bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extramedullary Multiple Myeloma Associated With Reduced Overall Survival: A Retrospective Single-Center Study
Authors: Barkay Ido , Maziarz Richard T. , Chen Andy I. , Dibb William , Chen Yiyi , Scott Emma C. 
Published: October 2019

Abstract

Introduction
Multiple Myeloma (MM) is an incurable neoplasm, however recent advancements in therapies have led to median overall survival of 7-10 years in standard risk patients. High risk patients still succumb to the disease within 3 to 5 years. Traditionally used clinical prognostic markers such as the International Staging System (ISS), the Durie-Salmon (DS) staging system, and cytogenetics do not adequately predict response to novel agents or overall prognosis. We previously presented data identifying high risk sub-groups that succumb to shorter progression free survival (PFS) and overall survival (OS) after hematopoietic stem cell transplant (HSCT). Extramedullary disease (EMD) was a highly significant risk factor for poor survival.

Methods
A retrospective single institution cohort study was performed of 251 patients who underwent HSCT for MM between 1/1/2001 and 12/31/2011. Of these 251 patients, 18 were identified as having EMD, which was defined by the presence of ≥ 2 plasmacytomas in organs other than bone marrow or bone at any stage of disease. Data points collected included patient and disease characteristics, ISS and DS stage, cytogenetics and FISH, induction therapy, type and number of HSCT, treatment type and cycles, as well as maintenance therapy. Outcome measures included overall response rate (ORR), PFS and OS. Descriptive statistical analysis was conducted for all primary and secondary endpoints. Univariate and multivariate analysis were conducted using the Cox proportional hazards regression model.

Results
Patients with EMD represented 6.6% of our total population. Patient and disease characteristics are found in table 1. Seven of 18 patients had died by the time of data collection. With a median follow up time of 29 months, the median PFS and OS for the entire group (n= 251) compared to the EMD group (n= 18) were PFS: 22.3 months (95% CI 19.75 – 30.32) vs. 12.9 and OS: 57.3 months (95% CI: 46.52 - 77.77) vs. 17.2 (Figs 1 and 2). Results of univariate and multivariate analysis are in table 2.

Conclusion
Extramedullary multiple myeloma represents a small but highly aggressive subgroup of multiple myeloma. It prevails as a poor prognostic indicator despite the use of novel agents, yet it is not included in traditionally used staging systems. Further confirmatory studies are needed, and likely, new therapeutic approaches will be required for MM patients with EMD.

Disclosures:
Chen: Genzyme: supported database used for this study Other. Scott:Millenium Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Research Funding.
CXCR4 Is a Regulator Of Disease Involvement Of Extramedullary Myeloma Confirmed By a Novel Mouse Model For Extramedullary Disease
Authors: Mishima Yuji , Moschetta Michele , Reagan Michaela R , Zhang Yong , Sahin Ilyas , Maulkhan Niraj , Roccaro Aldo M , Ghobrial Irene M. 
Published: October 2019

Abstract

Background
Extramedullary disease (EMD) in patients with multiple myeloma occurs mostly in advanced disease or relapse. EMD seems to have a different pathogenesis from medullary myeloma and is often characterized by a more aggressive clinical course. To date molecular mechanisms of development of EMD have not been fully understood. Methods: Human MM cell lines, IM-9 and MM1S were serially selected in immune-deficient mice. IM-9 and MM1S cells were inoculated intravenously and harvested from the tumors developed in the bone marrow (BM) and liver (site of extramedullary disease), aiming to establish BM-prone and liver-prone clones. Tumor progression was periodically checked by bioluminescence (BLI) and in vivo live confocal imaging. After three rounds of in vivo selections, the cells of both BM- and liver-prone were characterized by gene and protein expression and cellular functional assays. Results: We obtained three liver-prone sub-clones in both IM-9 and MM1S after serial in vivo selections. These cells had equal proliferation rates in vitro compared to the original or BM-prone cells, but exhibited more aggressive phenotype in vivo. Liver-prone clones had significantly higher migration ability than BM-prone clones (11.6% vs 6.1% migration, respectively p=0.018). Gene and protein expression analysis revealed that each liver-prone clone had a higher expression of sets of chemokine receptors specifically CXCR4. Using thein vivo metastatic model CXCR4-over expressing myeloma cells exhibited higher metastatic property to the extramedullary organs whereas CXCR4-knockdown cells has less tumor metastasis to the liver. Discussion: We established EMD-prone human multiple myeloma cell lines that reproducibly developed liverinvolvement consistent with human extramedullary disease. These cells exhibited higher migratory ability and increased expression of several chemokine receptors, specifically CXCR4. We validated the effect of CXCR4 on developing extramedullary myeloma using our established in vivo mode. Further studies to determine the role of CXCR4 for therapeutic targeting of extramedullary disease in MM are ongoing.

Disclosures:
Ghobrial: Sanofi: Research Funding; Noxxon: Research Funding; BMS: Advisory board, Advisory board Other, Research Funding; Onyx: Advisoryboard Other.
Baicalein Synergy Lenalidomide To Induce Apoptosis Of Myeloma Cell
Authors: Zhang Ruibo , Ma Zi , Liu Shangqin , He Li , Xu Chaoping , Hu Guiying , Huang Jianying , Zhang Yicheng 
Published: October 2019

Abstract

Objective
To understand the apoptotic effects and cereblon (CRBN) gene and protein expression induced by baicalein in MM cells.

Methods
Apoptotic MM cells induced baicalein，lenalidomide or combination of BAI and lenalidomide were stained by using Annexin-V and analyzed by flow cytometry. RT-PCR was used to detect CRBN gene expression in MM cells. CRBN protein expression was detected by western blot in MM cell lines.

Results
At the concentration of 40 μmol/L, baicalein can induce apoptosis of U266 cells in a time-dependent manner. At the different BAI treated time points (24h, 48h, 72h), the apoptotic cell percentages were 6.11%, 11.9%, 16.7%; After treated RPMI 8226 cells for 72 hours, combined application of baicalein and lenalidomide (both concentrations are 40 μmol/L) could induce more cell apoptosis than baicalein or lenalidomide alone. The apoptotic cell percentages induced by baicalein, lenalidomide or combined application of baicalein and lenalidomide were 15.9%, 4.27%, and 57.5%. CRBN gene expression detected by RT-PCR could be induced by baicalein in U266 cells in a dose-and time-dependent manner. Treated U266 cells for 24h at concentrations of 10 μmol/L, 20 μmol/L and 40 μmol/L, baicalein upregulated CRBN gene expression times were 2.246 ± 0.068, 2.399 ± 0.178 and 3.591 ± 0.061,respectively，compared to the control group. Statistically, the P values were 0.003, 0.009 and 0.001; Treated U266 cells at concentrations of 40 μmol/L at different time points (6h, 12h and 24h), baicalein upregulated CRBN gene expression times were 2.372 ± 0.079, 2.494 ± 0.189 and 3.228 ± 0.151, its P values were 0.002, 0.008 and 0.002.CRBN protein expression detected by using western blot could be induced by baicalein in both U266 and RPMI8226 cell lines.

Conclusions
Baicalein at suitable concentrations induced MM cells apoptosis in a time-dependent manner. Comparison with the single component used alone,combined application of baicalein and lenalidomide exhibited stronger inhibition effect on proliferation of RPMI 8226. Considering CRBN is the cellular target for lenalidomide, baicalein can up-regulate the CRBN gene and protein expression in MM cells and may enhance MM cell sensitivity to apoptotic stimuli. Therefore, baicalein up-regulated CRBN gene and protein expression and sensitized MM cells to apoptosis stimuli induced by lenalidomide. It provides us a possibility for baicalein clinical application to overcome the resistance to lenalidomide for MM patients in the future

Disclosures:
No relevant conflicts of interest to declare.
Circulating microRNA 483-5p in multiple myeloma as a novel biomarker for diagnosis and predicting survival
Authors: Xiaoyan Qu , Zhao Min , Wu Shuang , Wenjun Yu , Jiaren Xu , Xu Ji , Li Jianyong , Lijuan Chen 
Published: October 2019

Abstract

Background
MicroRNAs (miRNAs) are a class of small non-coding single stranded RNAs whose dysregulation of expression plays an important role in cancer development. Circulating miRNAs are novel biomarkers in several cancers including acute myeloblastic leukemia and diffuse large B cell lymphoma. Thus, we explored whether the miRNAs in plasma could be a useful clinical biomarker for multiple myeloma (MM) patients.

Methods
MiRNA microarray was conducted to determine deregulated miRNAs in plasma of MM patients. TaqMan real-time PCR was used to validate the results. Receiver operating characteristic (ROC) analysis was performed to reveal the diagnostic accuracy of the significantly deregulated miRNAs as potential biomarkers. The Kaplan-Meier and log-rank tests were used to assess the correlation of miRNAs with progression-free survival (PFS).

Results
The expression levels of five miRNAs in plasma were up-regulated while eight miRNAs were down-regulated in MM patients compared to normal controls according to microarray. Validation of the five miRNAs detected as promising biomarkers was carried out. MiR-483-5p was found to have potential as diagnostic biomarkers in myeloma. ROC analysis revealed that miR-483-5p had considerable diagnostic accuracy, yielding an ROC-AUC (the areas under the ROC curve) of 0.722 (sensitivity 61%, specificity 75%). The expression levels of miR-483-5p are associated with Durie-Salmon (DS) staging system and ISS staging system (p < 0.01). After a median follow up of 10 months (range: 2-60 months) from diagnosis, the median PFS of patients highly expressing miR-483-5p and of low expression patients was 11 and 21 months, respectively (p=0.04).

Conclusions
These data demonstrate that miR-483-5p highly expresses in the plasma of MM patients. MiR-483-5p may serve as a diagnostic and prognostic biomarker in MM.

Disclosures:
No relevant conflicts of interest to declare.
Jewish Immigrants Of Middle Eastern Origin Have a Lower Incidence Of Multiple Myeloma Compared To Both North African and European Jews In a Cohort Of 746,200 Israeli Men Followed From Late Adolescence
Authors: Leiba Merav , Afek Arnon , Derazne Estela , Leiba Adi , Keinan-Boker Lital , Shamiss Ari , Nagler Arnon , Kark Jeremy D. 
Published: October 2019

Abstract
Differences in the prevalence of Multiple Myeloma across races have been observed, with a two to three fold greater prevalence of Multiple Myeloma in African Americans compared with Caucasians. Little is known about the incidence or prevalence of Multiple Myeloma in other populations.
The association between father's country of origin and the incidence of Multiple Myeloma was examined in a nationwide population-based cohort.
Health-related data on 746,200 16-19 year old Jewish males examined for fitness for military service between 1967 and 1998 were linked to the Israel National Cancer Registry to derive Multiple Myeloma incidence up to 2006.
During 17,352,349 person-years of follow-up, 109 examinees developed plasma cell dyscrasias. West Asian origin (predominantly Middle Eastern) was protective compared to European (predominantly Ashkenazi) origin (HR 0.40; 95% CI 0.23-0.70; p=0.001). The association persisted when adjusted for year of birth (HR 0.39; 95% CI 0.22-0.68; p=0.001), and also when restricted to Israeli-born males (HR 0.44; 95% CI 0.24-0.82; p=0.01).
In conclusion, adolescents of Middle Eastern origin are at persistently lower risk of developing Multiple Myeloma compared to European origin, suggesting a genetic background in the pathogenesis of Multiple Myeloma.

Disclosures:
No relevant conflicts of interest to declare.
Multiple Myeloma In Patients Under 40 Years Old Is Associated With High-Risk Features and Worse Outcomes
Authors: Costello Caitlin L. 
Published: October 2019

Background
The median age of patients diagnosed with multiple myeloma (MM) is approximately 70 years old. It is an uncommon malignancy in persons younger than 40 years, representing only 2% of all patients diagnosed with MM. It has been suggested that young patients may present with more aggressive and less common disease features, frequently delaying the initial diagnosis and thereby affecting outcomes. With this background, we explored the outcome of young MM patients presenting to our institution over the past thirteen years.

Methods
We performed a retrospective review of a cohort of 236 patients with MM who received treatment for active MM at the University of California, San Diego Moores Cancer Center between January 2000 and July 2013. The demographics and disease features of patients up to 40 years of age at diagnosis were analyzed using descriptive statistics. The survival outcomes of these young patients were compared with the remainder of the cohort using the Kaplan-Meier method.

Results
Nineteen (6.5%) out of the 236 patients with MM were ²40 years of age at diagnosis, with a median age of 35.5 years old. The median follow-up of this group of young patients was 42 months (range 5-92). The patient and disease characteristics are outlined in Table 1. Seven young patients (37%) had MM with no heavy chain component, including light chain only secreting or non-secretory disease. Seven patients (37%) had a non-IgG paraprotein. Nine (56%) patients presented with extramedullary plasmacytomas. Two (10%) patients had plasma cell leukemia. All patients received at least one treatment regimen that included a novel agent. Fifteen patients (79%) had received high-dose therapy, and four patients (21%) underwent allogeneic stem cell transplantation (SCT) after at least one prior autologous SCT. The 5-year and 7-year overall survival (OS) from diagnosis was 51.7% and 28%, respectively, and the median OS was 60.7 months. In contrast, the median OS of patients ≥41 years old at diagnosis was 78.6 months (p=0.15, figure 1).

Conclusion
In this single center study with long follow up, we demonstrate that patients diagnosed with MM ²40 years of age exhibit several high-risk features and frequently present with advanced stage disease. Despite the use of novel agents in this population, there is a statistical trend towards a worse outcome with an 18-month difference in median overall survival when compared to older patients with MM. More aggressive treatment strategies are needed to improve survival in this young patient population.

Disclosures:
No relevant conflicts of interest to declare.
Multiple Solitary Plasmacytoma: Characteristics, Response To Therapy, Survival In Nine Patients From a Single Institute
Authors: Zhang Yanru , Qi Junyuan , Qiu Lugui 
Published: October 2019

Abstract

Objective
The International Myeloma Working Group in 2003 recognized a separate classification of plasmacytomas that occur as multiple sites of disease in soft tissue, bone, or both as multiple solitaryplasmacytoma (MSP). There are only few cases of MSP described in literatures. As a rare mylema, relatively little is known about its features, treatment response, and survival.

Method
we have retrospectively analyzed nine patients with MSP in our hospital from 2009 to 2013.

Result
The median age was 49 (26-49) years old. There were six males and three females. All but one had M-protein in serum and/ or urine. There was a predominance of lambda light chain (6/8). Most cases had multiple bone lesions (8/9).Only one had multiple solitary extramedullary plasmacytoma localized on CNS tissue and right lumber. Most (6/9) were stage III of DS for and seven cases were stage I of ISS. Six patients were treated with regimen containing bortezomib as induction therapy. And one of them underwent high-dose of chemotherapy with autologous stem cell transplantation (HDT/ASCT) at CR as part of their front-line therapy. Another three patients were treated with conventional alkylating agent combined with glucocorticoid based chemotherapy. After initial chemotherapy, seven patients reached CR, one PR. In first line combinational chemotherapy that containing bortezomib (Btz) (n=6), 100% patients achieved CR ,compared with that of 33.3% in patients treated with conventional chemotherapy (P =0.083). Date cut-off was July 20, 2013, a median follow-up of 28.5 (range2-38) months. The median OS time was 29, median progression -free survival (PFS) was 8 months. However, none of them progressed to MM. In addition, compared with the patients whose regimes included Btz (n=6), the patients who got conventional chemotherapy (n=3) had a trend towards poorer median OS (not reach versus 28 months, P = 0.116) and shorter median PFS (6 months versus 38 months, P = 0.356).

Conclusion
MSP was at early stage at diagnosed. Most cases were male and λ light chain type. Although there was a good treatment response, these patients easily progressed. ISS may not suitable for evaluation of prognosis with MSP.Bortezomib based therapy could further deepen degree of remission , prolong the survival.

Disclosures:
No relevant conflicts of interest to declare.
Tryptophan Metabolites Analogue, N-(3,4-dimethoxycinnamonyl) Anthranilic Acid, Ameliorates Acute Graft-Versus-Host Disease Through Inhibiting Th1 Responses
Authors: Xu Jinhuan , Zhang Yicheng 
Published: October 2019

Abstract
Local catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is considered an important mechanism of regulating T cell immunity. N-(3,4-dimethoxycinnamonyl) anthranilic acid (3,4-DAA) is an active synthetic anthranilic acid derivative which was proved to be effective to treat type±helper T lymphocytes (Th1) mediated autoimmune diseases such as multiple sclerosis. In this report, we investigated the effects of 3,4-DAA on the acute graft versus host disease (aGVHD) following allogeneic bone marrow transplantation (allo-BMT) and its potential mechanism of action. we established a murine aGVHD model, 3,4-DAA was injected intraperitoneally at 200 mg/kg/day per mouse immediately after allo-BMT or at the onset of aGVHD for 14 consecutive days; the signs of aGVHD and the survival were recorded periodically; the histological changes of target organs were evaluated with hematoxylin-eosin staining; the IDO activity and cytokine levels in plasma were measured by reverse-phase high-performance liquid chromatography (HPLC) and enzyme linked immunosorbent assay (ELISA), respectively. We revealed that administration of 3,4-DAA after allo-BMT significantly reduced the severity and the histological score of aGVHD; The survival for mice receiving 3,4-DAA prophylaxis and treatment were prolonged in comparison to the vehicle control mice. The plasma levels of IFN-γ, TNF-α, IL-12 and IL-2 in 3,4-DAA treatment group were found to be decreased, while the IDO activity, the IL-10, IL-5 and IL-4 levels elevated in these mice. In consistent with the in vivo results, 3,4-DAA also inhibited IFN-γ and IL-2 production of spleen T lymphocytes in vitro. Our findings suggest that 3,4-DAA can diminish the murine experimental aGVHD through inhibition of Th1 response; this property makes it a potential alternative agent for prevention and treatment of GVHD in the clinic.

Disclosures:
No relevant conflicts of interest to declare.
Chemotherapy With Infusion Related HLA-Mismatched Hematopoietic Stem Cells For Hematologic Malignancies: A Novel Therapeutic Strategy
Authors: Fu Li , Wang Zhao 
Published: October 2019

Abstract

Objective
To investigate the therapeutic outcomes of chemotherapy with infusion related HLA-mismatched hematopoietic stem cells for hematologic malignancies.

Method
Therapy responses and hematopoietic recovery as well as complications of 9 patients were analyzed.

Result
In the 9 patients aged 29-67 years, four were acute myeloid leukemia, one was acute B lymphocytic leukemia, two were multiple myeloma, one was Hodgkin’s disease, one was diffuse large B cell lymphoma. The average MNC was (3.12±1.29)×108/kg, CD34+ cells was (1.71± 1.00)×106/kg, CD3+ cells was (2.13±0.99)×108/kg. There was complete remission in four patients, partial remission in one, disease progression in four. Following up 2 to 14 months, four patients was in survival. No donor chimerism was detected and no graft-versus-host disease was observed in any patient.

Conclusion
Chemotherapy with infusion related HLA-mismatched hematopoietic stem cells for hematologic malignancies may provide a promising treatment method as a novel therapeutic strategy.

Disclosures:
No relevant conflicts of interest to declare.
Oral Cryotherapy For The Prevention Of Mucositis Following Myeloablative Conditioning and Hematopoietic Stem Cell Transplantation
Authors: Lu Yin , Zhu Xiaming , Depei Wu 
Published: October 2019

Abstract

Purpose
To investigate the effect of oral cryotherapy for the prevention of oral mucositis in recipients of Hematopoietic Stem Cell Transplantation(HSCT) after myeloablative conditioning and to specify its best timing and duration.

Methods
This study was a prospective randomized controlled clinical study, involving 37 patients from the bone marrow transplantation unit of the First Affiliated Hospital of Soochow University. In addition to the basic oral care given to all patients, study participants were divided into two experimental groups given oral cryotherapy and one control group. Optimal timing of the oral cryotherapy intervention was explored, based on pharmacokinetics of drug elimination. During the period of conditioning, experimental group 1(Exp.1) received oral cryotherapy from the beginning of drug infusion continuously until the end of drug infusion; experimental group 2 (Exp.2) received oral cryotherapy starting half way through the infusion of the drug. The rate and severity of mucositis was evaluated according to the National Cancer Institute-Common Toxicity Criteria. Data were then analyzed using SPSS15.0.

Results
Oral mucositis occurred on cheeks (43.9%), tongue (27.57%) and lips (15.7%). There was no difference regarding the incidence of severe mucositis ≥ Grade 3 (33% in Exp.1 group, 15% in Exp.2 group, and 25% in the control group, p = ns) and its duration (8 days in Exp.1 group, 2.5 days in Exp.2 group, and 7 days in the control group, p = ns). However, the frequency of vomiting episodes was significantly reduced in Exp.2 with 10 episodes (2-28) versus 21 (2-60) in the control group (p=0.01) and 12.5 (2-39) in exp 1. [Conclusions] A short duration of oral cryotherapy beginning at midpoint of infusing the chemotherapy schedule significantly reduced vomiting associated with myeloablative conditioning. These preliminary results in view of the low statistical power of the study justify further trials.

Disclosures:
No relevant conflicts of interest to declare.