells/µL predicts a median CD34 + value of 64.6 cells/µL on day 5 whereas a baseline value of CD34+≥3 predicts a median CD34 value of 101.1 cells/µL on day 5.
CONCLUSIONS: Baseline, HDs PB CD34+ cell counts correlated with the effectiveness of allogeneic HPC mobilization and could be useful to plan the collection.

Disclosures
No relevant conflicts of interest to declare.
SHQ1 Regulates MYC mRNA Splicing and Promotes T Cell Leukemogenesis
Authors: Su Hexiu , Hu Yufeng , Jiang Jue , Chen Zhichao , Liu Hudan 
Published: October 2019

Abstract
T-acute lymphoblastic leukemias (T-ALLs) are aggressive hematologic tumors resulting from the malignant transformation of T cell progenitors. In this context, constitutive activation of NOTCH1 signaling is the most prominent oncogenic pathway in T cell transformation. Yet functional role(s) of NOTCH1 in T-ALL pathogenesis and precise mechanism(s) of action remain to be fully determined. SHQ1 is an essential assembly factor for H/ACA ribonucleoproteins which are required for spliceosomal small nuclear RNA (snRNA) maturation. We here identify SHQ1 as a NOTCH1 downstream target that plays a pivotal role in maintaining MYC splicing fidelity and promoting T-ALL cell proliferation in vitro and in vivo.
We identified SHQ1 as a NOTCH1-regulated gene from multiple human T-ALL genome-wide expression studies. To validate this finding, we analyzed SHQ1 expression in a spectrum of human T-ALL cells upon NOTCH1 pathway inhibition. NOTCH1 inactivation caused a marked downregulation of SHQ1 in all T-ALL cell lines tested. We further demonstrated NOTCH1 bound to the canonical CSL binding sites in the SHQ1 promoter and directly activated the transcription.
We next systematically analyzed the SHQ1 expression in 174 T-ALL primary samples and found that SHQ1 expression was significantly elevated in T-ALL compared with normal peripheral blood. To explore the functional role of SHQ1, we knocked it down in T-ALL using specific shRNAs. SHQ1 depletion profoundly inhibited T-ALL cell proliferation and induced massive apoptotic cell death. Consistent with these in vitro findings, SHQ1 depletion in a human T-ALL xenograft significantly delayed leukemia onset and prolonged survival.
To decipher the molecular mechanism whereby SHQ1 contributes to T cell leukemogenesis, we performed genome-wide RNA-Seq and analyzed alternative splicing across the genome. Approximately 70% of genes exhibited abnormal intron retention upon SHQ1 depletion. Among those whose expression levels and mRNA splicing were prominently altered by SHQ1, MYC gained our attention because of its vital role in T-ALL. Depletion of SHQ1 resulted in marked downregulation of mature MYC mRNA and protein. Endogenous mRNA analysis and mini-gene experiments showed aberrant accumulation of MYC pre-mRNA in SHQ1-depleted cells. Expectedly, SHQ1 knockdown had minimal effects on T-ALL cells constitutively expressing a human MYC protein.
In addition to the well-documented transcriptional control of MYC by NOTCH1, we herein report a previously unsuspected mechanism in which NOTCH1 modulates MYC splicing by activation of SHQ1. Our findings not only shed new insights in the molecular pathology of NOTCH1-induced T-ALL but also provide a new layer of regulation of oncogene MYC at the post-transcriptional level, mechanism of which may apply to other MYC involved tumors.

Disclosures
No relevant conflicts of interest to declare.
The Outcomes of Korean Patients with Primary Plasma Cell Leukemia: Analysis of Korean Multiple Myeloma Working Party (KMM160)
Authors: Jung Sung-Hoon , Lee Je-Jung , Kim Kihyun , Yoon Dok Hyun , Min Chang-Ki , Sohn Sang Kyun , Choi Chul Won , Lee Ho Sup , Kim Hyo Jung , Shin Ho-Jin , Bang Soo-Mee , Yoon Sung-Soo , Park Seong Kyu , Yhim Ho-Young , Kim Min Kyoung , Jo Jae-Cheol , Mun Yeung-Chul , Lee Jae-Hoon , Kim Jin Seok 
Published: October 2019

Abstract
Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell neoplasm, with rapid clinical course. In this study, we evaluated the treatment status and survival outcomes of Korean patients with pPCL. Seventy patients were diagnosed with pPCL between February 1998 and December 2015. The median age of the patients was 63.5 years (range, 34-85). Most of patients (70.0%) had International Staging System III.Conventional karyotyping was assessed in 47 patients and FISH analysis was performed in 43 patients. Abnormal karyotype was detected in 34 patients (72.3%). The most common abnormalities were complex karyotype (65.9%). Hypodiploidy, del (13q14), del (17p13), and t(11;14) were found16 (34%), 14 (29%), 12 (25%), and 11 (23%) patients, respectively. Amongthe 70 patients, 60 patients were treated.Thirty-six patients were initially treated with novel agents and 12 received novel-containing regimens as salvage therapy. Twelve patients received conventional chemotherapies only. Twenty-two patients underwent high dose chemotherapy and autologous stem cell transplantation (HDT/ASCT), and one received the allogeneic stem cell transplantation. After a median follow-up of 16.5 months, overall survival (OS) was 16.1 months (95% CI, 11.7-20.8). Twenty patients (33.3%) died within less than one year following the diagnosis, and the early mortality rate was lower in patients who were initially treated with novel agents (22.2% vs. 50.0%, p = 0.049). The median OS of three treatment groups comprising conventional chemotherapy only, novel agents only, and novel agents + HDT/ASCT were 2.9, 12.3, and 31.1 months, respectively (P=0.001). Patients who achieved complete response (CR)after initial therapy had significantly improved OS than did others (36.4 vs. 14.1 months, P < 0.011). On multivariate analysis, achievement of complete response (CR) after induction therapy (HR 0.066, 95% CI 0.007-0.615, P = 0.017), increased lactate dehydrogenase (HR 4.803, 95% CI 1.202-19.186, P = 0.026), andserum beta2-microglobulin > 5.5 mg/dl (HR 3.218, 95% CI 1.011-10.238, P = 0.048)were significantly associated with survival outcomes. In young patients (age < 65 years), performance of HDT/ASCT (HR 0.038, 95% CI 0.004-0.381, P = 0.005) was significantly associated with improved OS. In conclusion, patients with pPCL had poor survival outcomes, and achieving CR after induction therapy associated with increased OS. In addition, performance of HDT/ASCT is important treatment modality to improve OS in young patients with pPCL.
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Prevention of Chronic Gvhd By Targeting Xbp-1 Genetically or Pharmacologically in Mice
Authors: Schutt Steven D , Tang Chih-Hang Anthony , Wu Yongxia , Bastian David A , Del Valle Juan , Hu Chih-Chi Andrew , Yu Xue-Zhong 
Published: October 2019

Abstract
Inhibition of the endoplasmic reticulum (ER) stress response via blockade of inositol-requiring enzyme-1α (IRE-1α) is currently a promising therapeutic strategy to treat B-cell leukemia, lymphoma, and myeloma. Because B cells play an important role in the development of chronic graft-versus-host disease (cGVHD), we hypothesize that the ER stress response contributes to B-cell function and pathogenicity in cGVHD. Here, we report that the ER stress response mediated by IRE-1α and its target X-box binding protein-1 (XBP-1) plays a critical role in cGVHD pathophysiology and represents a potential therapeutic target to prevent cGVHD.
We tested the role of XBP-1 specifically in B cells by testing XBP-1 conditional knockout B cell grafts (XBP1fl/flCD19Cre+) in two mouse models of cGVHD. In the first model (B6 to BALB/c), recipients given XBP-1-deficient donor grafts showed significantly reduced cGVHD clinical scores, which were associated with reduced frequencies of donor-derived CD4 helper T cells within the lungs compared to the recipients of XBP-1fl/flCD19Cre- littermate donor grafts. XBP-1-deficient B cells produced significantly higher levels of IL-10 compared to WT control B cells after activation ex vivo. In the second model (B6 to B10.BR), the conversion of donor B cells to plasma cells (B220+CD38+CD138+) was reduced in both the spleens and lungs of recipients transplanted with XBP1fl/flCD19Cre+ grafts compared to those of the recipients given XBP1fl/flCD19Cre- grafts. Recipients given XBP1fl/flCD19Cre+ grafts also showed significantly higher total splenocytes and vastly increased splenic B-cell populations when compared with the recipients of XBP1fl/flCD19Cre- grafts.
To expand on these findings, we tested if systemic XBP-1 blockade via a novel IRE-1α inhibitor, B-I09, would attenuate cGVHD. In a cutaneous model of cGVHD (B10.D2 to BALB/c), we found that prophylactic administration of B-I09 significantly reduced clinical features of cGVHD compared to vehicle controls (Fig. 1A). Validating these findings, hematoxylin and eosin stained skin sections of B-I09-treated mice had significantly lower pathology scores compared to vehicle controls (Fig. 1B). Isolated skin lymphocytes from recipients treated with B-I09 showed significant reductions in donor derived T cells and DCs compared to those treated with vehicle controls (Fig. 1C and D).
Taken together, our findings reveal a novel role of the IRE-1α/XBP-1 pathway of the ER stress response in cGVHD pathophysiology and provide a readily translatable strategy to prevent the development of cGVHD in the clinic.

Disclosures
No relevant conflicts of interest to declare.