bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of 90Y-Ibritumomab Tiuxetan (Zevalin) in Refractory or Relapsed MALT Gastric Non Hodgkin’s Lymphoma.
Authors: Vanazzi Anna , Ferrucci Pier F. , Grana Chiara , Pruneri Giancarlo , Crosta Cristiano , Pinto Antonello , Chinol Marco , Paganelli Giovanni , Martinelli Giovanni 
Published: October 2019

Abstract
Radio-immunotherapy (RIT) is an effective approach for patients with relapse-refractory NHL. The aim of RIT is to use the monoclonal antibody to target radiation to the tumor bulk while limiting exposure of normal tissues. Toxicity is prevalently hematologic, but transient and reversible. Zevalin in particular has demonstrated activity in follicular (FL) and diffuse large B-cell (DLBC) NHL, but data are still lacking in MALT NHL. In this setting of pts Zevalin could offer an alternative option to those pts who relapse or do not respond to conventional treatment. We report efficacy results of a pilot study of Zevalin delivered at conventional activity (0,4 mCi/kg) in gastric NHL pts resistant or refractory to conventional systemic treatment. From May 2004 to January 2006, 7 patients were enrolled. They all had gastric resistant-refractory CD-20 positive B-cell NHL: 2 DLBC and 5 MALT. Median age was 57 ys (range 36–64), 3 female and 4 male. At time of treatment 5 out of 7 patients had stage I/IIA (MALT), while 2 out of 7 pts had stage III/IV (DLBCL) of disease. Helicobacter Pylori was negative in all pts at time of treatment, positive at diagnosis in 3 out of 5 pts affected by MALT gastric NHL. Median number of previous therapies received was 2 (1–4): all of them had received prior CT, 3 prior Rituximab, no one had received prior RT. Toxicities were primarily haematological, as expected, and reversible. Response evaluation was performed two months after Zevalin administration by upper gastrointestinal endoscopy with multiple biopsy and endoscopic ultrasonography. All patients are now evaluable for response: 5 CR (all MALT), 2 PD (both DLBC NHL). All responders still maintain a CR at 27, 20, 16, 9 and 8 months after treatment.
Conclusions: Zevalin seems to be very active in pts with MALT gastric NHL resistant or refractory to conventional systemic treatment. Its mechanism of action mimics conventional RT already known as valid option in MALT gastric NHL. If these preliminary results are confirmed in larger number of pts, one single administration of Zevalin delivered at conventional activity (0,4 mCi/kg) could be considered a possible alternative option in the treatment of such indolent disease.
Smudge Cells on Routine Blood Smear Predict Clinical Outcome in Chronic Lymphocytic Leukemia: A Universally Available Prognostic Test.
Authors: Nowakowski Grzegorz S. , Hoyer James D. , Shanafelt Tait D. , Geyer Susan M. , LaPlant Betsy , Call Timothy G. , Jelinek Diane F. , Zent Clive S. , Kay Neil E. 
Published: October 2019

Abstract
Background: The prognosis of patients with early Rai and Binet stage CLL is variable. Recently developed prognostic tests (mutation status, ZAP-70, chromosome evaluation by FISH) require significant technologic expertise and are not available worldwide to most patients with CLL. Smudge cells are ruptured CLL cells appearing on a blood smear. Using a proteomic approach, we recently discovered that the cytoskeletal protein vimentin is expressed at higher levels in CLL cells with unmutated IgVH and that vimentin expression is a marker of poor prognosis in early stage CLL (Blood, 2005;106:707).
Hypothesis: Since vimentin plays an important role in the cytoskeleton and lymphocyte rigidity, we hypothesized that smudge cell formation is inversely correlated with vimentin expression and that the percentage of smudge cells may predict prognosis in CLL.
Methods: We blindly reviewed the blood smears archived at the time of diagnosis of patients with untreated, early stage CLL. A total of 200 lymphocytes and smudge cells were counted per slide and results reported as percentage of total lymphocytes (intact and smudged). The percentage of smudge cells was correlated with vimentin expression measured by flow cytometry, IgVH mutation status, time to treatment (TTT), and survival.
Results: Blood smears of 75 patients were reviewed. The median percentage of smudge cells was 27% (range, 4–72%). The percentage of smudge cells did not correlate with lymphocytosis (r=0.04, p=0.73) and did not change overtime for serial evaluations for individual patients (p=0.61). The percentage of smudge cells appeared to correlate inversely with vimentin expression (r = − 0.627; p = 0.0017). The percentage of smudge cells was higher in patients with mutated IgVH than in patients with unmutated IgVH (median 31% vs. median 13%, p=0.02). The percentage of smudge cells as a continuous variable correlated with both a prolonged TTT (p=0.0023) and overall survival (p=0.04). Patients with less than 30% smudge cells had a median TTT of 72.7 months. The median TTT in patients with ≥30% smudge cells was not reached (p=0.0011), Figure 1.
Conclusion: A lower percentage of smudge cells is associated with unmutated IgVH status and with worse clinical outcome in early stage CLL. The percentage of smudge cells does not vary based on the magnitude of the lymphocytosis, but is patient specific and remains constant over time. Evaluation of the percentage of smudge cells on blood smears could be a universally available prognostic test for patients with early stage CLL.
Figure Figure
Highly Purified Hematopoietic Stem Cell Can Generate Cardiomyocytes Via Myeloid Progenitors through Cell Fusion.
Authors: Fukata Mitsuhiro , Ishikawa Fumihiko , Shimazu Hideki , Nakamura Ryu , Shimoda Kazuya , Akashi Koichi , Leonard Shultz D. , Harada Mine 
Published: October 2019

Abstract
[Introduction] Recent reports demonstrating the ability of bone marrow (BM) cells to regenerate cardiomyocytes have prompted clinical as well as basic studies for the treatment of ischemic and non-ischemic cardiomyopathies. However, the responsible BM cells and underlying mechanism of regeneration remain unclear. In this study, we checked the cardiomyogenic potential of BM cells in vivo, to identify the cell populations in BM that possess the capacity to give rise to cardiomyocytes and clarify whether cardiomyogenic potential of BM-derived cells require cell fusion with host cardiomyocytes.
[Method and Result] BM cells of mice constitutively expressing green fluorescent protein (GFP) was intravenously injected into irradiated syngeneic newborn C57BL/6 mouse within 48hours after the birth. At 4–5 weeks after transplantation, the cardiac tissue of recipients was analyzed for the number of GFP+ cardiomyocytes per 40 sections. We first separated Linaege antigen− BM cells to CD45+ cells (Lin−CD45+) and CD45− cells (Lin−CD45−) and transplanted each. In the recipients of Lin−CD45+, 37.0±23.9 GFP+ cardiomyocytes were detected (n=6). While no GFP+ cardiomyocyte was detected in the recipients of Lin−CD45− (n=4). Since hematopoietic cells generated cardiomyocytes, we next transplanted limiting numbers of purified HSCs and hematopoietic progenitors by cell sorting. Both HSCs and hematopoietic progenitors generated cardiomyocytes dose-dependently, suggested that HSC can generate cardiomyocytes via hematopoietic progenitors. To explore the hematopoietic lineage, we further transplanted purified myeloid progenitors and common lymphoid progenitors by cell sorting. The number of GFP+ cardiomyocytes were 12.8±10.7 and 0.91±1.20 in the recipients of myeloid progenitors (n=7) and common lymphoid progenitors (n=10) respectively (p<0.005), suggested that myeloid lineage is more strongly involved in the generation of cardiomyocytes than lymphoid lineage. Furthermore, we confirmed the contribution of myeloid cells to cardiomyocytes by transplanting common myeloid progenitors (CMPs) and granulocyte/macrophage lineage-restricted progenitors (GMPs). Finally, we transplanted GFP+ HSCs and myeloid progenitors into CFP (cyan fluorescent protein) transgenic mouse. Linear unmixing analysis using confocal microscopy revealed that donor-derived GFP+ cardiomyocytes coexpressed CFP, indicated cell fusion had occurred. We are now analyzing recipients transplanted with single GFP+ HSC.
[Conclusion] Our results suggested that HSC can contribute to the post-natal generation of cardiomyocytes via myeloid progenitors through cell fusion.
Precise Prediction of Response to Therapy by Using the Chemosensitivity Index Ci in Patients with Chronic Lymphocytic Leukemia.
Authors: Staib Peter , Lube Rabea , Schinkothe Timo 
Published: October 2019

Abstract
There are quite a few number of prognostic factors known to determine the prognosis of patients with chronic lymphocytic leukemia (CLL). However, the individual response to therapy may still not be predicted by these factors. Therefore, we investigated prospectively the prediction of response to therapy and the prognostic relevance of the in-vitro chemosensitivity profile in patients with CLL within a randomized trial. For the evaluation of the chemosensitivity profile we applied the methodology of the chemosensitivity index Ci, which we described before in AML (Staib et al., Br J Haematol 2005). Peripheral blood samples from patients with the established diagnosis of B-CLL were taken with written informed consent before treatment was started. For in vitro chemosensitivity testing the Differential Staining Cytotoxicity (DiSC) Assay was used. The fresh leukemic cells were incubated with fludarabine, bendamustine and six other cytotoxic drugs. DiSC assay results were expressed as percent tumor cell survival (%TCS). The chemosensitivity index Ci was calculated according to dose-response curves for each clinically used drug and the area under the curve (AUC). The cut off point between resistance and sensitivity was adjusted at 0,5 for each drug by the AUC data of a subgroup of clinically resistant patients: Ci ≤0.5 indicates resistance, Ci >0.5 sensitivity to the drug.
Results: 53 patients were recruited to a two-arm randomized second line treatment trial from 2001 to 2005. The patients were treated with either fludarabine or bendamustine as a monotherapy. For all patients a chemosensitivity test was performed to predict the clinical outcome for the used treatment. 25 (47%) patients received fludarabine and 28 (53%) bendamustine. 41 pts. (77%) achieved a complete or a partial remission whereas 12 pts. had a stable or progressive disease (23%). All of the responding patients were predicted as sensitive (100%), and all 12 non-responding patients were predicted as resistant (100%). The over all accuracy was 100% (Pearson Chi-square p<0.001). The progression free survival time in patients who were tested to be resistant was 4 months compared to 22 months in patients who were tested to be sensitive (p<0.001).
Conclusion: The presented study demonstrates that the in-vitro chemosensitvity profile is able to predict the clinical treatment outcome in patients with CLL precisely. Therefore, the in-vitro chemosensitivity testing evaluated by the Ci may serve as a powerful tool for assay directed and individualized therapy strategies in B-CLL.
Chronic Lymphocytic Leukemia Cells Have Increased Expression of Cyclic Nucleotide Phosphodiesterase 7B, Which May Serve as Disease-Specific Therapeutic Target.
Authors: Zhang Lingzhi , Murray Fiona , Kanter Joan R. , Chou Daisy , Rassenti Laura , Kipps Thomas J. , Insel Paul A. 
Published: October 2019

Abstract
Non-specific inhibition of cyclic nucleotide phosphodiesterase (PDE) in chronic lymphocytic leukemia (CLL) cells leads to intracellular accumulation of cyclic nucleotides, which in turn can sensitize the CLL cells to spontaneous and/or drug-induced apoptosis. Recent studies have identified at least 11 isoforms of PDE, each of which catalyzes the hydrolysis of cAMP and/or cGMP and regulates the intracellular levels of cyclic nucleotides. The finding that various tissues differentially express selected PDE isoforms has prompted development of isoform-specific inhibitors that can selectively increase intracellular levels of cyclic nucleotides in target cells that over-express the inhibited PDE isoform. Accordingly, we examined for differential expression of PDE isoforms by CLL B cells by assessing the levels of mRNA encoding each of the 11 different PDE isoforms in CLL cells and normal blood lymphocytes using quantitative real-time RT-PCR. CLL cell samples (n = 24) and lymphocytes of healthy adults (n = 16) each expressed detectable levels of PDE isoforms 1A, 1B, 2A, 3A, 3B, 4A, 4B, 4C, 4D, 5A, 7A, 7B, 8A, 8B, and 9A. However, we discovered that CLL cells of each patient had significantly higher levels of PDE7B mRNA (2.8-fold to 368-fold) and significantly lower levels of PDE3B mRNA (5-fold to 138 fold) than did lymphocytes from healthy donors (n = 16). As such, the ratios of PDE7B/PDE3B in CLL cell samples were >3 (ranging from 3 to 1019), whereas normal lymphocytes had ratios of < 0.3 (ranging from 0.006 to 0.23). The mean PDE7B/PDE3B ratio for CLL cells (123.6 ± 45.0, S.D., n=24) was significantly higher than that for B-lymphocytes of normal donors (3.8 ± 1.1, n=10) (P<0.0001). Immunoblot analyses demonstrated that CLL cells uniformly expressed high levels of PDE7B and low levels of PDE3B relative to those of normal lymphocytes. Moreover, we found that PDE7B contributed predominantly to the total PDE activity in CLL cells but not in normal lymphocytes. We thus studied effect of a selective PDE7 inhibitor (BRL-50481) on CLL cells and normal lymphocytes in vitro and found that BRL-50481 dose-dependently promoted apoptosis of CLL cells, but not normal lymphocytes. Collectively these findings indicate that CLL B cells selectively over-express PDE7B and under-express PDE3B relative to normal lymphocytes or isolated blood B cells and suggest that selective inhibitors of PDE7B may be effective in the treatment of this disease.
Remarkable Differences in Cellular Activation State and Migratory and Proliferative Potential among Clonal Cells Derived from Different Tissues of Chronic Lymphocytic Leukemia Patients.
Authors: Damle Rajendra N. , Banapour Taraneh , Temburni Sonal , Wasil Tarun , Kolitz Jonathan E. , Allen Steven L. , Sherry Barbara , Rai Kanti R. , Chiorazzi Nicholas 
Published: October 2019

Abstract
An antigen-independent process that takes place in the bone marrow (BM) leads to the birth of B cells from bone marrow precursors. Cross-talk between components of the microenvironment of BM or secondary lymphoid compartment(s), eg. spleen (SP), nurtures the subsequent evolution of B cells and governs in large part the natural history of normal B cells and B cell malignancies including chronic lymphocytic leukemia (B-CLL). Interaction of B cells with stromal elements confers upon them features enabling their transient sequestration, proliferation and extended survival. In this report we have compared the characteristics of clonal B-CLL cells obtained from paired specimens (peripheral blood, PB with corresponding BM or SP obtained within an interval of less than 1 month of each other) from 17 individual untreated B-CLL patients. These cells were tested by surface immunofluorescence and flow cytometry for their expression of a panel of chemokine receptors (CCR −1, −2, −4, and −7 and CXCR−1, −2, −3, and −4) and markers of cellular activation (CD23, CD62L, CD69, CD71 and HLA-DR). The relative age of the B cells (telomere length) and their ability to maintain telomere length (telomerase activity) were studied in paired BM/SP and PB samples from 15 of these cases. Although PB-, BM- and SP-derived B cells expressed activation markers, specifically, the percentages of cells expressing ZAP-70 and Ki-67 were significantly higher in BM- and SP-derived B cells than those expressed by corresponding PB-derived B cells (p<0.01). Increase in extent of CD38-positivity among members of the clone correlates with poor prognosis in B-CLL. Interestingly, in cases with low CD38 expression (<30% cells expressing CD38), the percentage of B-CLL cells expressing CXCR3 and CCR7 was significantly higher among PB-B cells, than BM/SP-derived B cells. No such differences existed in cases with high CD38 expression. This suggests a role for these receptors and their ligands in maintaining homeostasis of B-CLL cells in this subset of cases (that does not show remarkable progression of disease). In each of the 15 cases studied BM and SP-B cells had significantly higher telomerase activity (p<0.01) than those in PB, although telomere lengths of B cells from both sources were comparable. These findings highlight important differences in cellular kinetics among lymphoid compartments in B-CLL.
Fludarabine, Cyclophosphamide, Mitoxantrone Plus Rituximab (FCM-R) as Frontline Therapy for CLL: Results of a Phase 2 Study.
Authors: Faderl Stefan , Wierda William G. , O’Brien Susan , Ferrajoli Alessandra , Ravandi-Kashani Farhad , Detry Michelle , Kantarjian Hagop M. , O’Neal Brandi , Keating Michael J. 
Published: October 2019

Abstract
Combinations of monoclonal antibodies (moabs) with chemotherapy have produced higher rates of complete remission (CR) and better quality of responses (minimal residual disease [MRD]-negative) than have been achieved with chemotherapy or moabs alone. We have previously shown an overall response (OR) rate of 95% with a CR rate of 73% when combining fludarabine, cyclophosphamide, and rituximab (FCR) as first-line treatment for symptomatic patients with CLL (Keating et al. J Clin Oncol23:4079; 2005). Recent reports of FC plus mitoxantrone (FCM) have demonstrated response rates of 60% and up to 88% in pts with relapsed and untreated CLL, respectively. Here we report preliminary results of a pilot study exploring FCM plus rituximab and pegfilgrastim as frontline therapy for pts with untreated and symptomatic CLL and b2M < 4 mg/L. Treatment consisted of F 25 mg/m2 i.v. d2–4, C 250 mg/m2 i.v. d2–4, M 6 mg/m2 i.v. d2, and R 375 mg/m2 i.v. d1. Pegfilgrastim was 6 mg s.c. d4. For courses 2–6, FCM started day 1 together with R 500 mg/m2, and pegfilgrastim on d3. Courses were repeated q4–6 wks. The primary objectives included efficacy [clinical response by NCI-WG criteria and based on 2-color flow (CD5/CD19) response rate at 3 and 6 mos] and toxicity (especially myelosuppression). Thirty-one pts were enrolled of whom 29 pts are evaluable for response at 3 mos, and 21 pts at 6 mos (1 pt was taken off for insurance reasons after one course, and 1 did not receive any therapy). The median age was 57 yrs (range 38–69). Fourteen pts (48%) were male. Four pts (14%) had Rai stage ≥ 3. Median b2M was 2.6 mg/dL (1.4–4) and the median WBC 59.9 x 109/L (5.6–355). Two pts had 11q23 and 17p− abnormalities by cytogenetics/FISH. Unmutated IgVH occurred in 12/17 (71%) pts; ZAP-70 immunohistochemistry was positive in 11/19 (58%) pts. Twenty-eight pts (97%) responded at 3 mos (41% CR, 17% nPR, 39% PR); 10 pts (34%) had <1% CD5/CD19+ cells in the marrow. Response rates at 6 mos: 33% CR, 10% nPR, 57% PR for an OR rate of 100%. Nine pts had PR because of persistent cytopenias without marrow involvement or residual lymphadenopathy. Eleven pts (55%) had < 1% CD5/CD19+ cells in the marrow at 6 mos. Grade >/= 3 neutropenia occurred in 77% of the pts, thrombocytopenia in 7%, and anemia in 13%. Infectious episodes were seen in 13 pts (45%). Of 21 pts who completed therapy, 3 have received less than 6 courses because of ongoing cytopenias. In conclusion, FCM-R is an active induction regimen for symptomatic patients with CLL. However, clinical response rates and frequency of pts with flow cytometry response < 1% CD5/CD19+ cells does not appear to be different from the FCR experience. Neutropenia occurs in most patients and continued use of hematopoietic growth factors throughout therapy is recommended.
Subcutaneous Alemtuzumab in Patients with Refractory/Relapsed B-Cell CLL after a Fludarabine-Based Regimen. An Interim Analysis.
Authors: Bezares R. Fernando , Stemmelin German , Argentieri Daniel , Lanari Emilio , Guy-Garay Efrain , Campestri Reinaldo , Bartomioli Miguel , Garcia Juan Jose , Giralt Sergio , Milone Gustav ,   on Behalf of the Latin American Cooperative Onco-Hematology Group (LACOHG)
Published: October 2019

Abstract
Background: Alemtuzumab is the only single agent immunotherapy to demonstrate a survival benefit in patients with B-cell chronic lymphocytic leukemia (B-CLL), who have relapsed from or are refractory to Fludarabine therapy. The optimized schedule for alemtuzumab that achieves maximal efficacy with manageable toxicity is still being explored. Here, we report the second interim analysis of a new, less intensive schedule of alemtuzumab administered subcutaneously (SC) to patients with refractory/relapsed B-CLL.
Methods: Alemtuzumab was dose escalated from 10 to 20 mg during the first week, 30 mg twice week during the second and third weeks, and 30 mg once weekly during Weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 34, and 40. Antiviral prophylaxis included TMP/SMX bid 3 times a week and acyclovir 200 mg three-times daily.
Results: Of the 38 patients who were recruited to participate in the trial, 12 (31.6%)were refractory and 26 (68.4%) had relapsed from prior therapy. Patients had a median age of 66.5 years (range, 43–86 years), 30 were male (79%), 45%/53% had Binet stage B/C disease. The median number of prior therapies was 1 (range: 1–4). The median duration of therapy was 7 weeks (range, 2–24 weeks), with a median cumulative alemtuzumab dose of 457 mg (range, 120–1,080 mg). Among the 35 patients who were evaluable for response, the overall response rate was 88.6%: 45.8%complete response (CR), 2.9% unconfirmed CR, 42.8% partial response (PR). Four patients ( 11.5%) did not respond to therapy. Of the 9 patients with refractory disease, 1 achieved a CR, 6 a PR and 2 did not respond. Median follow up was 13 months and median overall survival was not achieved. Minimal residual disease (MRD) was measured by flow cytometry in 6 patients who achieved a CR: 4 patients had <0.5% of CD5/CD19+ cells, 1 patient had <5% of CLL cells, and 1 patient had <10% CLL cells. According to WHO toxicity criteria, over 38 evaluable patients, 4 (10,6%) experienced grade 3/4 infection; 2 patients had grade 2/3 granulocytopenia/thrombocytopenia; 1 patient had cytomegalovirus (CMV) reactivation without CMV disease; and 1 patient developed Epstein-Barr Virus with prolonged bone marrow hypoplasia.
Conclusion: Results of this second interim analysis suggest that a less intense regimen of alemtuzumab is feasible, effective, and safe for patients with refractory/relapse B-CLL after fludarabine therapy.