bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunophenotypic Analysis of Waldenstrom’s Macroglobulinemia: A Study of 63 Cases.
Authors: Toma Andrea , Le Garff-Tavernier Magali , Brissard Martine , Bonnemye Patrick , Musset Lucile , Azar Nabih , Leblond Veronique , Merle-Beral Helene 
Published: October 2019

Abstract
The immunophenotypic characterization of Waldenstrom’s macroglobulinemia (WM) is still unclear, despite being an essential tool in the diagnosis of hematological malignancies. We retrospectively reviewed the immunophenotypic profile of 63 cases of WM showing monoclonal IgM in the serum and morphological lymphoplasmacytic bone marrow infiltration, and of 26 cases of other chronic B-cell lymphoproliferative disorders having monoclonal IgM in the serum (LPD-M), including marginal zone (n=16), mantle cell (n=8) and follicular (n=2) lymphomas. The median age at diagnosis was 64[46–92] years. Immunophenotypic analysis was performed by flow cytometry between January 1998 and July 2007, using four or six monoclonal antibody combinations. In WM and LPD-M groups, all patients showed a monoclonal tumoral B-cell population, detected and studied in blood (21 and 23 patients, respectively), blood and bone marrow (19 and 2 patients, respectively) or bone marrow samples (23 and 1 patient, respectively). Patients with a Matutes score > 3 were excluded. Neoplastic cells, in all cases, expressed a monoclonal immunoglobulin light chain (kappa for 70% WM and 73% LPD-M, lambda for 30% WM and 27% LPD-M). The intensity of expression of the monoclonal light chain was particularly heterogeneous in both groups: high, normal or low expression in 43%, 27% or 30% of WM, and in 52%, 33% or 15% of LPD-M, respectively. Pan-B antigens (CD20, CD19, CD79b) were positive for at least 97% of patients. The results obtained with other antigens in WM compared to LPD-M were: CD10 = 10 versus 7%, CD23 = 33 versus 56%, CD5 = 14 versus 26%, FMC7 = 76 versus 89%, CD38 = 56 versus 41%, CD25 = 86 versus 84%, CD43 = 12 versus 16%, and CD11c = 10 versus 36%. The intensity of expression of these antigens was heterogeneous in both groups. Among the antigens only tested in the WM group, CD1c and CD27 were positive for 70% of patients, IgM and IgD for 95% of patients, and CD103 as well as CD117 were negative in all cases. Considering all (blood and/or bone marrow) WM samples, plasma cells (CD38/CD138 positive cells) were found at low levels (less than 2.5% of B-cells) for 46% of WM. Comparing blood versus bone marrow WM samples, no differences were found for all previous antigens except the higher frequency of low counts of plasma cells in bone marrow (observed in 71% of WM) versus blood samples (28% of WM). Among the 10 WM patients tested for ZAP-70 expression, nine were negative and one showed a low intensity expression. In conclusion, our results show that the immunophenotypic analysis usually performed with standard antigens in WM overlaps with other B-cell lymphoproliferative disorders. Studies involving the expression of new antigens and/or other biological approaches are required to identify the WM among the B-cell malignancies and are ongoing in our group.
Phase I Trial of Multiple Infusions of Autologous Activated T Cells with Anti-CD3 x Anti-CD20 Bispecific Antibody (CD20Bi) after Autologous Peripheral Blood Stem Cell Transplant for NonHodgkins Lymphoma To Improve Graft-vs-Lymphoma Effects.
Authors: Lum Lawrence G. , Uberti Joseph P. , Al-Kadhimi Zaid , Skuba Cassara , Steele Pat , Sandborg Rebecca , Ratanatharathorn Voravit 
Published: October 2019

Abstract
Relapse rates after high dose chemotherapy (HDC) autologous peripheral blood stem cell transplant (PBSCT) for high risk refractory or relapsed non-Hodgkin’s lymphoma (NHL) patients remain unacceptably high. In order to augment the anti-lymphoma effect and decrease relapsed rates, our strategy combines 1) the cytotoxicity mediated by anti-CD3 activated autologous T cells (ATC) armed with a bispecific antibody (BiAb) that redirects ATC to kill CD20 + lymphoma cells and circumvents rituximab resistance (Exp Hemat33:452, 2005) and 2) autologous PBSCT after high dose chemotherapy. Arming ATC with anti-CD3 x anti-CD20 (CD20Bi) converts each ATC into a CD20-specific cytotoxic T cell. Our phase I trial tests whether multiple infusions of armed ATC armed given after HDC followed by PBSCT are safe and whether such infusions will provide an anti-lymphoma effect to improve overall survival and disease free survival after PBSCT. On day +4, the patients receive immune consolidation consisting of 3 infusions of CD20Bi-armed ATC per week for 3 weeks and then 1 infusion per week for 6 additional weeks. The dose levels are 5, 10, 15, and 20 x 109 cells/infusion with total armed ATC doses equaling 75, 150, 225, and 300 x 109 CD20Bi-armed ATC. Subcutaneous IL-2 (300,000 IU/m2/day) will be given daily beginning d+4 and ending after the last dose of armed ATC. The dose of CD34+/kg ranged from 1.04 to 3.4 x 106. T cells in the leukopheresis product were activated with anti-CD3 and expanded in low dose IL-2, harvested, armed with CD20Bi, and cryopreserved for infusions after PBSCT. The ATC harvest ranged from 119–140 billion with >94% viability with 96–99% CD3+, 33–67% CD4+, 32–53% CD8+, and <6.5% CD4+CD25+ and CD8+CD25+ cells. All three patients received all of their infusions. Three patients completed the first dose level (total of 70 x 109 CD20Bi armed ATC) without any dose limiting toxicities. All of the patients are alive 780, 650, and 521 days after PBSCT. Two are free of disease and one was transplanted with persistent disease went into remission after PBSCT and relapsed 8 months after PBSCT. He is now in remission following chemotherapy and a MUD PBSCT. The cytotoxicity mediated by the patients’ ex vivo expanded, armed ATC against the B9C cell line was significantly higher than unarmed ATC. CTL activity directed at B cell targets was detected by 3 weeks after PBSCT. These results suggest that large numbers of armed autologous ATC can be infused after PBSCT without major side effects related to the armed targeted ATC. This strategy may provide a unique opportunity to increase the GVL effect without increasing toxicities after autologous PBSCT for CD20+ lymphomas.
In Vitro Characterization of OP-R003-1, a New Fully Human Anti-IL6 Antibody.
Authors: Vermot-Desroches Claudine , Wang Wei , Subiger Olivier , Abribat Thierry , Alberici Gilles , Zauderer Maurice , Ernest Smith 
Published: October 2019

Abstract
Potential applications for drugs targeting IL-6 include a range of inflammatory and proliferative disorders, including rheumatoid arthritis, multiple myeloma, post transplant lymphoma, Crohn’s disease and Systemic Lupus. Using the ActivMab® technology, a high-affinity, fully human antagonistic monoclonal antibody (MAb) OP-R003-1 was structurally derived from elsilimomab (B-E8, a murine anti-IL-6 MAb) which had previously been shown to be effective in several proof-of-concept clinical trials. In vitro studies demonstrated that OP-R003-1 shares similar biological properties, including affinity and epitope specificity with its “parent” murine antibody. OP-R003-1 detected human and monkey IL-6 but not murine or rat IL-6. No binding was observed with other IL-6 superfamily members. This novel fully human MAb inhibited the binding of IL-6 to its receptor as evidenced by flow cytometry using U266 cells and also inhibited IL-6 induced cell proliferation in murine B9, human TF1 or U266 cells. The conversion of the murine B-E8 MAb into a fully human MAb will result in an improved therapeutic MAb clinical profile, including reduced immunogenicity and improved half-life, while preserving the specificity and clinical effectiveness of the murine Mab.
Cytotoxicity of Genetically Engineered Fusion Protein with CD154 Peptide Mimetic (OmpC-CD154p) on B-NHL Cell Lines.
Authors: Martinez-Miguel Bernardo , Martinez-Paniagua Melisa A. , Huerta-Yepez Sara , Hernandez-Pando Rogelio , Gonzalez-Bonilla Cesar R. , Bonavida Benjamin , Vega Mario I. 
Published: October 2019

Abstract
The interaction between CD40, a member of the tumor necrosis factor super family, and its ligand CD154 is essential for the development of humoral and cellular immune responses. Selective inhibition or activation of this pathway forms the basis for the development of new therapeutics against immunologically-based diseases and malignancies. CD40 is expressed primarily on dendritic cells, macrophages and B cells. Engagement of CD40-CD154 induces activation and proliferation of B lymphocytes and triggers apoptosis of carcinoma and B lymphoma cells. Agonist CD40 antibodies mimic the signal of CD154-CD40 ligation on the surface of many tumors and mediate a direct cytotoxic effect in the absence of immune accessory molecules. CD40 expression is found on nearly all B cell malignancies. Engagement of CD40 in vivo inhibits B cell lymphoma xenografts in immune compromised mice. Several clinical trials have been reported targeting CD40 in cancer patients using recombinant CD154, mAbs and gene therapy, which were well tolerated and resulted in objective tumor responses. In addition to these therapies, CD54 mimetics have been considered with the objective to augment and potentiate the direct cytotoxic anti-tumor activity and for better accessibility to tumor sites. This approach was developed by us and we hypothesized that the genetic engineering of a fusion protein containing a CD154 peptide mimetic may be advantageous in that it may have a better affinity to CD40 on B cell malignancies and trigger cell death and the partner may be a carrier targeting other surface molecules expressed on the malignant cells. This hypothesis was tested by the development of a gene fusion of Salmonella typhi OmpC protein expressing the CD154 Trp140-Ser149 amino acid strand (Vega et al., Immunology2003; 110: 206–216). This OmpC-CD154p fusion protein binds CD40 and triggers the CD40 expressing B cells. In this study, we demonstrate that OmpC-CD154p treatment inhibits cell growth and proliferation of the B-NHL cell lines Raji and Ramos. In addition, significant apoptosis was achieved and the extent of apoptosis was a function of the concentration used and time of incubation. The anti-tumor effect was specific as treatment with OmpC alone had no effect. These findings establish the basis of the development of new fusion proteins with dual specificity (targeting the tumor cells directly or targeting the tumor cells and immune cells). The advantages of this approach over conventional CD40-targeted therapies as well as the mechanism of OmpC-CD154p-induced cell signaling and cell death will be presented.
MTHFR 677CC/1298CC Genotypes Are Highly Associated with Chronic Myelogenous Leukemia: A Case-Control Study in Korea.
Authors: Moon Hee Won , Kim Tae Young , Oh Bo Ra , Min Hyun Chung , Cho Han Ik , Lee Jae Hoon , Yoon Sung Soo , Lee Dong Soon 
Published: October 2019

Abstract
Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism and DNA methylation. Studies on MTHFR polymorphism in leukemia have largely focused on the protective role of MTHFR polymorphism in ALL. We evaluated the C677T and A1298C polymorphisms using the TaqMan® allelic discrimination assay in various malignancies. The study population included 115 subjects with CML, 200 with AML, 196 with MM and 434 healthy control subjects. The frequency of 1298 CC was statistically significantly higher in subjects with CML than that of the controls (OR = 5.12, 95% CI: 1.75–14.9, P value =.003). Of note, the frequencies of 677CC/1298CC genotype was statistically significantly higher in subjects with CML, AML and MM than that of the controls (OR = 8.8, 3.5, 3.83, P value =.002, 0.036, 0.023, respectively). Our results demonstrate that the MTHFR 1298CC homozygote variant is strongly associated with an increased risk of CML, while MTHFR C677T does not significantly affect the risk of CML. Moreover, we demonstrated that MTHFR 677CC and 1298CC genotype might have combined effect on risk of CML, AML and MM and it is inferred that the A1298C may play a different role in carcinogenesis, depending on the types of organs involved, the types of disease entities and the genotype of C677T.
Efficacy of Lenalidomide for Treatment of Anemia in Secondary Myelodysplastic Syndrome (MDS) with Chromosome 5q Deletion.
Authors: Mintzer David Michael , Billet Shira N. 
Published: October 2019

Abstract
Lenalidomide can be effective in treatment of MDS, particularly in patients with isolated 5q deletion, as well as in patients with 5q− with other karyotypic abnormalities (List et. al. NEJM355, 1456; 2006). However, there is little data for secondary MDS. We report two patients with chemotherapy-induced MDS with 5q−, both treated with lenalidomide, one of whom responded. Case 1: An 81-year-old female with multiple myeloma who had been treated with melphalan and prednisone developed worsening anemia despite continued biochemical remission of her myeloma. Three years after melphalan treatment, a bone marrow revealed MDS with only 2% plasma cells. Cytogenetics showed: 46, XX, del(5)(q13q33), del(14)(q1?3), add(22)(q13)[1]/46, sl, del(20)(q13.1) [9]/47, sdl1, +8[10]. The patient was transfusion dependent despite treatment with EPO. She was treated with lenalidomide 10 mg daily and began responding after eight weeks of therapy. Her anemia improved, and she became transfusion independent until her death 6 months later from infection.
Figure 1. HCT before and after lenalidomide treatment (patient 1) Figure 1. HCT before and after lenalidomide treatment (patient 1)
Case 2: A 54-year-old male developed MDS after multiple therapies for low grade non-Hodgkins lymphoma, including rituximab, ibritumomab tiuxetan, chlorambucil, and CHOP. While in remission for lymphoma, he developed pancytopenia. A bone marrow revealed no lymphoma, but demonstrated evidence of MDS. Cytogenetics showed: 46, XY, del (5)(q13q33) [3]/44, idem, −7, add(19)(q13), −21[3]/46, XY [14]. The patient was transfusion dependent. He was treated with lenalidomide 10mg daily, demonstrating no significant benefit after 10 weeks. We report that one of our two patients with secondary MDS and 5q− responded to lenalidomide with a resolution of her transfusion requirement. Two prior cases of improvement in secondary MDS with 5q− after lenalidomide treatment have been reported (Melchert et. al. Leukemia21: 1576–78, 2007). Lenalidomide is active in some cases of secondary MDS with 5q−. Further studies are needed to better define the activity of lenalidomide in secondary MDS with and without 5q−.
JAK2 (V617F) Mutation Levels and Marrow Fibrosis in Patients Affected by Budd-Chiari Syndrome and Non-Cirrhotic Extra-Hepatic Portal Vein Obstruction.
Authors: Rago Angela , Marzano Chiara , Mammì Corrado , Laganà Carmelo , Fama Angelo , Bizzoni Luisa , Tomei Gabriella , Trasarti Stefania , Gioisa Francesca , Breccia Massimo , Carmosino Ida , Latagliata Roberto , Alimena Giuliana , Foa Robert , Riggio Oliviero , Tafuri Agostino 
Published: October 2019

Abstract
Budd-Chiari syndrome (BCS) and Non-Cirrhotic Extra-Hepatic Portal Vein Obstruction (EHPVO) are two rare vascular diseases of the liver. Inherited and acquired disorders including Myeloproliferative Disorders (MPD) have been frequently reported associated with these diseases, although the large majority of cases is still defined as “idiopathic disease”. The somatic mutation in the tyrosine kinase JAK2 has been described in MPD, specifically in the majority of patients with polycythemia vera (PV), in about half of cases with essential thrombocythemia (ET) and in one third of idiopathic myelofibrosis (IMF), suggesting its pathogenetic role in these diseases. Since the diagnosis of MPD is often difficult in patients with BCS or EHPVO because of spleen enlargement and secondary pancitopenia that can mask erythrocytosis and thrombocytosis, recent observations have included in their diagnostic work-up the analysis of JAK2 mutations. In fact, recently, a high prevalence of JAK2 mutations has been described in splanchnic vein thrombosis. The aim of this study was to evaluate the prevalence and the levels of JAK2 mutation in the patient population affected by BCS and EHPVO followed at our Hepatology Division. The JAK2 mutation was evaluated by allele-specific real-time TaqMan polymerase chain reaction. We enrolled in this study 18 patients (median age: 38 ± 9.8 years) affected by BCS (7 patients), EHPVO (10 patients), or both (1 patient). In 9 of them the JAK2 mutation was absent, while it was demonstrated in the remaining cases. Among these, an heterozygous deletion (JAK2 mutation ranging between 2.7% and 48%) was detected in 5 and an homozygous deletion (55.7%–88%) in 4. A diagnosis of PV was made in 2 patients with JAK2 heterozygous deletion affected by BCS and EHPVO. The 3 IMF were all characterized by homozygous deletions: 1 had BCS and 2 EHPVO. In the remaining 3 patients, in the absence of other diagnostic criteria, only the bone marrow biopsy revealed the presence of initial marrow fibrosis: grade 0–1 (2 patients both affected by EHPVO with heterozygous and homozygous deletion) and grade 1 (in a heterozygous patient affected by EHPVO). In summary, the JAK2 mutation was demonstrated in half of the cases with vascular liver diseases, regardless of the JAK mutation levels. The marrow fibrosis was, in these cases, frequently associated with both BCS and EHPVO, suggesting a common potential pathogenetic role in these vascular diseases of the liver.
ZAP-70 Expression in Chronic Lymphocytic Leukemia Is Associated with Altered Signal Transduction.
Authors: Wolniak Kristy L. , Marvin James , Goolsby Charles 
Published: October 2019

Abstract
B-cell chronic lymphocytic leukemia (CLL) is a malignancy of mature B-cells with a variable clinical course. Given the heterogeneity of disease course, identification of prognostic factors is imperative. One recently identified negative prognostic indicator in CLL is the T-cell tyrosine kinase ZAP70. ZAP70 is analogous to, and can functionally substitute for, the B-cell tyrosine kinase Syk and is activated following B cell receptor (BCR) crosslinking in CLL cells. However, the role of ZAP70 expression in CLL remains elusive. Utilizing flow cytometric analyses of signal transduction molecules, this study examined if ZAP70 expression affects signal transduction in CLL. Peripheral blood samples from ZAP70+ and ZAP70− CLL patients were analyzed. The levels of phosphorylated ERK, STAT5, and S6 (p-ERK, p-STAT5, p-S6) were measured by flow cytometry with and without BCR stimulation. Kinase inhibitors were used to verify the measured phosphorlyated protein levels. Increased constitutive levels of p-ERK, p-STAT5, and p-S6 were seen in ZAP70+ CLL cells as compared to ZAP70− CLL cells. BCR crosslinking gave variable responses in both ZAP70+ and ZAP70− CLL. The majority of ZAP70− cases showed no significant activation or a predominant activation of ERK with rare p-S6 activation. ZAP70+ cells showed activation of either, or both, ERK and S6 pathways and fewer showing no activation. In summary, though the role of ZAP70 in B cell signaling is poorly understood, expression of ZAP70 in CLL correlates with a constitutively active phenotype. Additionally, differential response in ZAP70+ versus ZAP70− cases following BCR crosslinking suggests a possible modulatory role of the BCR pathway. Current studies are underway to determine if these measures carry prognostic information and if the varying signal responses to BCR stimulation correlate with reported differences in apoptotic versus proliferative response.
Epidemiology and Clinical Outcomes of the M-Component Immunoglobulin Types of Multiple Myeloma in an Inner City Hispanic Population.
Authors: Batty George Nicolas , Brower Jonathan , Aziz Adel , Maddukuri Neelima , Tadros James , Uhm Kyudong , Maroules Michael 
Published: October 2019

Abstract
Introduction: Different types of myeloma are classified by the type of immunoglobulin. From prior analysis, we know that IgG is the commonest class of myeloma and that this type seems to be the most benign. While IgA myeloma appear to be of intermediate outcome, IgD myeloma and lambda light-chain disease are the most aggressive types. Breakdown by immunoglobulin type reveals higher prevalence of IgG myeloma among Whites, compared to Blacks. This study examines the type of immunoglobulin and clinical implication in Hispanics compared to other ethnic groups.
Methods: In a single inner city institution, we retrospectively examined patients diagnosed with multiple myeloma over a 5-year period. This investigation defined Hispanic patients as those of Latin American descent. We identified the M-component immunoglobulin type from immunoelectrophoresis as reported in medical records. New onset renal failure and disease related mortality are considered as adverse clinical outcomes. Various ethnic groups were compared between the type of immunoglobulin and adverse clinical outcomes using chi-square test.
Results: A total of 203 patients were examined, of which 63 (30.9%) were Hispanics, 87 (42.9%) Caucasians and 53 (26.2%) African American, (104 males, 99 females, age range 34 – 93 yrs, mean age 67.45 ± sd 10.28 yrs). IgG and IgA M-components predominated among all ethnic groups respectively Hispanics 36 (57.9%), 6 (10.5%), Caucasians 51 (59%), 18 (22.7%) and African Americans 25 (50%), 20 (37.5%). A higher proportion of light-chain cases were seen among Hispanics since 21 (31.6%) had no peak on immunoelectrophoresis compared to Caucasians 31 (18.3%) and African Americans 8 (12.5%) (chi-square test, two-tailed p=0.426). Adverse clinical outcomes of new onset renal failure developed correspondingly in 20 (31.6%) Hispanics, 31 (36.3%) Caucasians and 15 (28.6%) African Americans while disease related mortality occurred in 20 (31.6%) Hispanics, 18 (21.4%) Caucasians and 9 (18.2%) African Americans (chi-square test, two-tailed p= 0.132). However, differences were not statistically significant.
Conclusion: Although Hispanics exhibited more myeloma of light chain type and worse clinical outcomes compared to other ethnic groups, our study was unable to detect a statistical disparity. Further prospective large population based studies via the new light chain immunodiagnostic assay are warranted to define the epidemiology of this disease.