bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mcl-1 Is Overexpressed in Multiple Myeloma and Correlates with Disease Severity.
Authors: Wuilleme-Toumi Soraya , Robillard Nelly , Gomez-Bougie Patricia , Moreau Philippe , Le Gouill Steven , Avet-Loiseau Herve , Harousseau Jean-Luc , Amiot Martine , Bataille Regis 
Published: April 2020

Abstract
Multiple Myeloma (MM) is a fatal malignancy of B-cell origin characterized by the accumulation of plasma cells within the bone marrow. The expression of the pro-survival members of the Bcl-2 family has been shown to be a key process in the survival of myeloma cells. More particularly, Mcl-1 expression turned out to be critical for their survival. Indeed, knockdown of Mcl-1 by antisenses induces apoptosis in myeloma cells. Finally, Mcl-1 was found to be the only anti-apoptotic Bcl-2 family member which level of expression was modified by cytokine treatment of myeloma cells. For these reasons, we have evaluated the expression of Mcl-1 in vivo in normal, reactive and malignant plasma cells (PC) i.e., myeloma cells from 55 patients with MM and 20 human myeloma cell lines using flow cytometry. We show that Mcl-1 is overexpressed in MM in comparison with normal bone marrow PC. Forty-seven percent of patients with MM at diagnosis (p=.017) and 80% at relapse (p=.014 for comparison with diagnosis) overexpress Mcl-1. Of note, only myeloma cell lines but not reactive plasmocytoses have abnormal Mcl-1 expression, although both plasmocyte expansion entities share similar high proliferation rates (&gt;20%). Of interest, Bcl-2 as opposed to Mcl-1, does not discriminate malignant from normal PC. This shows that the overexpression of Mcl-1 is clearly related to malignancy rather than to proliferation. It will be important to know whether the overexpression of Mcl-1 is related to an abnormal response to cytokines like Interleukin-6 or to mutations of the promoter of the Mcl-1 gene as already described in B chronic lymphocytic leukemia. Finally, level of Mcl-1 expression is related to disease severity, the highest values being correlated with the shortest event-free survival (p=.01). In conclusion, Mcl-1 which has been shown to be essential for the survival of human myeloma cells in vitro is overexpressed in vivo in MM and correlates with disease severity. Mcl-1 represents a major therapeutical target in MM.
Non-Myeloablative Allogeneic Hematopoietic Transplantation in Relapsed/Primary Refractory Follicular Lymphoma.
Authors: Fabre Claire , Recher Christian , Huynh Anne , Rigal-Huguet Françoise , Abbal Michel , Dastugue Nicole , Saati Talal Al , Brousset Pierre , Attal Michel 
Published: April 2020

Abstract
Allogeneic stem cell transplantation (SCT) can induce long-term disease-free survival in refractory follicular lymphomas (FL) but is impaired by high rate of transplant-related mortality (TRM). Reduced conditioning followed by allogeneic SCT is a promising concept in FL, allowing a graft-versus-lymphoma (GVL) effect while reducing the TRM. We piloted a clinical trial using this approach in relapsed/primary refractory low-grade lymphomas. From 1998 to 2003, 31 patients (pts) with an HLA-identical sibling have been enrolled. Main pts characteristics were : age = 49 years (range, 32–61 y); grade : I/II FL = 26; FL with histologic transformation = 5; gender = 16 male and 15 female; ≥ 2 prior therapies before transplantation = 23; primary refractory = 8; stage IV = 22; Bulky disease = 16; mean LDH rate before transplantation = 335 UI/l (range, 205–858); residual disease at transplantation (partial response (PR) + progression) = 20. Previous treatments were as follow : anthracyclins = 26, alkylants = 21, anti-CD20 = 15, purine analogs = 7, autologous SCT = 6, radiotherapy = 5. The conditioning regimen was IV fludarabine 30 mg/m²/day (from day −5 to −2); PO busulfan 2 mg/kg/day (from day −7 to −6); antithymocyte globulin (ATG) 2.5 mg/kg/day (from day −4 to −3). 14/31 (45%) and 17/31 (55%) pts received peripheral blood and bone marrow stem cells respectively with a median number of CD34+ cells of 5 x 106/kg (range, 1.8–11.9). Graft-versus-host-disease (GVHD) prophylaxis consisted in cyclosporine A alone. All patients achieved complete donor (&gt; 95%) chimerism after allogeneic SCT. Median duration of neutropenia (&lt; 0.5 G/L) and thrombocytopenia (&lt; 25 G/L) were 3 days (range, 0–16) and 3 days (range, 0–29) respectively. 8/31 pts (26%) had CMV reactivation but no CMV disease. 3/31 (10%) developed grade II–IV acute GVHD. 10/31 (32%) developed chronic GVHD (5 moderate and 5 extensive). The median follow-up time was 20 months. The TRM was 19% (6/31). Causes of death were aGVHD = 1, auto-immune hepatitis = 1, bacteraemia = 2, pulmonary toxoplasmosis = 1 and Lyell syndrome = 1. Overall response rate was 97% (21 CR + 9 PR) at day 100 and at 1 year (24 CR + 6 PR). The estimated 2-year overall survival (OS), event-free survival (EFS) and relapse-free survival (RFS) rate were 75%, 65% and 85% respectively. 2 relapses occurred. Both were treated by anti-CD20, achieved CR and are still alive. Donor age, Bulky disease and LDH were significant for EFS. Altogether, these data suggest that non-myeloablative SCT can induce a high rate of durable remissions with reduced toxicity in this poor risk population.
Reduced-Intensity Conditioning Regimen with BEAM/Rituximab for Patients with Refractory Non-Hodgkin’s Lymphomas.
Authors: Khouri Issa F. , Saliba Rima M. , Okoroji Grace-Julia , Acholonu Sandra , Maadani Farzaneh , Hosing Chitra , Champlin Richard E. 
Published: April 2020

Abstract
Non-myeloablative allogeneic stem cell transplantation using the combination of fludarabine/cyclophosphamide/rituximab as a conditioning regimen has been successful in treating patients with relapsed, chemosensitive non-Hodgkin’s lymphoma (Blood98:3595, 2001; J Clin Oncol21:4407, 2004). A more intense regimen however is required to have an early disease control for patients with refractory disease or in kinetic failure. We used the BEAM regimen for that purpose. Because of potential synergy and without overlapping toxicity, Rituximab (375 mg/m2 on days −6, −1, +7 and +14) was added to the preparative regimen. Transplantation was performed on day 0. Fourteen consecutive patients with refractory lymphoma or in kinetic failure were studied. The study group included 11 males and three females of median age of 46 (range, 19–60) yrs. Underlying histologies include diffuse large cell lymphoma (n= 9), follicular (n=1), mantle cell (n=1), lymphoplasmacytic (n=1), and CLL in Richter transformation to diffuse large cell (n=2). Median # of prior chemoregimens received was 3 (range, 1–8). Twelve patients had a matched sibling donor, one a mismatched sibling, and one a matched unrelated donor. The median # of CD34+ cells infused was 5 x 106 CD34 + cells/kg. Twelve patients received blood and 2 received marrow as the source of the hematopoietic graft. Tacrolimus and methotrexate were used for GVHD prophylaxis. The day-100 mortality was 7%. Eleven patients (79%) had a complete, and 2 (14%) had a partial remission. One patient (7%) had no response. All patients engrafted donor cells (median of 100% at day 30) post transplantation. Median time to ANC &gt; 500 was 13 (11–15) days and median time to platelets &gt; 20K was 14 (9–25) days. The actuarial risk of Gr 2–4 GVHD was 57%, Gr 3–4 GVHD 28%. Eleven of the 13 patients who were alive at day 100 developed chronic GVHD. With a median follow-up time among survivors of 34 (8–48) months, overall survival and disease-free survival were 63% (95% CI, 33–83) and 57% (95%CI, 28–78), respectively.
Our results indicate that a pronounced graft-versus-lymphoma occurs after BEAM/Rituximab and allogeneic transplantation for patients with refractory lymphoma or in kinetic failure. This treatment has been associated with a lower than expected treatment-related mortality and a higher chance of durable remission.
Mesenchymal Stem Cell Deficiencies in Myeloma Patients.
Authors: Garderet Laurent , Doucet Christelle , Holy Xavier , David Catherine , Ernou Isabelle , Lopez Manuel , Lataillade Jean Jacques 
Published: April 2020

Abstract
Progression of Multiple Myeloma (MM) is associated with disrupted bone remodelling resulting from increased osteoclast activity and reduced osteoblast number in involved bones. The aim of this study was to investigate Mesenchymal Stem Cells (MSCs) properties in MM patients to find out whether disorders exist within the Bone Marrow (BM) microenvironment and during disease progression. We examined MSCs derived from 6 MM patients at diagnosis, 3 patients with Bone Lesions (BL-MSCs) and 3 patients Without Lesions (WL-MSCs), and 3 Normal Donors (ND-MSCs). We focused on mesenchymal phenotype, clonogenic and proliferative capacities, Growth Factor Receptors (GF-R) expression, as well as osteogenic differentiation. BM adherent mononuclear cells were used to initiate MSC cultures and 2 passages were performed when confluency was reached. Adherent MSCs were numbered after each passage and CFU-F was counted (at 11 day culture). Analysis of MSC immunophenotype and GF-R expression were performed by flow cytometry. Osteoblastic differentiation assay was performed in inducible specific medium by analysing alkaline phosphatase activity and matrix mineralisation deposition (Von Kossa method). MSCs represented 0.1 to 1% of BM nuclear cells from all sources. The characteristic MSC phenotype (CD45−/CD90+/CD73+/CD105+) was observed in all sources of cells (MM- and ND-MSCs). The clonogenic capacity of BL-MSCs was 2 fold lower than that of WL-MSCs (44 ± 21 vs 89 ± 23, p = 0.05) and their proliferative capacity was 7.5 fold decreased (16,5 x 106 ± 15 vs 124 x 106 ± 68, p = 0.02, total cells after 2 passages). Expression level of PDGFa & b, IGF-1, EGF and NGF Receptors was lower in MM-MSCs than in ND-MSCs (185 ± 39 vs 413 ± 50 UA, p = 0.0004, 212 ± 63 vs 383 ± 143 UA, p = 0.01, 227 ± 50 vs 534 ± 67 UA, p = 0.0007, 229 ± 34 vs 535 ± 84 UA, p = 0.0001 and 179 ± 26 vs 441 ± 98 UA, p = 0.001, respectively), while the percentage of FGF receptor-expressing cells was dramatically decreased in MM as compared to ND (59 ± 31.5 vs 90 ± 6 %, p = 0.01). Interestingly, the osteogenic differentiation capacity of MSCs was maintained in MM-MSCs whatever the progression status of the disease. This study demonstrates that impaired bone formation in MM could be related to a deficient proliferation capacity of MSCs associated with a low growth factor receptors expression. The lack of expansion capacity increases with disease progression. Therapeutic approaches using normal expanded MSCs grafts may improve bone reconstruction in myeloma patients.
The OPG/TRAIL Interaction in an In Vitro Osteoclastogenesis Model Derived from Human Multiple Myeloma-Bone Disease.
Authors: Molica Stefano 
Published: April 2020

Abstract
The development of multiple myeloma (MM)-bone disease is mediated by increased recruitment and activity of osteoclasts (OCs). Osteoclastogenesis is regulated by a complex signaling system, that involves receptor activator of nuclear factor-kappa B (RANK), receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG), all belonging to the Tumor Necrosis Factor (TNF) family. The aims of our study were to investigate: the MM T cell involvement in osteoclastogenesis, and the expression of the major osteoclastogenic mediators. Unstimulated and unfractionated peripheral blood mononuclear cells (PBMCs) isolated from 32 MM patients with or without osteolytic bone lesions, and parallel T cell-depleted cultures were used as in vitro osteoclastogenesis models. In addition, unstimulated and unfractionated PBMC cultures from 32 controls with nonneoplastic disease without any skeletal involvement were also established. Our results showed that the OCs derived from MM-bone disease PBMCs spontaneously developed and displayed a longer survival in a T cell-dependent way. Differently in T cell-depleted MM PBMC cultures, the addition of macrophage-colony stimulating factor (M-CSF) and RANKL was necessary to promote the formation of OCs, that however did not exibit a longer survival. MM-bone disease T cells overexpressed RANKL, OPG and TNF-related apoptosis inducing ligand (TRAIL), also detected in large amounts in the culture media. Despite high OPG levels, the persistence of osteoclastogenesis in our system can be related to the interaction between OPG and TRAIL, that were coimmunoprecipitated by a monoclonal antibody (mAb) against TRAIL. The evidence that TRAIL binds to OPG blocking OPG anti-osteoclastogenic effect is also supported by the addition of different concentrations of functional anti-TRAIL mAb, significantly decreasing the OC formation. The OCs developed from MM-bone disease PBMCs expressed a T cell-modulated balance of death and decoy TRAIL receptors. In particular, we found these OCs overexpressed TRAIL decoy receptor DcR2 in the presence of T cells, and death receptor DR4 in the T cell-depleted cultures. In conclusion, our results highlight that MM-bone disease T cells support the spontaneous OC formation with longer survival, involving the OPG/TRAIL interaction and the unbalanced OC expression of TRAIL death and decoy receptors.
Increased Bone Marrow Erythroid Precursors Is Associated with Shorter Survival in Low-Grade Myelodysplastic Syndromes.
Authors: Amin Hesham M. , Pierce Sherry A. , Kantarjian Hagop M. , Keating Michael J. , Freireich Emil J. , Koller Charles A. , Beran Miloslav , Albitar Maher , O’Brien Susan M. , Estey Elihu H. 
Published: April 2020

Abstract
According to the FAB and WHO classifications, the diagnosis of acute erythroid leukemia is based on the numbers of nucleated red blood cells and myeloid blasts in the bone marrow. The WHO classification recognizes two types of acute erythroid leukemia; M6A with 51–80% erythroid precursors and with 20% or more of the non-erythroid precursors being myeloid blasts; and M6B with more than 80% of the nucleated cells in the bone marrow consisting of erythroid precursors, regardless of the percentage of the myeloid blasts. Previous studies have shown that many cases of acute erythroid leukemia arise in patients with a history of myelodysplastic syndrome and in other cases acute erythroid leukemia is associated with significant dysplastic features. The significance of the number of erythroid precursors is not well known in the myelodysplastic syndromes. In the present study, we included 617 consecutive patients with low-grade myelodysplasia (482 patients with refractory anemia [RA] and 135 patients with refractory anemia with ringed sideroblasts [RARS]). Among this group, 82 patients with 50% or more of erythroid precursors had shorter survival compared with 535 patients with less than 50% erythroid precursors (P &lt; .01; Figure 1). The shorter survival in those with 50% or more of erythroid precursors may reflect the tendency of these patients to have worse International Prognostic Scoring System (IPSS) scores. Thus, among the patients with less than 50% erythroid precursors and primary MDS, 35% were IPSS low, 52% IPSS intermediate 1, and 13% IPSS intermediate 2. For the patients with 50% or more of erythroid precursors, the corresponding proportions were 14%, 57%, and 29%, respectively (P &lt; .001). As a result of the association between IPSS and the percentage of erythroid precursors, the percentage of erythroid precursors had no effect on survival within individual IPSS groups. Similarly, the percentage of erythroid precursors had no prognostic significance in patients with refractory anemia with excess blasts (RAEB) or chronic myelomonocytic leukemia (CMML). Our findings demonstrate that in low-grade dysplasia (RA and RARS) the number of erythroid precursors may represent an important prognostic marker. These findings implicate that the percentage of erythroid precursors should be considered in the classification of the low-grade myelodysplastic syndromes. A multivariate analysis will be performed to ascertain the relative effects of IPSS score and the percentage of erythroid precursors on prognosis in patients with low-grade myelodysplasia.
Figure Figure
Phenotypic Aberrations of Myeloid CD34+ Cells in Patients with Myelodysplastic Syndrome (MDS): Clinical Significance and Correlation with Cytogenetics Abnormalities.
Authors: Subira Dolores , Font Patricia , Arranz Eva , Soraya Ramiro B , Castanon Susana , Renedo Mónica , Blas Carlos , Garcia B Maria F. , Gonzalez B Olga , Tomas José F. , Fernandez-Rañada José M. 
Published: April 2020

Abstract
Expression of abnormal markers in myeloid CD34+ cells of patients with MDS is common, but few immunophenotypic data have been compiled so far. Based on the statement that CD7 and TdT are markers associated with a bad prognosis in acute myeloid leukemia, we intended to describe the incidence of their aberrant expression in CD34+ cells and its role helping to establish the diagnosis of MDS.
OBJECTIVES: To explore the aberrant expression of TdT and CD7 in myeloid CD34+ cells of MDS patients and to describe their possible correlation with cytogenetic features.
DESIGN AND METHODS: Bone marrow specimens from 45 patients with MDS were included in this study (17 RA, 12 RARS, 5 CMML, 9 RAEB, 2 RAEB-t). In addition, we analyzed 28 samples of bone marrow from patients with cytopenias, but no diagnosis of MDS, as a cohort control. Immunophenotyping was performed with the following combination of monoclonal antibodies: TdT FITC / CD7 PE/ CD34 PCy-5. A case was regarded as positive for any of these markers when their expression was described in at least, 25% of myeloid CD34+ cells. Besides, adequate cytogenetic data and FISH analysis of chromosomes 5, 7 and 8 were obtained from 42 out of the 45 MDS samples.
RESULTS: The percentage of CD34+ myeloid cells in MDS samples was fewer than 2% in 25 cases, ranged from 2–5% in 6 cases and was equal or greater than 5% in 14 cases. Aberrant expression of CD7 and/or TdT was observed in 28 cases: 20 were positive for CD7, 5 cases were positive for TdT and co-expression of both antigens was described in 3 cases. Prevalence of these abnormal markers was much higher in patients with MDS (28/45; 62%) than in the cohort control (2/28; 7%) . Besides, we identified at least one abnormal marker in 14 of the 16 patients with high risk MDS (9 RAEB, 5 CMML, 2 RAEB.t). According to the IPSS, karyotypes were divided into subgroups of favorable, intermediate or unfavorable, being classified 29 patients with favorable karyotypes and 13 patients with no favorable cytogenetics. In the first group, the abnormal expression of CD7 and/or TdT was detected in 13/29 patients (44.8%) and in 10/13 patients in the non-favourable group (76.9%).
CONCLUSIONS: CD7 and/or TdT expression in myeloid CD34 + cells may be helpful in establishing the diagnosis of MDS. Prevalence of these aberrancies seems to be higher in cases with no favorable karyotypes, but a larger number of patients will be required to state significant differences. Possible correlation between high risk MDS patients and immunophenotypic aberrancies suggests the convenience of following the outcome of those low risk MDS patients who have expression of any of these abnormal markers.
Hematopoietic Progenitors in Myelodysplastic Syndrome (MDS) Demonstrate Cell Cycle Arrest, Mitotic Failure, and DNA Damage.
Authors: Head David R. , Jacobberger James W. , Jagasia Madan H. , Goodman Stacey A. , Flye Leanne , McClintock-Treep Sara A. , Boulos Fouad I. , Jiang Fen , Stelzer Greg , Briggs Robert C. , Shults Keith 
Published: April 2020

Abstract
To assess biologic characteristics of marrow progenitors in MDS, we studied a consecutive series of MDS patients receiving no current treatment.
Methods: Patients’ (n=17) clinical histories, lab data, cytogenetics, and morphology were reviewed for confirmation of diagnosis and blinded to study results. Patients lacking primary marrow disease (n=9) were used as controls. Marrow samples were studied at 2-5 hours after procurement (mean 3.1 hours), and re-assessed at 24 hours. A small number of marrow samples were fixed within minutes of procurement to validate findings. Each sample was assessed for CD45 antigen density, log side scatter, CD34, CD71, DRAQ 5 (DNA content), MPM-2, p-H2A.X (serine 139), and Annexin V with an FC500 (Beckman-Coulter) flow cytometer. Analysis was performed using Winlist 5.0 software (Verity Software) with DDE links to ModfitLT3.0 using modifications of published methods along with Esoterix Center for Innovation generated algorithms. Analyses were blinded to clinical results. Results: Most MDS patients demonstrated increased S-phase cell cycle fractions. Despite this, neither myeloid nor erythroid progenitors in MDS demonstrated an increased mean mitotic index vs. normals (0.315/0.359 and 1.33/1.48 respectively), and 7 MDS patients demonstrated no mitotic events in myeloid precursors (never observed in the normal dataset). DNA damage (H2A.X binding) was increased in myeloid and erythroid progenitors in MDS vs. normals (19/4% and 9/1.6% respectively). Annexin V staining was modestly elevated in maturing progenitors in MDS patients vs. normals (16.4% vs. 10.9%), and increased 4% in each group at 24 hours. Stem cells (CD34+) and lymphocytes were negative for both H2A.X and Annexin V binding. Discussion: These results indicate abnormalities in MDS marrow biology that may be useful as diagnostic tests for MDS. They suggest a model of MDS characterized by DNA damage in maturing hematopoietic progenitors in MDS, with late cell cycle arrest, accumulation of cells in S or G2, and decreased cell division (mitotic events) despite cellular marrow. In this model, DNA damage may initiate apoptosis in cells, but the findings are inconsistent with massive successful programmed cell death as a central event in MDS pathogenesis. The model has therapeutic implications for MDS.
Atiprimod (N-N-diethl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) Inhibits Myeloma in Vivo.
Authors: Hamasaki Makoto , Hideshima Teru , Tassone Pierfrancesco , Neli Paola , Ishitsuka Kenji , Akiyama Masaharu , Hayashi Toshiaki , Yasui Hiroshi , Shiraishi Norihiko , Chauhan Dharminder , Mitsiades Constantine , Podar Klaus , Gupta Deepak , Picker Donald H. , Jacob Gary S. , Richardson Paul G. , Munshi Nikhil C. , Anderson Kenneth C. 
Published: April 2020

Abstract
Atiprimod (N-N-diethl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) is an orally-bioavailable cationic amphiphilic compound which significantly inhibits inflammation in rat arthritis and multiple sclerosis models. It acts, at least in part, by significantly inhibiting production of interleukin (IL)-6. Since IL-6 mediates MM cell growth, survival and drug resistance in the bone marrow (BM) microenvironment, we in this study characterized the effect of Atiprimod on human MM cells. We first demonstrated that Atiprimod significantly inhibited growth (p&lt;0.05) in MM.1S, U266, and RPMI8226 MM cell lines in a time- and dose-dependent fashion, with IC50s of 0.5–1.25 mM. It also induced cytotoxicity in dexamethasone (Dex)-, doxorubicin (Dox)-, and melphalan (Mel)-resistant MM cell lines; as well as in patient MM cells, but not in normal PBMCs. Atiprimod triggered MM cell apoptosis via activation of caspase-8 and caspase-3, followed by PARP cleavage. Importantly, neither IL-6 nor insulin-like growth factor (IGF)-1, which completely abrogate Dex-induced apoptosis, protects against Atiprimod-induced apoptosis in MM.1S cells. In combination treatment studies, both conventional (Dex, Dox, Mel) and novel (As2O3) agents augment MM cell apoptosis induced by Atiprimod. Atiprimod inhibits STAT3 and Akt, but not ERK1/2, phosphorylation triggered by IL-6, BAX, Bcl-xl, and Mcl-1 in MM.1S cells. Importantly Atiprimod inhibits both IL-6 and vascular endothelial growth factor (VEGF) secretion in BM stromal cells (BMSCs) triggered by MM cell adherence to BMSCs, as well as associated MM cell growth. Finally, Atiprimod inhibits tumor OPM1 MM cell growth in vivo and prolongs survival in a SCID mouse model. Our data therefore demonstrate that Atiprimod both induces MM cell apoptosis and inhibits cytokine secretion in the BM milieu, providing the framework for ongoing clinical trials of this agent to improve patient outcome in MM.