bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Significance of CD33, CD34 and CD117 Expression on Bone Marrow Blasts of Patients with Myelodysplastic Syndromes.
Authors: Nador Guido , Molteni Alfredo , Cesana Clara , Nichelatti Michele , Scarpati Barbara , Cairoli Roberto , Barbarano Luciana , Nosari Annamaria , Morra Enrica 
Published: October 2019

Abstract
Introduction: Although blast-rich specimens immunophenotype studies in myelodysplastc syndromes (MDS) could associate bone marrow (BM) blast expression of CD7 and/or CD117 antigens with poor outcome (Ogata et al., Blood 2002), the prognostic role of markers of myeloid cell immaturity and committment in not enriched BM samples is largely unexplored.
Patients and Methods: The expression of CD33, CD34 and CD117 antigens in not enriched BM samples of 50 newly diagnosed MDS was compared with both BM blast WHO category and IPSS score. Immunophenotyping was carried out by using the panel of quadruple monoclonal antibodies CD34/CD117/CD45/CD33, conjugated with the fluorochromes FITC, PE, PerCP, APC, respectively. Acquisition of information on 1x105 stained cells corresponding to the whole BM cellularity was assessed on a dual-laser FACSCalibur flow cytometer using the CellQUEST software (Becton Dickinson, San José CA USA). Multiple group comparisons were made using non parametric ANOVA for BM blasts; general linear model with Wald’s test and Kruskal-Wallis (KW) test to confirm significance was used for IPSS.
Results: According to IPSS, 5 (10%) low risk, 27 (54%) intermediate risk-1, 14 (28%) intermediate risk −2 and 4 (8%) high risk pts were identified, respectively. The expression of CD33, CD34 and CD117 significantly correlated with both blast WHO category and IPSS, as shown in the Table 1. Interestingly, by analyzing the subset of 30 pts with BM blasts <5%, a correlation was found between IPSS and the expression of both CD33 (p=0.0097) and CD34 (p=0.0299); CD117 expression increased in pts with higher IPSS, without, however, reaching statistical significance.
Conclusions: Both markers of myeloid cell committment (i.e., CD33 and CD34) and markers of myeloid cell immaturity (i.e., CD117) correlate with BM blast WHO category and IPSS score. Expression of CD33 and CD34 may have prognostic significance independently from blast percentage. The evaluation of CD33, CD34 and CD117 expression on not enriched BM samples may represent a simple tool for the prognostic assessment of MDS patients, in addition to previously established methods.
Tab. 1: Correlation of CD33, CD34, CD117 expression with IPSS and percentage of BM blast in 50 MDS pts at diagnosis
Reduced Dose Lenalidomide Is Safe and Effective in Deletion (5q) MDS Patients with Severe Renal Impairment: Report of Two Cases.
Authors: Knop Stefan , Einsele Hermann , Bargou Ralf , Cosgrove Denise , List Alan 
Published: October 2019

Abstract
Introduction: Lenalidomide (Len) is highly active in the treatment of MDS with deletion 5q (del[5q]) (List et al. NEJM 2006). Patients with renal impairment have often been excluded from Len studies because of potential for delayed excretion with increased risk for adverse events. We present 2 MDS patients with 5q− syndrome and renal impairment who were treated with Len at reduced dosage.
Patient 1: A 50-year-old woman presented with shortness of breath on exertion, pallor, and tachycardia. Laboratory tests showed hemoglobin (Hb) 3.9 g/dL with significant macrocytosis; white blood cell count (WBC) of 3.2 × 109/L; and creatinine 2.66 mg/dL (normal value, < 1.1 mg/dL). Bone marrow aspirate was consistent with World Health Organization 5q− syndrome. Abdominal ultrasound revealed unilateral renal agenesis. The patient required 2 packed red blood cell (RBC) units every 2 to 3 weeks. Glomerular filtration rate (GFR) was severely impaired (23 mL/min). Len was initiated at 5 mg/d and increased to 10 mg/d after 4 weeks. The patient showed a fast and sustained hematologic response, Hb of 10–11 g/dL without exogenous erythropoietin, and achieved transfusion independence within 6 weeks. Due to decreased WBC of 1.3 × 109/L, and a platelet count (plt) of 57 × 109/L, indicating thrombocytopenia, Len was adjusted to a daily alternating dose of 5 mg and 10 mg, respectively. Complete cytogenetic remission was achieved by 6 months of treatment.
Patient 2: An 83-year-old female presented with sustained anemia despite treatment with recombinant erythropoietin. Bone marrow findings and peripheral blood features were consistent with the 5q− syndrome. The patient was transfusion dependent and received a single treatment cycle with azacitidine, but developed acute renal insufficiency, accompanied by an elevation in creatinine to 4.8 mg/dL. She continued supportive care measures receiving 2 units of RBC every 4 weeks. Len was initiated at 5 mg daily. GFR at start of therapy was moderately decreased (31 mL/min). After 6 weeks of treatment the patient developed a generalized rash, occupying 30–50% of the body, which subsided with temporary therapy cessation. Laboratory studies at 6 weeks revealed a WBC of 1.58 × 109/L, with an absolute neutrophil count (ANC) of 3.5 × 109/L, Hb of 12.3 g/dL and plt of 42 × 109/L. Because of progressive decline in the patient’s Hb levels Len was resumed 5 months later at a dose of 5 mg 3 times per week. This was well tolerated. Complete cytogenetic remission was achieved after 10 months of follow-up.
Conclusions: These cases show that Len can be administered safely to MDS patients with renal insufficiency and with preserved clinical activity. In addition, the present observations suggest that Len therapy could abrogate the need for use of additional erythropoietin in these patients.
CD200 Expression May Help in Differential Diagnosis between Mantle Cell Lymphoma (MCL) and B-Cell Chronic Lymphocytic Leukemia (B-CLL).
Authors: Palumbo Giuseppe A. , Forgione Giovanna , Parrinello Nunzia , Cardillo Katia , Chiarenza Annalisa , Berretta Salvatore , Stagno Fabio , Villari Loredana , Di Raimondo Francesco 
Published: October 2019

Abstract
Mantle cell lymphoma (MCL) is a B-cell malignancy that shares many morphologic and immunophenotyping features with B-cell chronic lymphocytic leukemia (B-CLL). However, these two entities are characterized by a very different prognosis and response to therapies. Differential diagnosis is assessed by a panel of monoclonal antibodies (moAbs) to screen the expression of CD5, CD23 and Cyclin D1. Nevertheless, some of these antibodies work better on fresh or frozen tissues; for example, on fixed tissues (expecially by B5) CD5 and Cyclin D1 can give equivocal or even negative results. In addition, it is cumbersome to evaluate Cyclin D1 by flow cytometry. CD200 (previously referred to as OX2) is a membrane glycoprotein, belonging to the immunoglobulin superfamily, expressed on T and B lymphocytes (but not on NK cells) and it might play an immunosuppressive role. Its expression has also been reported on human myeloma plasmacells and B-CLL cells. We investigated the expression of CD200 on fresh neoplastic cells of 90 patients (82 B-CLL and 8 MCL in leukemic phase) by flow cytometry, using a mouse IgG1 anti-human moAb (MRC OX-104, BD Pharmingen, U.S.A.). In our series, CD200 was present on neoplastic cells of all 82 B-CLL (expression on 62–100% of CD5+ cells, mean 96%, standard deviation 7%). On the contrary, in MCL patients (Cyclin D1+ and/or t(11;14) FISH+) CD200 was positive in less than 20% of CD5+ cells in 3 subjects (4–18%) and totally absent in the remaining 5 (two-sided Fisher’s exact test p<0.0001). To further extend the study, we examined CD200 by immunohistochemistry on paraffin-embedded formalin-fixed lympoid tissues and Lowy-fixed bone marrow (BM) trephine biopsies from 18 B-CLL (12 lymphnodes and 7 BM samples) and 19 MCL (11 lymphoid tissues and 9 BM) patients, using a goat anti-human IgG affinity-purified polyclonal antibody (R&D Systems, U.S.A.). Again, all B-CLL neoplastic cells were positive for CD200 both in lymphnodes and in BM while all MCL cells were negative, both in lympoid tissues and in BM (two-sided Fisher’s exact test p<0.0001). Notably, in all MCL CD200-negative lympoid tissue biopsies, it was possible to observe CD200+ residual dendritic cells (useful as immunohistochemistry reaction positive control). Moreover, results were consistent in old archival samples and even in non-perfectly prepared tissues referred to our Center. We would propose to add CD200 in flow cytometry and immunohistochemistry routine panels, as it can be of diagnostic utility in distinguishing between MCL and B-CLL, in particular in mantle cell leukemia patients. Finally, these data have to be considered in view of the proposed targeted therapy with anti-CD200, to eventually exclude MCL patients.
Comparison of Gene Expression between T Cells from CLL Patients, Myeloma Patients and Healthy Individuals.
Authors: Choudhury Aniruddha , Osterborg Anders , Mashayakhi Kaveh , Mosfegh Ali , Kiaii Shahryar , Mellstedt Håkan 
Published: October 2019

Abstract
A unique feature of chronic lymphocytic leukemia is the expansion in absolute numbers of circulating T cells, accompanying the increase in the leukemic B cell clone. T cells of CLL patients may have a role in contributing to the microenvironment that favors the survival and progression of the malignant clone. We have looked at the gene profile of highly purified peripheral T cells from indolent CLL patients using Affymetrix global gene arrays and compared them with purified T cells from multiple myeloma patients as well as healthy individuals. T cells from five indolent, treatment-naïve CLL patients were examined for gene expression by Affymetrix-based microarray alongside T cells from 5 stage I, multiple myeloma patients and 5 age-matched healthy volunteers. Differential expression analysis revealed that 356 genes were differentially expressed by T cells from CLL patients. Based on a two-fold or greater difference, 107 genes were specifically upregulated and 247 genes were noted to be specifically downregulated in T cells of CLL patients. The highest level of upregulation was noted for the chemokines XCL1, XCL2, and the cytokine IFN-g. CCL4 and CCL5 were two other important chemokines that also were found to be specifically upregulated in T cells of B-CLL patients as well as KLF6 and TRAF1. The findings of the microarray analysis was further confirmed using quantitative real-time PCR and immunoblotting with specific antibodies. using T cells from an additional 14 CLL, 6 multiple myeloma and 10 healthy individuals. Our results indicate that T cells from B CLL patients may express a variety of genes that contribute to the creation of a microenvironment that sustains the survival of the leukemic clone and may produce soluble factors that inhibit apoptosis and facilitate proliferation of the leukemic B cells.
Quantitative Assessment of DNA Editing Enzymes in B-Cell Lymphomas.
Authors: Wang Y. Lynn , Lu Pin , Chung Sun M. , Cerutti Andrea , Song Zibo , Chadburn Amy , Tam Wayne , Cesarman Ethel , Knowles Daniel M. 
Published: October 2019

Abstract
Somatic hypermutation of immunoglobulin genes (SHM) is a physiological process that helps generate high affinity antibodies in germinal center B cells, and error-prone DNA polymerases are key enzymes involved in this process. Unlike polymerases that are responsible for DNA replication, error-prone DNA polymerases copy DNA with low fidelity leading to variations in immunoglobulin DNA sequences. Chronic lymphocytic leukemia (CLL) has been classified into mutated and unmutated subtypes based on the mutation status of the IGH variable region (IgVH). The latter has been associated with rapid disease progression and unfavorable outcome. Since determination of the IgVH mutations rely on direct sequencing of multiple PCR products and complex data analysis, the assay, although clinically useful, is not provided by many clinical laboratories. To determine whether error-prone DNA polymerases can be used as surrogate markers for IgVH mutation analysis, we examined the levels of several of them to see whether higher levels are associated with higher degree of IgVH mutation. We analyzed 30 CLL samples, of which 18 were unmutated and 12 were mutated. Quantitative PCR was performed to determine the expression levels of error-prone DNA polymerases mu, eta, iota, lambda and zeta. as well as DNA editing enzymes, terminal deoxynucleotidyl transferase (TdT) and activation-induced cytidine deaminase (AID). Statistical analysis revealed no differences in the levels of mRNA expression of any of these seven enzymes between mutated and unmutated cases of CLL. In addition, no differences were found between ZAP-70 positive and negative subgroups. The expression levels of the seven enzymes were then compared among CLL, follicular lymphomas (FL, n=8) and diffuse large B cell lymphomas (DLBCL, n=8). FL and DLBCL, being post-germinal center lymphomas that have undergone SHM, are expected to express higher levels of these enzymes than CLL. However, the statistical analysis revealed that CLL has significantly higher amount of mu, eta, iota, lambda, zeta and TdT expression than DLBCL. CLL also has significantly higher expression of iota, lambda, zeta and TdT than FL. In conclusion, our results suggest that DNA polymerases studied cannot be used as surrogate markers for IgVH analysis. Contrary to the common belief, the mRNA levels of DNA polymerases/DNA editing enzymes do not reflect the SHM activity in different B cell malignancies.than FL. In conclusion, our results suggest that DNA polymerases studied cannot be used as surrogate markers for IgVH analysis. Contrary to the common belief, the mRNA levels of DNA polymerases/DNA editing enzymes do not reflect the SHM activity in different B cell malignancies.
Variable Contribution of Different Monocloncal Antibodies to NK Cell-Mediated ADCC Against Primary CLL Cells.
Authors: Weitzman James , Betancur Monica , Boissel Laurent , Rabinowitz Arthur P. , Klingemann Hans 
Published: October 2019

Abstract
Chronic Lymphocytic Leukemia (CLL) is characterized by the expression of the B-cell antigens CD19, 20 and 22, along with CD5 and CD23. These antigens make the malignant cells an ideal target for monoclonal antibody (mAb) therapy. Although the mechanism of action of mAbs is complex and not fully understood, one well-described action is antibody-dependent cellular cytotoxicity (ADCC). Binding of mAb to its target surface antigen initiates cytotoxicity through the interaction of the Fc portion of the mAb with the Fc receptor (FcR) on natural killer (NK) cells. This triggers release of perforin and granzymes from NK cells, and subsequent killing of the target cells. This study’s objectives were to measure ADCC of 4 different mAbs against primary CLL cells, and determine if cytotoxicity is dependent on antigen density.
Methods: Mononuclear cells from 16 patients with untreated CLL were separated by density gradient separation and served as targets. The antigen density for CD20, 22 and 23 of each patient sample was quantified by flow cytometry. Effector cells for ADCC were NK-92 cells that do not express FcR, and a high affinity Fc receptor-expressing NK-92 variant (NK92.26.5) that also expresses inhibitory receptors (i.e. KIR). A fluourochrome-based flow cytometric assay determined ADCC by subtracting NK-92 induced cytotoxicity from NK-92.26.5 induced killing. Monoclonal antibodies tested were Rituximab (anti-CD20, Biogen/IDEC), Veltuzumab (anti-CD20, Immunomedics), Epratuzumab (anti-CD22, Immunomedics), and Lumiliximab (anti-CD23, Biogen/IDEC).
Results: Mean ADCC of the four antibodies tested against 16 primary CLL cells were: 46.5% for Rituximab; 43.4% for Veltuzumab; 5.8% for Epratuzumab; 8.8% for Lumiliximab. Cytotoxicity of NK-92 and NK-92.26.5 against CLL cells without antibody ranged from 2–6%. Mean antigen density on the 16 CLL patient specimens were: CD20: 27,900 (range: 10,000–56,100); CD22: 820 (600–1300); CD23: 9870 (2340–14,800).
Conclusions: We have developed a reliable in vitro assay to measure ADCC of mAbs against CLL cells. Our results indicate that ADCC contributes to cytotoxcity of CLL in vitro, and suggest that the magnitude of ADCC depends upon the surface antigen targeted. Anti-CD20 antibodies had significantly greater ADCC than the anti-CD22 and CD23 antibodies. This pattern was consistent in all patient cells tested. A similar pattern was observed with the surface antigen density on CLL cells tested, suggesting a correlation between cell surface antigen density and ADCC. Our results also suggest that resistance of primary CLL cells toward NK-mediated killing can be overcome by monoclonal antibodies even in the presence of inhibitory KIR expression on NK cells.
B-Type Natriuretic Peptide (BNP) and Mitral Velocity E/A Ratio (MV E/A) Are Two Important Noninvasive Functional Indices of Cardiac AL Amyloidosis.
Authors: Kabos Peter , Bashir Qaiser , Chen Robert , Lindenfeld JoAnn , Myint Han , Lee Choon Kee 
Published: October 2019

Abstract
Cardiac AL amyloidosis is characterized as global myocardial dysfunction, oftentimes complicated by pulmonary events during stem cell mobilization and autotransplant. Although BNP or N terminal proBNP has been shown to be prognostically significant for survival following autotransplant, pathophysiologic processes of the heart for elevated levels of these molecules are unclear. In the current study, we sought to evaluate functional cardiac indices assessed by two-dimensional and Doppler echocardiography and to correlate to BNP and clinical events. Evaluations were done on 39 serial echocardiogrmas obtained between July 2006 and July 2007 from 5 patients with established cardiac AL amyloidosis as a part of systemic amyloidosis (3 primary; 2 secondary to free kappa light chain multiple myeloma). Their median age was 78 years (range 48 to 80). One patient presented with pulmonary edema initially and three others developed pulmonary edema (n = 2) or congestion with pleural effusion (n = 1) during the course of therapy. Two patients underwent melphalan-based autotransplant, and three received melphalan 50 mg/m2 up to 2 cycles every 3 months without stem cell infusion. The median BNP at diagnosis was 1110 pg/mL (range, 115 to 2540); right ventricular diastolic diameter (RVDd) 3.8 cm (2.9 to 4.0); left ventricular end diastolic volume (LVEDV) 88 mL (50 to 125); ejection fraction 60% (53 to 77); MV E/A 2 (1.3 to 2.9); right ventricular systolic pressure (RVSP) 48 mmHg (40 to 68). In multiple regression analyses, BNP levels were most significantly correlated to the RVDd, β = 0.58, p < 0.05. The RVSP as a surrogate index of pulmonary arterial pressure was shown most dependent on the left ventricular diastolic filling assessed by the MV E/A (β = 0.93, p < 0.05) that in turn was dependent on the LVEDV (β = 2.68, p < 0.05). None of the myocardial wall measurements and left ventricular indices except these were found to be significant. Although the RVDd was dependent on the RVSP (β = −1.17, p < 0.05), both BNP and RVSP were independent of each other (β = −0.25, p = 0.6). RVSP levels were significantly elevated in 4 patients who had pulmonary complications: 50, 55, 57, 68 mmHg, respectively. The MV E/A was elevated at or above 2.5 at the time of these episodes: 2.5, 2.9, 2.9, 3.7, respectively. Decrease in both BNP and RVSP appeared to be minimally related to improving serum free light chain levels following therapy: β = 0.29, p = 0.08 and β = 0.34, p = 0.05, respectively. There was no correlation between the MV E/A and serum free light chain level either, β = 0.19, p = 0.3. The data suggests that the MV E/A and RVSP may be useful indices for monitoring patients for potential pulmonary complications, and the BNP appears to reflect more of the right-sided heart events. Further studies are needed to confirm the current findings.
An Observational Post Authorization Study on the Use of Bortezomib in Multiple Myeloma Patients in The Netherlands: Results of an Interim Analysis.
Authors: Biesma Douwe H. , Lokhorst Henk M. , van der Hem Klaas , van der Heul Cees 
Published: October 2019

Introduction: Bortezomib (Velcade®) is a relatively new drug in the treatment of patients with Multiple Myeloma (MM). Most data on efficacy and safety are from randomised controlled studies in selected groups of patients with MM.
Aim of the study: To evaluate safety and efficacy of bortezomib in daily practice after its registration for second and later line therapy in patients with MM.
Materials and methods: In an observational, multicentre study, the efficacy and safety of treatment with bortezomib was assessed in MM patients. An interim analysis was performed on data of the first 50 patients enrolled from November 04 until March 06.
Results: All results are given as median ± SD. The patients’ age was 65 yrs, Karnofsky Performance Score was 80%, time from initial diagnosis was 3.4 years, 62% of the patients had more than 2 previous treatment lines, 88% of the patients had disease stage III. Patients were treated with 4 cycles (95% CI: 4.0 – 5.4) of bortezomib. The patients had Response Rate (RR; based on serum M-protein values) of 64% (2.0% nCR, 2.0% VGPR, 22% PR, 38% MR). Best RR remained 64% with an increasing depth of response (2% CR, 8% nCR 6.0% VGPR, 32% PR, 16% MR); 6 patients were not evaluable for response. Time to initial response was 45 days; time to best response was 63 days. The duration of response (DOR) was 6.4 months. Also, a relation between treatment duration and DOR was found (correlation coefficient 0.4118, p-value 0.0192). Overall survival was 1.3 yrs and PFS 6.4 months. The treatment was generally well tolerated. Most common adverse events (AE’s) were in order of decreasing frequency thrombocytopenia, nausea, constipation, diarrhoea, fatigue, malaise, polyneuropathy, pyrexia, anaemia, dizziness and leukopenia. Only 6.1% of all AE’s resulted in a permanent discontinuation of bortezomib; 13% of all AE’s were reported as serious of which 54.7% were considered as grade 3 or higher (CTCAE) and at least possibly related to bortezomib in 45.3%. In one patient (2%), Herpes zoster was reported.
Conclusion: Response Rates in this study were comparable to those in other community studies and higher than reported in previous clinical studies. The somewhat shorter DOR observed versus previously reported studies might have been caused by a shorter duration of bortezomib treatment, although more data is needed to derive a final conclusion. Overall the treatment with bortezomib was well tolerated and overall survival was as expected in this patient population. The clinical significance of the observed relation between treatment duration and response duration requires further exploration.