bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sustained Response Duration Seen after Treatment with Single Agent Blinatumomab (MT103/MEDI-538) in the Ongoing Phase I Study MT103- 104 in Patients with Relapsed NHL
Authors: Bargou Ralf C , Kufer Peter , Goebeler Mariele , Knop Stefan , Einsele Hermann , Noppeney Richard , Viardot Andreas , Baeuerle Patrick A , Reinhardt Carsten , Schmidt Margit , Klappers Petra , Nagorsen Dirk , Zugmaier Gerhard 
Published: April 2020

Abstract
Introduction: Blinatumomab (MT103/MEDI-538), a BiTE antibody targeting the CD19 antigen, is a member of a novel class of molecules that redirect T cells for lysis of target cells. A Phase 1 dose escalation study is being conducted in patients with advanced NHL.
Methods: Relapsed NHL patients requiring treatment were included. Most patients were pre-treated, with a median of 3 previous chemo/immunotherapy regimens. To date, 7 dose levels ranging from 0.0005 to 0.09 mg/m2/24 h have been tested. Blinatumomab was continuously infused as single agent over a period of 4–8 weeks. Objective responses were assessed by Cheson criteria and centrally reviewed.
Results: To date 39 patients have been treated. Most common adverse events (AEs) included lymphopenia, pyrexia, and leukopenia. The majority of AEs (&gt;95%) improved or resolved during treatment. Permanent treatment discontinuation due to AEs occurred in a total of 8 patients, of which 6 had fully reversible CNS events. One patient with a history of nearly fatal sepsis, pre-existing hypogammaglobulinemia and bone marrow affection by chemotherapy, experienced a fatal sepsis 5 weeks after treatment start. Dose-dependent activity was observed in mantle cell lymphoma, follicular lymphoma and CLL with responses observed in 11 out of 27 patients treated at doses of 0.015 mg/m2/24 h and higher. Five of those patients had complete and six had partial responses. At the dose level of 0.060 mg/m2/24 h, 7 out of 7 patients have shown objective responses. Beside one relapse after 14 months, no treatment failure has so far been observed for responders at dose levels of 0.030 mg/m2/24 h and 0.060 mg/m2/24 h. Five patients at these dose levels have ongoing responses for more than 6 months. Interestingly, partial remissions converted into complete remissions in two patients four weeks after end of infusion suggesting either reduction in lesion size due to efflux of a previously expanded T cell pool or prolonged T cell activity.
Conclusions: Blinatumomab as single agent induced apparently durable responses in pre-treated B-NHL patients with the highest response rate at a dose level of 0.06 mg/m2/24 h. Recruitment is ongoing.
Growth Differentiation Factor 15 Plasma Level in patients with Multiple Myeloma: A Study of Intergroupe Francophone Du Myelome
Authors: Corre Jill , Roussel Murielle , Huynh Anne , Gadelorge Melanie , Labat Elodie , Laharrague Patrick , Moreau Philippe , Facon Thierry , Avet-Loiseau Hervé , Fournié Jean-Jacques , Attal Michel , Bourin Philippe 
Published: April 2020

Abstract
We previously reported that bone marrow mesenchymal stem cells (BMMSCs) from multiple myeloma (MM) patients were abnormal. In particular, we showed that Growth Differentiation 15 (GDF15) expression was higher in MM BMMSCs than in normal BMMSCs and that GDF15 was a growth factor for the MOLP-6 stromal cell-dependant myeloma cell line. GDF15 is a divergent member of the human TGFβ superfamily. In normal human subjects, it is highly expressed in the placenta and its serum concentration increases during pregnancy. GDF15 concentration is increased in the serum of patients with prostate, colorectal or pancreatic cancers. However, GDF15 has never been studied in haematological malignancies. The first objective of this study was to evaluate the relashionship between GDF15 plasma concentration (pGDF15) of 131 MM patients and main prognostic factors of the disease. We found a significant relationship with ISS (p&lt;0.003) and DS stage (p&lt;0.02), b2 microglobulin, haemoglobin, creatinin, calcemia (p&lt;0.001), deletion of chromosome 13 (p&lt;0.004), serum monoclonal protein, bone status (p&lt;0.02), and albumin (p&lt;0.05). The second objective of this study was to appreciate the potential relationship between pGDF15 and survival. We demonstrate such a relationship. Indeed, in the group of 81 patients with high pGDF15, the probabilities of event-free and overall survival 30 months after diagnosis is 50 percent and 75 percent, respectively. In the group of 50 patients with low pGDF15, the probabilities of event-free and overall survival 30 months after diagnosis is 80 percent and 97 percent, respectively (p&lt;0.0045 and p&lt;0.013, respectively). On the opposite, pGDF15 is not related to response to treatment. We analysed impact of known prognostic factors and pGDF15 on event-free survival for all the 131 patients. In univariate analysis, event-free survival was significantly related to age (p=0.003), ISS (p=0.09), b2-microglobulin (p=0.02) and pGDF-15 (p=0.003). In multivariate analysis, event-free survival was significantly related to age (p=0.001) and pGDF15 (p=0.04). In conclusion, our study demonstrates a significant relationship between GDF15 and MM survival. This result strongly suggests the implication of microenvironment in the disease evolution. The exact role of GDF15 in MM physiopathology (directly responsible or simple reflect of an abnormal microenvironment) is still unclear and should be investigated.
Bone Morphogenic Protein 6: A Prognostic Factor Expressed by Normal Plasma Cells and Multiple Myeloma Cells Inhibiting Their Proliferation and Angiogenesis Induction
Authors: Seckinger Anja , Meißner Tobias , Moreaux Jérôme , Goldschmidt Hartmut , Benner Axel , Hundemer Michael , Rème Thierry , Shaughnessy John D. , Barlogie Bart , Bertsch Uta , Hillengass Jens , Ho Anthony D. , Pantesco Véronique , Jauch Anna , De Vos John , Rossi Jean François , Möhler Thomas , Klein Bernard , Hose Dirk 
Published: April 2020

Abstract
BACKGROUND: Pathogenesis of multiple myeloma is partly attributed to an aberrant expression of proliferation-, pro-angiogenic and bone-metabolism modifying factors by malignant plasma-cells.
AIM. Given the long and variable time-span from first diagnosis of early-stage plasma-cell dyscrasias to overt myeloma and the low proliferation rate of malignant plasma-cells, we hypothesize these to concomitantly express a novel class of anti-proliferative factors of potential prognostic relevance. Here, bone morphogenic proteins (BMPs) represent possible candidates, as they inhibit proliferation, stimulate bone formation, and have an impact on the survival of cancer patients.
PATIENTS AND METHODS. We assessed expression of BMPs and its receptors by Affymetrix DNA-microarrays (n=434) including CD138-purified primary myeloma-cell-samples, normal bone-marrow plasma-cell-samples, polyclonal plasmoblasts-samples, human myeloma-cell-lines (HMCL), and whole bone-marrow. Presence and differential gene expression was determined by PANP-algorithm and empirical Bayes statistics. Event-free (EFS) and overall survival (OAS) were investigated for the 168 patients undergoing high-dose chemotherapy (HM-group) using Cox’s proportional hazard model. Findings were validated using the same strategy on an independent group of 345 patients from the Arkansas-group. For validation, quantitative real-time PCR and flow cytometry were performed. In vitro induction of angiogenesis was assessed using the AngioKit-assay. Effect of BMP6 on proliferation of HMCL was assessed by 3H-thymidine uptake.
RESULTS. BMP6 is the only BMP expressed by normal- (13/14 samples) and malignant plasma-cells (228/233 samples). It is significantly lower expressed in proliferating non-malignant plasmablastic cells and human myeloma cell-lines. In vitro, BMP6 significantly inhibits proliferation of myeloma-cell-lines with an IC50 ranged from 0.08–2.15μg/ml, survival of primary myeloma-cells, and in vitro tubule formation down to the level of the negative control. High BMP6-expression in malignant plasma cells delineates significantly superior overall-survival for patients undergoing high-dose chemotherapy in both independent series of patients (n=168, P=.02 and n=345, P=.03, respectively, see below).
CONCLUSION. With BMP6 we report for the first time the autocrine expression of a prognostically relevant anti-angiogenic and anti-proliferative factor and its receptors by normal and malignant plasma-cells.
Figure Figure
Hepatitis C Virus (HCV) Infection, Monoclonal Immunoglobulin Specific for HCV Core Protein, and Plasma-Cell Malignancy
Authors: Bigot-Corbel Edith , Gassin Michelle , Corre Isabelle , Le Carrer Didier , Delaroche Odile , Hermouet Sylvie 
Published: April 2020

Abstract
Hepatitis C virus (HCV) infection can lead to B-cell malignancy via direct infection and transformation of B-lymphocytes, or via indirect transformation by chronic antigen-driven stimulation. Both mechanisms may occur simultaneously, as we previously reported in a case of HCV infection followed by plasma-cell leukemia (PCL), where blasts were infected with HCV and the monoclonal immunoglobulin (Ig) they produced was directed against the core protein of the virus (New Engl J Med, 2003; 348:178). Approximately 10% of HCV-positive patients develop a monoclonal Ig, the specificity of which is usually unknown. To evaluate the link between chronic HCV-antigen driven stimulation and plasma–cell transformation, we studied the specificity of monoclonal Ig developed in the context of HCV infection. Over a period of 13 months, sera from patients consulting or hospitalised at the Centre Hospitalier Universitaire of Nantes found positive for monoclonal Ig, were systematically tested for the presence of HCV RNA and anti-HCV Ig. Among the 700 patients thus studied, 10 (1.4%) were found positive for HCV. Purification of the monoclonal Ig was achieved for 7/10 patients. Using immunoblotting, the purified monoclonal Ig (2 IgG, 1 IgA, 1 IgM) of 4 patients, all with HCV genotype 2, recognized the C22–3 fragment of HCV-core protein; 2 (IgG) recognized NS-4 and 1 did not recognize HCV. Among the 4 patients with anti-HCV-core monoclonal Ig, two presented with mixed (type II) cryoglobulinemia and one was diagnosed with multiple myeloma. Hence, 2/5 patients with anti-HCV core monoclonal Ig developed plasma-cell malignancy. Anti-HCV treatment resulted in the disappearance of the monoclonal Ig for 3/3 treated patients. In summary, in the context of HCV infection monoclonal Ig were typically directed against the virus, and could distinguish patients with increased risk of plasma-cell malignancy. Efforts should be made to identify such patients, as anti-viral therapy should help eradicate the HCV-driven plasma-cell clone.
CD28 Supports Normal Plasma Cell Survival and Interactions with Microenvironment
Authors: Rozanski Cheryl H , Nair Jayakumar , Carlson Louise , Lee Kelvin P. 
Published: April 2020

Abstract
The long term generation of protective antibodies (Abs) requires the continuous survival of long-lived plasma cells that are maintained within specialized bone marrow niches by complex interactions that remain largely uncharacterized. Previous studies have shown that the T cell costimulatory receptor CD28 is expressed on normal and transformed (murine plasmacytoma, human multiple myeloma) plasma cells – however, its role in the B cell lineage remained unclear. We have recently shown that CD28 expressed on transformed human plasma cells (multiple myeloma cells) directly delivers pro-survival signals to the myeloma cells and protects them against intrinsically and extrinsically induced death (Bahlis et al, 2007). Furthermore, myeloma cells directly interact with dendritic cells (DC, both in vitro and in patient bone marrow biopsies), and the DC provide the ligands (i.e. CD80 and CD86) for myeloma-CD28. Others studies utilizing competitive bone marrow reconstitution have indirectly suggest a role for CD28 in the function and/or survival of normal murine plasma cells (Delogu et al, 2006). These observations led us to directly investigate the role of CD28 in normal plasma cell survival as well as cell-cell interactions with CD80/CD86+ bone marrow derived dendritic cells (BMDC). In vitro serum starvation experiments, direct activation of CD28 by an agonistic anti-CD28 mAb increased survival of serum-starved PC by 63% (p&lt;0.001). Addition of BMDC improved the survival of PC by 20% over that seen with media alone, and resulted in a significant increase in IgG production (p&lt;0.01). We and others have shown that CD28 binding to CD80/CD86 on DC also “backsignals” to the DC to produce the PC survival factor IL-6. We found that co-culture with the murine plasmacytoma cell line S194 induced 155 pg/ml of IL-6 from BMDC (p&lt;0.01 vs. BMDC alone and S194 alone), and primary plasma cells isolated from bone marrow induced 290 pg/ml of IL-6 from BMDC (p&lt;0.001 vs. BMDC alone). Induction of BMDC production of IL-6 by both primary and transformed PC was significantly inhibited (p&lt;0.05) by antibody blockade of CD80 and CD86. Our data demonstrates that signaling through CD28 directly supports the survival of normal bone marrow plasma cells, and that “backsignaling” through PC-CD28 engagement of DC-CD80/CD86 induces DC to secrete the pro-survival cytokine IL-6. These findings suggest that CD28 is a key molecular bridge that connect normal plasma cells to the supportive microenvironment.
Prognostic Significance of Both the Cytoplasmic and Nuclear Overexpression of Yin-Yang 1 (YY1) among Patients with Multiple Myeloma (MM)
Authors: Huerta-Yepez Sara , Rivera-Pazos Clara , Libra Massimo , Baritaki Stavroula , Chen Haiming , Berenson James R. , Bonavida Benjamin 
Published: April 2020

Abstract
Objective and Rationale Yin-Yang 1 (YY1) is a multi-functional DNA-binding protein, which can activate, repress or initiate transcription depending on the context in which it binds. In addition, YY1 can modulate protein levels or activity through protein-protein interaction. YY1 has been identified as a potential repressor factor for several genes. We have reported that YY1 can act as a transcription repressor for both Fas and TRAIL DR5. In addition to YY1-mediated regulation of tumor cell resistance to cytotoxic immunotherapy, it also has been shown to regulate resistance to chemotherapy [Baritaki et al., J Immunol 80:6199,2008]. Overexpression of YY1 has been shown to be of prognostic significance in prostate cancer [Seligson et al., Int J Oncol 27:131,2005].
Hypothesis In this study, we have examined the expression of YY1 in MM (cell lines and patients’ bone marrow [BM]) by hypothesizing that the resistance of MM cells to various cytotoxic agents may be, in part, regulated by overexpression of YY1 and that YY1 may also be of prognostic significance.
Designs and Methods MM cell lines and fresh BM samples from MM patients (n=21) were examined for YY1 expression, cytoplasmic and nuclear, by immunohistochemistry and by Western. The specificity of the anti-YY1 antibody was demonstrated by the competitive inhibition with a peptide used for immunization. Control isotype IgG did not show any staining on the cells.
Results First, we found that various MM cell lines (RMPI 8226, IM-9, U266) overexpress YY1 both in the cytoplasm and the nucleus. Next, we examined the expression of YY1 in BM derived from MM patients by immunohistochemistry. BM from MM patients showed overexpression of YY1 as compared to normal bone marrow samples. Furthermore, analysis of both the intensity and frequency of cells expressing YY1 in both the cytoplasm and nucleus was shown to be significantly higher among patients with progressive disease as compared to patients with stable or responsive disease.
Conclusions and Implications These findings show that the expression of YY1 among patients with MM may correlate with progression and also suggest the prognostic significance of YY1 in MM patients. Inhibition of YY1 by various agents (example: low-dose chemotherapy, proteasome inhibitors, NO donors, NF-kB inhibitors, etc.) all result in the reversal of resistance to various cytotoxic agents (eg CDDP, TRAIL) therefore, the findings also imply that agents that can inhibit YY1 expression in MM patients may be of therapeutic potential when used in combination with conventional therapeutics.
Immunoglobulin Variable Light Chain Restriction, Cytokine Expression and Plasma Cell-Stromal Cell Interactions in POEMS Syndrome Patients
Authors: Aravamudan Bharathi , Tong Caili , Lacy Martha Q. , Hayman Suzanne R. , Buadi Francis , Gertz Morie A. , Kumar Shaji , Dispenzieri Angela 
Published: April 2020

Abstract
POEMS syndrome is defined by the presence of peripheral neuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal protein expression (M), and skin changes (S). In addition, patients also have sclerotic bone lesions, papilledema, extravascular volume overload, thrombocytosis, and restrictive lung disease/pulmonary hypertension. A striking but inexplicable feature of the clonal plasma cells in patients with POEMS is that they are virtually always lambda restricted. More surprising is that of the 81 functional immunoglobulin light-chain variable-region genes (IgVL) available in the plasma cell/B cell repertoire, among the 13 cases in which variable gene light chain usage has been reported, all have been either IgVL1-40 or IgVL1-44. The molecular mechanisms triggering the initiation and the progression of POEMS syndrome or the clonal expansion of plasma cells marking this condition remain unclear. We have analyzed the immunoglobulin heavy and light chains sequences in the plasma cells of POEMS patients at the Mayo Clinic Rochester. We found that in 8 out of the 9 patients tested, we could document heavy chain clonality in any given patient; however, no restriction of gene usage among patients was observed in the variable regions of these chains. In the case of light chains, in 14 out of 17 patients we could document not only clonality but also restriction of light chain variable gene usage to IgVL1-40 or IgVL1-44. Our goal is to understand the relevance of this restricted expression of light chain variable region, and its effect on the communication between plasma cells and the neighboring stromal cells that might provide more insight into the disease pathology. To this end, we are generating viral vector constructs that will harbor the germline or mutant versions of IgVλ1-40 and IgVλ1-44 genes and introduced into pre-established malignant plasma cell lines (i.e. myeloma cell lines). We will assay the effects of this over expression in terms of alterations in the expression of cytokines such as VEGF and TNF, and on plasma cell-stromal cell interaction (in a co-culture system). Results from these assays will be discussed.
RGB 286638, a Novel Multi-Targeted Small Molecule Inhibitor, Induces Multiple Myeloma (MM) Cell Death through Abrogation of CDKDependent and Independent Survival Mechanisms
Authors: Cirstea Diana , Hideshima Teru , Pozzi Samantha , Vallet Sonia , Ikeda Hiroshi , Santo Loredana , Loferer Hannes , Vaghela Nileshwari , Okawa Yutaka , Perrone Giulia , Gorgun Gullu , Calabrese Elisabetta , Munshi Nikhil C. , Anderson Kenneth C. , Raje Noopur 
Published: April 2020

Abstract
Uncontrolled proliferation and development of drug resistance in multiple myeloma (MM) cells are consequences of the numerous genetic aberrations which are further stimulated in the context of bone marrow microenvironment. Thus, inhibition of complementary pro-survival signaling and transcriptional networks rather than individual pathway is required for induction of optimal cytotoxicity in MM cells. Recent studies have shown that cyclin-dependent kinases inhibitors (CDKIs), designed to block cell cycle progression through inhibition of CDK/cyclin complexes, block transcription through suppression of RNA polymerase II phosphorylation at its C-terminal domain (CTD), resulting in downregulation of cell proliferation (cyclins: D, A, B1, pRb) and anti-apoptotic proteins (i.e. Mcl-1, survivin, XIAP). Here we examined the anti-MM activity of RGB 286638, a novel multi-targeted small molecule inhibitor, originally designed to induce broad cell cycle suppression via multiple CDK inhibition. Treatment with RGB 286638 triggered a dose-dependent cytotoxicity in conventional drug-sensitive (MM.1S, RPMI 8226, U266, OPM2), and resistant (MM.1R, Dox-40, LR5) MM cell lines, as well as primary tumor cells from MM patients. Induction of apoptosis was evidenced by Annexin V/PI staining, and confirmed by PARP and caspase cleavage. Additionally, RGB 286638 overcame the proliferative advantage conferred by MM patient-derived bone marrow stromal cells (BMSCs) and cytokines (IL-6, IGF-1) on MM cells. To determine molecular mechanisms responsible for RGB 286638-induced cytotoxicity, we assessed the cell cycle profile, which revealed G2/M arrest followed by increased sub-G1 phase. Importantly, RGB 286638 inhibited phosphorylation of RNA polymerase II in a dose- and a time-dependent fashion, followed by suppression of CDK1/cyclin B, CDK4, 6/Cyclin D1, D3, and CDK2/Cyclin E complexes associated with rapid down-regulation of Rb phosphorylation. Interestingly, RGB 286638 effectively reduced IL-6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation (Tyr705) and Janus kinase 2 (JAK2) phosphorylation (Tyr 1007/1008), suggesting that RGB 286638 is a possible JAK2 inhibitor. Based on sufficient in vitro cytotoxicity, we examined anti-tumor activity of RGB 286638 in vivo using a human MM cell xenograft model in SCID mice and demonstrated that RGB 286638 inhibited tumor growth and prolonged survival. In conclusion, our data demonstrate preclinical activity and provide the rational to test RGB 286638 in the treatment of MM.