bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thrombotic Microangiopathy in Multiple Myeloma
Authors: Yui Jennifer , Van Keer Jan , Vij Ravi , Jhaveri Kenar , Kastritis Efstathios , Buadi Francis , Dispenzieri Angela , Dingli David , Russell Stephen J. , Leung Nelson 
Published: October 2019

Abstract
Background: Thrombotic microangiopathy (TMA) is a hematologic syndrome associated with endothelial injury, microvascular thrombosis, and hemolytic anemia resulting in end organ damage. TMA is rarely associated with multiple myeloma (MM) and is usually reported in the setting of allogeneic hematopoietic stem cell transplants (AHSCT), with associated graft versus host disease and calcineurin inhibitor use. We present 11 cases of TMA in MM patients not associated with AHSCT.
Methods: Cases were collected from multiple centers in patients with confirmed diagnosis of MM. TMA was diagnosed by the presence of thrombocytopenia and evidence of microangiopathic hemolytic anemia.
Results: Eleven patients with MM were identified to have developed TMA during the course of their disease. Two patients presented with TMA at the time of MM diagnosis. A third had been off treatment for over a year prior to presenting with a TMA which correlated with a significant increase in her free light chains. The other cases occurred during active treatment. All remaining patients received proteasome inhibitors, with three patients on bortezomib-based regimens and five patients on carfilzomib. One patient on a bortezomib-based regimen had been stable prior to developing a TMA in the setting of sepsis. In the remaining patients, the TMA developed rapidly after initiating the proteasome inhibitor. In all cases, the TMA improved after drug withdrawal. One patient was later rechallenged with bortezomib and again developed TMA.
Discussion: A review of the literature reveals only nine cases of TMA with MM. Of these, 4 patients had TMA as the initial presentation of MM, and 5 patients were on treatment, most often bortezomib-based regimens. Our series patients match those in the literature closely and demonstrate that TMAs can occur in MM outside of the context of AHSCT. In roughly one third of patients, TMAs were the initial presentation of MM and improved with treatment of the MM. In others, the use of proteasome inhibitors appears to be associated with development of TMA. In these cases, the temporal correlation, resolution of TMA after medication withdrawal, and the instance of recurrence of TMA with rechallenge of bortezomib, support a causal relationship between the medication and the TMA. Thus, a high clinical suspicion for TMA must exist for patients on proteasome inhibitors who develop worsening anemia and thrombocytopenia. Medication should be withdrawn if TMA is diagnosed.

Disclosures
Vij: Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy.
Free Light Chain Ratio As a Simple Prognostic Marker in a Single Institution Experience
Authors: Pena Camila , Voisin Javier , Peralta Alexis , Ortiz Manuela , Balboa Viviana , Delgado Florencia 
Published: October 2019

Abstract
Multiple myeloma (MM) is a plasma cell dyscrasia characterized by bone marrow plasma cell infiltration and the secretion of monoclonal immunoglobulin (Ig) in the serum or urine. Median survival in MM patients is approximately 5 years and significant morbidity may be experienced. The course is progressive and although, always incurable, the prognosis is highly variable. The two more widely used staging systems in MM are by Durie and Salmon and the International Staging System (ISS). Others have been studied, including serum free light chain (sFLC) concentrations and ratio (sFLCr).
Methods: We measured sFLC in 27 newly diagnosed MM (21 Intact Ig MM, 5 light chain MM, 1 non secretory MM) at our center (Hospital del Salvador, Santiago de Chile) from October 2013 until June 2015. The sFLCr was calculated with the involved monoclonal light chain as the numerator. The median sFLCr was 17. Patients were divided into a "low group" (<17 sFLCr) and a "high group" (>17 sFLCr). We also analyzed these patients using the cut off (sFLCr of 50) previously reported by Garcia de Veas Silva et al. [Hematology reports 2015; 7 (s1) p23] The median follow-up was 16 months.
Results: During the period of study there were 8 deaths (29,7%). Seven (87,5%) of these deaths presented with an ISS score of 3 (table 1). Mortality rates were lower in the group of patients with "low" sFLCr (15,3%, 2 deaths in a group of 13 patients), as compared to patients with a "high" sFLCr (42,9%, 6 deaths in a group of 14 patients) (table 2).
Using the cutoff established by Garcia de Veas Silva et al, the mortality rate for patients with sFLCr >50 was 66,7% vs. 11,1% in for patients in the <50 sFLCr group (table 3).
Discussion: Although a short follow up period was available for analysis, we believe these results are promising. sFLCr can be used as an easy prognostic indicator in newly diagnosed, symptomatic MM, especially when high risk patients (>50 sFLCr) are identified. The introduction of biomarkers in the evaluation of MM patients will enable better risk assessment and rational follow up.
Table 1. International Staging System. Stratification of our study population. ISS N Patients N Deaths Mortality (%) 1 2 0 0 2 12 1 8,3 3 13 7 53,9
Table 2. Mortality rate in our study population using the median sFLCr as a cut off value. Mortality MM N Patients N Deaths Mortality (%) All 27 8 29,6 sFLCr>17 14 6 42,9 sFLCr<17 13 2 15,4
Table 3. Mortality rate in our population using the published cut off sFLCr value. Mortality MM N Patients N Deaths Mortality (%) All 27 8 29,6 sFLCr>50 9 6 66,7 sFLCr<50 18 2 11,1

Disclosures
Delgado: The Binding Site: Employment.
Quercetin Displays Anti-Myeloma Activity and Synergistic Effect with Dexamethasone in Vitro and In Vivo Xenograft Models
Authors: Guo Xing , He Donghua , Yang Li , Li Yi , Chen Qingxiao , Chen Jing , Zhang Enfan , Lin Xuanru , He Jingsong , Yang Yang , Han Xiaoyan , Zheng Gaofeng , Wu Wenjun , Zhao Yi , Huang He , Cai Zhen 
Published: October 2019

Abstract
Background: Multiple myeloma (MM) is a hematological malignancy with clonal plasma cell hyperplasia, which is still an incrurable disease since chemoresistance remains the major problem in MM management. Quercetin, a kind of dietary flavonoids, has shown its anticancer activity in many kinds of cancer cell lines and we tried to explore the effect of quercetin in MM.
Methods: In vitro, we examined the proliferation of MM cell lines(RPMI8226,ARP-1,MM1R) after treatment with quercetin combined with or without dexamethasone by MTT.Flow cytometry was used to detect apoptosis and cell cycle of MM cells induced by quercetin with or without dexamethasone.Then we detected mRNA and protein expression associated with apoptosis and cell cycle arrest by semiquantitative real time-polymerase chain (qRT-PCR)and western blot analysis. In vivo,a xenograft mice model of human myeloma was established and the mice received vehicle or quercetin alone or dexamethasone alone or quercetin combinded with dexamethasone, and the tumorburdern and the tumor tissue samples were analyzed by tumor volume and immunohistochemistry.
Results: Quercetin inhibited proliferation of MM cells by inducing apoptosis and cell cycle arrest in the G0/G1 or G2 phase(quercetin group vs control,p<0.05).Western blot showed that quercetin activated caspase3,caspase9,PARP-1 and increased cytochrome C release. C-myc and cyclinD1 expression were down-regulated and p21 were upregulated. Quercetinalso displays synergistic inhibition effect with dexamethasone in vitro (quercetin with dexamethasone vs quercetin only or dexamethasone only,p<0.05) and western bolt confirmed these results.In vivo,tumor burdern of xenograft mice modeltreated by quercetin was significantly lower than those of control(quercetin group vs control,p<0.05).
Conclusions: Quercetin inhibits proliferation of MM cells by inducing apoptosis and cell cycle arrest in the G0/G1 or G2 phase through downregulating c-myc and cyclinD1 and upregulating p21 .Quercetinalso displays synergistic inhibition effect with dexamethasone.Thus,quercetin combination with dexamethasone therapy may be an effective option for MM patients.

Disclosures
No relevant conflicts of interest to declare.
Involvement of T-Cells in the Bone Pathology of Multiple Myeloma
Authors: Simantirakis Emmanouel , Giannakoulas Nikolaos , Siapati Elena , Vassilopoulos George 
Published: October 2019

Abstract
Introduction: Multiple myeloma (MM) is a plasma cell dyscrasia that is heavily dependent on a permissive BM micro-environment. Components of the WNT pathway have been implicated in this process and specifically, WNT-inhibitors such as Dkk1, have been blamed for the osteolytic lesions of MM. WNT signaling is required for proper osteoblast development while the pathway is also involved in enhancing the self renewal potential of various stem cells. A source of WNT ligands in the BM are the T-cells; when stimulated by parathormone, T-cells secrete wnt10b that affects hematopoietic stem cell numbers. In the present study, we evaluated WNT signaling in the T-cells of patients with MM in order to test whether these bystander T-cells have an altered phenotype that could influence disease pathology.
Methods: A total of 18 MM patients was analyzed after informed consent was obtained; the patients underwent BM biopsy for diagnostic and staging purposes. T-cells were isolated from BM mononuclear cells using magnetic beads with a purity of around 90%. Normal controls were T-cells isolated from healthy subjects. RNA was isolated and analyzed by RT-PCR for expression of PTH receptor (PTH1R), wnt10b and the canonical WNT signal transducer, b-catenin (bCAT).
Results and discussion: BM concentration of T-cells was 15%, close to the normal values, indicating no major deviation from normal conditions. Activity of the WNT pathway was estimated by bCAT mRNA levels; relative to the control, bCAT levels in MM T-cells were uniformily suppressed. In a total of 8 evaluable samples, there was a 3x decrease in bCAT levels. Although WNT activity could be influenced by different factors, there is a possibility that it may be related to PTH activity and PTH receptor expression on patient T-cells. In all our cases, calcium was recorded within normal range and PTH values were also normal. However, PTH1R mRNA levels in MM T-cells were 14.2x lower compared to normal T-cells, a value that argues for a biological role in disease pathogenesis. A direct consequence of low PTH1R mRNA levels, according to our hypothesis, would lead to a decrease in WNT10b. Indeed, WNT10b levels were on average 90% of the normal with relative wide variation; in 3 samples, there was an average 3.2x increase while in 8, the levels were on average 21% of normal. On the clinical level, lower wnt10b activity, was more often associated with bone pathology while higher wnt10b activity was more often associated with extramedullary plasmacytomas. Our data show that T-cells may not be bystanders in the MM disease progression and certain manifestations sush as bone disease, could be associated with, aberrant T cell function. Ongoing studies are under way to link clinical and laboratory data.

Disclosures
No relevant conflicts of interest to declare.
Bendamustine-Bortezomib-Desametasone (BVD) in the Management of Relapsed and Refractory Multiple Myeloma : A REAL-Life Experience
Authors: Cerchione Claudio , Catalano Lucio , Pareto Anna Emanuele , Basile Santina , Marano Luana , Peluso Ilaria , Simeone Luigia , Vitagliano Orsola , Palmieri Salvatore , Rocco Stefano , Ferrara Felicetto , Pane Fabrizio 
Published: October 2019

Abstract
Introduction:
Bendamustine is a bifunctional alkylating agent, with low toxicity, proved to be effective in relapsed, refractory and in new diagnosed Multiple Myeloma (MM).
It has been evaluated efficacy and tolerance of Bendamustine, in combination with bortezomib-dexametasone (BVD) in patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. A regional retrospective real-life analysis of patients with rrMM who had been treated with BVD as salvage therapy has been performed.
Methods:
35 patients (19 M/16 F), with rrMM, median age at diagnosis 57 years (r. 36-82), median age at start of treatment 62 years (r.37-83) treated with several lines of treatments (median 6, r. 2-11), every refractory to all the drugs previously received (also Bortezomib), received BVD (Bendamustine 90mg/sqm days 1,2; Bortezomib 1.3mg/sqm days 1,4,8,11, Desametasone 20mg days 1,2,4,5,8,9,11,12, Pegfilgrastim day +4) every 28 days, until progression.
ISS was equally distributed, and cytogenetic was evaluable in 9 patients, and in particular one del13q and one t(11;14). All the patients had previously been treated with schedule containing bortezomib and IMIDs, 90% of them with melphalan, 77% with cyclophosphamide, 34% with antracyclines and 30% had also received radiotherapy. 58% of them had undergone at least to a single auSCT. All patients were relapsed and refractory to last therapies received before BVD.
Results:
Bendamustine was well tolerated, with grade 3 transfusion-dependent anemia in 29% of patients, and 41% grade 3 neutropenia (no ospedalization was required, no septic shocks were observed). No severe extrahematologic toxicity was observed, only grade 1 gastrointestinal side effect (nausea), treated by common antiemetic drugs.
According to IMWG, after a median follow-up of 9 months (r.2-36), ORR was 54% (1 CR, 1 VGPR, 9 PR, 8 MR) with 7 PD and 9 patients in SD, which can be considered as an impressive result in this subset of rrMM patients. In particular, for 4 patients, BVD was, after having achieved a PR, a bridge to second auSCT, and for one patient a bridge to auSCT.
Median OS from diagnosis was 61.4 months (range 6-151), median OS from start of Bendamustine was 7.2 months (range 2-36).
Conclusion:
BVD has shown significant efficacy (ORR 54%) in a particular severe setting of patients, relapsed and refractory to all avaiable therapeutic resources, and in particular cases it could be considered as a bridge to a second autologous or allogenic BMT.

Disclosures
No relevant conflicts of interest to declare.
AML Relapse after Rituximab Treatment for Graft-Versus-Host Disease: Crucial Role for B Cells in Graft-Versus-Host and Graft-Versus-Leukemia
Authors: Gillissen Marijn Aletta , Levie Sophie E. , de Jong Greta , Yasuda Etsuko , Bakker Arjen Q. , van Helden Pauline M. , Jefferson Douglas M. , Huisman Cynthia , Spits Hergen , Hazenberg Mette D. 
Published: October 2019

Abstract
Patients with hematologic malignancies that develop graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT) have a reduced risk of disease relapse compared to patients that do not develop GvHD, suggesting that GvHD and graft-versus-leukemia (GvL) responses are co-dependent. T cells are important in these processes, as T cell depletion from the graft reduces the risk of GvHD at the expense of disease relapse. Much less is known about the effect of B cell depletion on GvHD and GvL responses. Small patient series have demonstrated variable efficacy of Rituximab in the treatment of steroid-refractory chronic GvHD but the effect of depleting allo-reactive B cells on disease relapse remains to be determined. We here report on a patient with steroid-refractory GvHD whose AML relapsed after Rituximab treatment.
This 39-year old male received an allogeneic HSCT for chemotherapy-related AML (AML-t) that however relapsed 8 weeks after the transplantation. Upon rapid cessation of immunosuppressive therapy (cyclosporine, mycophenolic acid) and without additional chemotherapy he obtained full remission, at the expense of severe GvHD of the skin, liver and intestine that was corticosteroid-refractory. B cell depletion with Rituximab was successful as second-line treatment for GvHD but eliminated the GvL response and the patient died of AML relapse several months after.
To evaluate the B cell repertoire of this patient at the moment of maximal GvH and GvL responses, we isolated peripheral blood B lymphocytes that were transduced with Bcl-xL and Bcl-6 to create clonal B cell lines. These B cells were screened for binding to AML and host tissues. One clone was retrieved that specifically bound to AML cell lines and AML blasts freshly isolated from newly diagnosed AML patients. Antibodies from this clone induced antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity of AML cells in vitro. Several other clones were retrieved that were specific for host tissues such as liver (HepG2 and H69 cell lines), skin (primary fibroblasts) and/or colon (CaCo cell line).
These data demonstrate the pivotal role of B lymphocytes in anti-leukemia and anti-host immune responses in an allogeneic HSCT recipient with relapsed AML-t.

Disclosures
No relevant conflicts of interest to declare.
Intensive Chemotherapy of 107 Primary Mediastinal B-Cell Lymphoma Patients. Single Center Experience
Authors: Mangasarova Jana Konstantinovna , Kravchenko Sergey Kirillovich , Magomedova Aminat Umaraskhabovna , Misyurina Anna , Baryakh Elena , Vorobiev Vladimir Ivanovich , Gemdzhian Eduard G. , Nesterova Ekaterina , Gilenko Alisa Igorevna , Gorenkova Liliya , Penskaya Ekaterina , Margolin Oleg Victorovich , Savchenko Valeri 
Published: October 2019

Abstract
Introduction. Primary mediastinal B-cell lymphoma (PMBCL) amounts from 0,9 to 4% of Non-Hodgkin Lymphomas. Predominantly suffer young women. All relapses in PMBCL occur as early events. Taking into account unfavorable prognosis in case of relapse or progression of PMBCL (2-year overall survival (OS) is about 15% [Kurvilla J., 2008]), it's necessary to achieve a complete remission (CR) in first line treatment.
Aim. To compare an efficacy of R-DA-EPOCH followed by R-DHAP and autologous peripheral blood stem cell transplantation (autoSCT) with BEAM conditioning regimen with modified (m) NHL-BFM-90 chemotherapy protocol in pts with partial remission (PR) of PMBCL.
Patients and Methods. In 107 pts (34 males, 73 females) diagnosis of PMBCL was established according to WHO criteria. All pts had stage II of disease according to Ann Arbor classification. 30 pts received R-DA-EPOCH, 77 pts - m-NHL-BFM-90 ± R. Median age of pts in R-DA-EPOCH group was 28 years old (from 20 to 67 years old); in m-NHL-BFM-90 ± R-group - 77 years old. Increased LDH concentration was revealed in 24 from 30 (80%) pts in R-DA-EPOCH group and in 75/77 (97%) pts from m-NHL-BFM-90 ± R group. Bulky mediastinal disease was in 30/30 (100%) pts in R-DA-EPOCH group and in 59/77 (76%) - m-NHL-BFM-90 ± R group. In case of CR after 6 courses according to computer tomography and PET scanning treatment was completed. In case of PR pts underwent 2 R-DHAP courses with autoSCT (BEAM conditioning regimen). All pts from m-NHL-BFM-90 ± R group independently from PET-results stopped treatment. All cases of treatment failure occurred till one year of observation. Kaplan-Meier method was used to calculate OS and relapse-free survival (RFS). OS was defined as time from diagnosis to death from any reason; RFS was defined as time from diagnosis until relapse or death from any cause.
Results: After 6 R-DA-EPOCH therapy CR was achieved in 24/30 (80%) pts, 6/30 (20%) pts had PR and underwent 2 R-DHAP courses followed by auto-SCT (BEAM). 2- RFS and OS was 100%. Median follow up was 16 months. In m-NHL-BFM-90 ± R group 10-year RFS and OS were 85% and 92%, respectively. Median follow up was 53 months.
Conclusion: High dose pulsed m-NHL-BFM-90-chemotherapy as well as R-DA-EPOCH allows getting high efficacy of primary mediastinal B-cell lymphoma therapy. Although future analysis will show more distant results of R-DA-EPOCH chemotherapy.

Disclosures
No relevant conflicts of interest to declare.
Effect of Severe Hypoalbuminemia on Myelosuppression and Other Toxicities of High Dose Melphalan and Autologous Stem Cell Transplantation in AL Amyloidosis Patients
Authors: Lee Shin Yin , Meehan Robert , Sloan John Mark , Quillen Karen , Brauneis Dina , Shelton Anthony C , Sanchorawala Vaishali 
Published: October 2019

Abstract
Background:
High-dose melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT) has been shown to extend survival as well as to induce hematologic and clinical responses in selected patients with light chain (AL) amyloidosis. The most frequent toxicities of HDM are profound myelosuppression and gastrointestinal (GI) side effects. Studies have shown that 80% of melphalan is bound to plasma proteins (60% albumin bound) with ~20% free. We hypothesized that AL amyloidosis patients with severe nephrotic syndrome and profound hypoalbuminemia might have greater free melphalan fraction and more treatment-related toxicity.
Methods:
Patients with AL amyloidosis treated with HDM/SCT between 2011 and 2014 with severe hypoalbuminemia (SH), defined as a pre-transplant serum albumin of ≤2g/dL, were studied retrospectively. The stem cell transplant database was queried for patient demographic information, pre-transplant albumin level, HDM dose, renal function, pre-transplant 24-hour urine protein level, time to neutrophil and platelet engraftment, and treatment-related complications. Patients with AL amyloidosis treated between 2011 and 2012 without severe hypoalbuminemia, defined as serum albumin level of > 2g/dL (WSH), served as a control group.
Results:
Of the 84 patients with AL amyloidosis treated with HDM/SCT in this 4 year period, 16 (19%) with SH were identified. 41 patients were identified in the control group (WSH). There was no difference in the proportion of patients with all non-hematologic grade 3 or 4 adverse events between the groups. All patients suffered from expected grade 4 myelosuppression. The only statistically different non-hematologic grade 4 toxicity in SH was acute renal failure requiring temporary hemodialysis (n=4/16, 25% SH vs n=2/41, 5% WSH; p=0.05), with 1 subject eventually needing long term dialysis. There were no grade 4 mucositis or GI toxicities in either groups. The only statistically different grade 3 non-hematologic toxicity was lightheadedness (n=3/16, 19% SH vs n=0/41, 0% WSH; p=0.02).
Conclusion:
These data suggest that patients with severe hypoalbuminemia do not have more prolonged myelosuppression or GI toxicities when treated with HDM/SCT compared to those with higher serum albumin levels in AL amyloidosis. Grade 4 renal toxicity with acute renal failure requiring temporary hemodialysis (p=0.05) and grade 3 lightheadedness (p=0.02) occurred more commonly in SH than WSH group. In this retrospective study, we did not measure free melphalan concentrations in the blood. However, these data suggest that patients with severe hypoalbuminemia do not require adjustment of melphalan dosing.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.