bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primary Extranodal Follicular Lymphoma: Clinicobiological Features and Outcome.
Authors: Mercadal Santiago , Martinez-Pozo Antonio , Bosch Francesc , Gine Eva , Muntanola Ana , Salamero Olga , Gutierrez Gonzalo , Montoto Silvia , Colomo Luis , Campo Elias , Montserrat Emili , Lopez-Guillermo Armando 
Published: October 2019

Abstract
Follicular lymphoma (FL) is typically a nodal disease. Primary extranodal FLs, that represent less than 10% of the cases, might have differentiated clinicobiological features. The aim of the present study was to analyze the main clinicobiological characteristics, response to therapy and outcome of a series of patients with FL primarily extranodal in origin, and compare them with nodal FLs. Twenty two patients (12M/10F; median age, 59 years) with FL with primary origin in extranodal location diagnosed in a single institution during a 24-year period, with primary origin in extranodal location were the subject of the study. The control group was constituted by 212 patients with nodal FL diagnosed during the same period of time. Main clinicobiological features were recorded and analyzed. The sites of the primary disease were: skin, 5 cases; Waldeyer’s ring, 4; GI tract, 3; bone marrow, CNS and parotid (two cases each); and pancreas, thyroid, kidney and orbit (one case each). Main histological and clinical features are listed in the table. Treatment was given without considering the nodal or extranodal origin of the disease and consisted of: monotherapy with alkylating agents (38 cases), polychemotherapy (149), and fludarabine alone or with other drugs (14) and others, including surgery and observation (33). CR rate was higher in extranodal than in nodal FL (82% vs. 53%, respectively; p=0.02), but no differences were found in overall survival. FLIPI score was the most significant variable predicting overall survival in the global series as well as in either in nodal or extranodal FL.
In conclusion, extranodal FL had some peculiar clinicobiological features with respect to nodal cases. Regarding the outcome, although patients with extranodal FL showed a higher CR rate, the overall survival was similar in both groups.
Extranodal FL (N=22) Nodal FL (N=212) p Age (median, range) 59 (28–82) years 55 (24–93) years NS Sex (M/F) 12/10 100/112 NS Histological grade 3 (%) 12 10 NS CD10+(%) 85 90 NS Bcl2+ (%) 67 91 NS Bcl2/JH (%) 37 65 0.03 Stage IV (%) 50 64 NS Bone marrow + (%) 36 62 0.02 LDH > 450 IU/L (%) 15 24 NS B2-microglobulin > 2.3 mg/L (%) 7 41 0.058 High-risk FLIPI (%) 19 35 NS CR rate (%) 82 53 0.02 5-year OS (%) 75 74 NS 5-year FFS (%) 67 27 <0.02
Front-Line Consolidation with Autologous Stem Cell Transplantation in Patients with Nodal Aggressive Peripheral T-Cell Lymphoma (PTCL). A Prospective Study of the GEL-TAMO.
Authors: Rodriguez Jose , Conde Eulogio , Gutierrez Antonio , Arranz Reyes , Leon Angel , Marin Julian , Bendandi Maurizio , Albo Carmen , Caballero Maria Dolores 
Published: October 2019

Abstract
Background: Nodal aggressive PTCL have a poor prognosis with conventional chemotherapy regimens for aggressive non-Hodgkin lymphomas. Therefore innovative approaches are needed. Among them, strategies including consolidation with high-dose chemotherapy and autologous stem cell transplantation in front line therapy may improve the outcome of these diseases.
Aim: To report the experience of a national cooperative group in 26 patients with aggressive nodal PTCL who underwent treatment including ASCT as consolidation of front line therapy.
Patients and Methods: Twenty-six patients Gallium scan positive with nodal PTCL entered into the study: 11 cases of PTCL-unspecified (42%), 8 ALCL (31%) and 7 AIL (27%). Patients received three courses of MegaCHOP and subsequently were evaluated by CT scan and Gallium scan. Those patients Gallium scan negative received another course of MegaCHOP and then the transplant. Those patients Gallium scan positive after 3 courses of MegaCHOP received 2 courses of the IFE regimen (Ifosfamide 3.3g/m2 days 1–3 and Etoposide 300 mg/m2 days 1–3) and if at least achieved a partial response received the transplant otherwise they are out of the study. Median age was 44 years, 96% of the patients presented Ann Arbor stage III or IV; 54% presented B symptoms; 31% bone marrow involvement and 72% of the patients presented 2–3 factors of the a-IPI.
Results: Thirteen patients (50%) achieved a CR after 3 courses of MegaCHOP and 12 patients received IFE as salvage therapy. Twenty patients out of the 26 initial patients were able to proceed to the transplant. After the transplant 85% of patients achieved a CR. The 6 patients who did not received the transplant was due to progression of the disease in 4 cases, lethal toxicity in one case and refusal in another case. With a median follow up of 35 months for alive patients, the overall survival (OS) and progression-free survival (PFS) at 3 years were 73% and 53%, respectively. OS, PFS and disease-free survival for the 20 patients who underwent the ASCT consolidation was 84%, 53% and 63%, respectively.
Conclusion: Early salvage therapy for patients not in CR after 3 courses of chemotherapy and ASCT consolidation for chemosensitive patients may improve the outcome of patients with nodal aggressive PTCL. Larger series and longer follow up are needed to confirm this promising approach.
Preclinical Efficacy of Campthothecin-Polymer Conjugate (IT-101) in Human Burkitt Lymphoma Bearing Mice.
Authors: Numbenjapon Tontanai , Wang Jianyi , Colcher David , Schluep Thomas , Forman Stephen J. , Raubitschek Andrew 
Published: October 2019

Abstract
First line combination chemotherapy can result in long-term disease-free survival (DFS) in 65–90% of patients with Burkitt lymphoma (BL) depending on prognostic factors at presentation. However, only a small number of patients with relapsed/refractory diseases can achieve long-term DFS after the high-dose therapy and hematopoietic stem cell rescue. Irinotecan (CPT-11) and topotecan, two analogues of campthothecin (CPT), have been successfully used alone or in combination with other cytotoxic agents as salvage treatments for patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL) other than BL. A disadvantage of CPT-11 and topotecan observed in early clinical trials was a high incidence of treatment-related toxicity (TRT). IT-101, a nanoparticulate conjugate of 20(S)-camptothecin and a cyclodextrin-based polymer, has recently been developed to minimize TRT and increase anti-tumor activity. To evaluate preclinical efficacy and toxicity of IT-101, we conducted an in vivo study in nude mice bearing subcutaneous xenografts from human BL-derived Daudi cell line stably transfected with plasmid DNA containing firefly luciferase (ffluc) reporter gene. The tumor-derived ffluc activity was evaluated in vivo using an IVIS 100 imaging system (Xenogen); background ffluc luminescence was defined as ≤106 p/sec/cm2/sr. Ten days after subcutaneous tumor injection, 42 nude mice with tumor-derived ffluc activity of >108 p/sec/cm2/sr were allocated into six different treatment groups as followings: Group 1 (no therapy); Group 2 (CPT-11 100mg/kg, ip, qwk × 3); Group 3 (IT-101 5mg/kg, iv, qwk × 3); Group 4 (IT-101 10mg/kg, iv, qwk × 3); Group 5 (IT-101 15mg/kg, iv, qwk × 2); and Group 6 (IT-101 single dose of 15mg/kg, iv). The average tumor-derived ffluc activity among all of the treatment groups was equally distributed. Tumor burden was monitored weekly by tumor-derived ffluc activity and physical tumor measurements. After completion of the treatment, there were two treatment-related deaths (TRDs; body weight loss >20%) and one non-TRD in group 5 and 6, respectively. At the 3rd week after starting therapy, all treatment groups that received two or three weekly doses of IT-101 (Groups 3, 4, and 5) had 100% complete tumor regression (CTR), determined by ffluc activity (<106 p/sec/cm2/sr) and remained tumor free at 90 days post-therapy. In contrast, 57% (4/7) of mice in Group 2 and 83% (5/6) of mice in Group 6 had initial CTR but all had tumor re-growth by day 69. These results demonstrate that a single dose of IT-101 at 15mg/kg is not sufficiently efficacious while two weekly doses of IT-101 at 15mg/kg are associated with unacceptable toxicity. However, we are able to demonstrate that the three weekly doses of IT-101 at 5 or 10mg/kg are well tolerated and can produce superior anti-tumor activity against Daudi cell line as compared with CPT-11.
Mechanistic Evaluation of Siplizumab (MEDI-507) Activity on Normal and Malignant T-Lymphocytes.
Authors: Hammond Scott A. , Fuhrmann Stacy , Roff Shannon , Kiener Peter A. , Coats Steve , Kinch Michael S. 
Published: October 2019

Abstract
Siplizumab is a humanized monoclonal antibody that selectively binds human CD2 (huCD2), which is expressed on virtually all cells of the T- or NK-cell lineage. Also, known as MEDI-507, siplizumab is being developed as a potential new treatment for lymphoid malignancies involving T- or NK-cells. Our present study was designed to increase further the mechanistic understanding of siplizumab activity. Preclinical studies demonstrated that siplizumab mediated efficient lysis of malignant T-cells in a concentration-dependent and effector-to-target cell ratio-dependent manner. ADCC contributed prominently to tumor cell clearance whereas complement-mediated killing (CDC) did not. Siplizumab treatment alone was sufficient to trigger limited internalization of its target antigen (CD2) from the surface of tumor cells. Moreover, the efficiency of CD2 internalization was increased when such studies were carried out in the presence of an activated monocyte cell line (THP-1) bearing Fcg receptors and incapable of mediating ADCC, and suggested that CD2 clearance from the cell surface can be distinguished from host effector mechanisms. CD2 has been long known to confer both inhibitory and stimulatory signals and we reasoned that target internalization might disrupt survival signals independent of host effector activity. Consistent with this concept, siplizumab treatment in the absence of effector cells transduced apoptotic signals as indicated by multiple standard markers of tumor cell apoptosis , including activation of caspase 3 activity and an increase in tumor cells with a sub-G1 DNA content. In addition, the use of transgenic mouse models demonstrated that intravenous administration of siplizumab caused a rapid (≤ 24 hours) but transient reduction in the number of peripheral huCD2-positive T-cells. The number of T-cells gradually recovered to normal levels within 30 days of treatment. In contrast, siplizumab treatment did not alter the number of CD19-positive B-cells. These results indicate that siplizumab can utilize host effector mechanisms (ADCC) to facilitate malignant T-cell elimination. Our present findings also suggest that siplizumab can mediate changes in CD2 expression or function that result in apoptosis of CD2-positive tumor cells. In light of this potent anti-tumor activity, two Phase I dose escalation trials (MI-CP099 and MI-CP107) are ongoing to assess the maximum tolerated dose and safety of siplizumab in patients with CD2-positive T- and NK-cell malignancies.
Prenylation Inhibitors as Potential Therapeutic Drugs in Hodgkin Lymphoma.
Authors: von Tresckow Bastian , Langendorf Peer , von Strandmann Elke Pogge , Sasse Stefanie , Tawadros Samir , Engert Andreas , Hansen Hinrich P. 
Published: October 2019

Abstract
Although the therapy of Hodgkin lymphoma has improved, patients still suffer from late toxicities and insufficient treatment of relapses. Hence, new treatment strategies are needed. Statins are used to treat hypercholesterolaemia and prevent cardiovascular disease. There is evidence for a preventive effect of statins in cancer, including lymphoma. So far, nothing is known about a therapeutic activity of statins or related drugs in Hodgkin lymphoma. Statins block the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to downstream isoprenoid products like farnesyl and geranylgeranyl-pyrophosphate, inhibiting protein prenylation and leading to apoptosis in several malignancies. The anti-tumour activity of the statin simvastatin and three specific prenylation inhibitors (FTI-277, GGTI-298 and tipifarnib) in Hodgkin lymphoma cells was evaluated in cytotoxicity and apoptosis assays. Furthermore, simvastatin was tested in a xenograft model for human Hodgkin lymphoma. First simvastatin induced caspase-related apoptosis in Hodgkin lymphoma cells via the isoprenoid pathway. The IC50 of simvastatin in cytotoxicity assays was < 2 μM. Second simvastatin showed high activity in a mouse model for Hodgkin lymphoma, delaying tumour establishment and inhibiting tumour growth. Finally the geranylgeranyltransferase inhibitor GGTI-298 and the farnesyltransferase inhibitors FTI-277 and tipifarnib displayed anti-tumour activity in Hodgkin lymphoma cells (approximate IC50 in cytotoxicity assays: 20, 7.5 and < 0.1 μM respectively). Importantly, the concentration of simvastatin that induced apoptosis in Hodgkin lymphoma cells was in the range of 2 μM. This corresponds to plasma levels reached in humans in clinical trials with high dose statins in cancer. Thus, our results suggest two possible applications of simvastatin in Hodgkin lymphoma: First simvastatin in high doses could be included in polychemotherapy regimens to improve the remission rate of relapsed patients. Second simvastatin in the cholesterol-lowering dose should be evaluated as a preventive drug for patients in remission to avoid relapses. Moreover, in comparison to other haematological malignancies, the farnesyltransferase-inhibitor tipifarnib was highly cytotoxic in Hodgkin lymphoma cells. Given its activity in clinical trials in haematological neoplasia, its clinical evaluation in Hodgkin lymphoma is warranted. Taken together, prenylation inhibitors are promising drugs for the treatment of Hodgkin lymphoma.
Evidence for an Underestimation of the Prognostic Impact of Poor Cytogenetics within the IPSS.
Authors: Haase Detlef , Germing Ulrich , Schanz Julie , Pfeilstoecker Michael , Hildebrandt Barbara , Luebbert Michael , Giagounidis Aristoteles , Aul Carlo , Truemper Lorenz , Mueller Thomas , Valent Peter , Gattermann Norbert , Fonatsch Christa , Krieger Otto , Stauder Reinhard , Steidl Christian 
Published: October 2019

Abstract
In the IPSS the variables bone marrow blasts, cytogenetics and cytopenias were found to be most relevant for clinical outcome by multivariate analysis. Comparing cytogenetics and blasts scoring points were assigned as follows: 0 (good cytogenetics and less than 5% blasts), 0.5 points (intermediate cytogenetics, and 5–10% blasts), 1.0 points (poor cytogenetics), 1.5 points (11–20% blasts), 2.0 (21–30% blasts). In order to examine the correctness of weighting of cytogenetics in comparison to blast counts we compared the survival curves, median survival times (mst) and differences of mst (mst diff.) related to the mst of 37.5 months (mo) of our entire study population (on the basis of 2124 pts. with MDS from our German-Austrian database) between patient subgroups. The results in the subgroups were as follows: Blasts below 5% (n=609) (mst: 58 mo, mst diff.: +20.5 mo), good cytogenetics (n=768) (mst: 55.3 mo, mst diff.: +17.8 mo), blasts 5–10% (n=231) (mst: 28.0 mo, mst. diff.: −9.5 mo), intermediate cytogenetics (n=222) (mst: 28.0 mo, mst diff.: −9.5 mo), blasts: 11–20% (n=160) (mst: 16.5 mo, mst diff.: −21 mo), poor cytogenetics (n=212) (mst: 11.1 mo, mst diff.: −26.3 mo), blasts 21–30% (n=92) (mst: 11.7, mst diff.: −25.7 mo). Our results clearly show that within the IPSS poor cytogenetics are significantly underweighed. Referring to the survival data unfavorable cytogenetics resulted in a survival disadvantage at the same scale as compared to 21–30% blasts. Thus, in a revised IPSS this cytogenetic feature should get the same scoring points as compared to 21–30% blasts when using the FAB-classification. For a scoring system based on the WHO-classification unfavorable cytogenetics should get an even higher scoring value as compared to the maximum blast count of 19%. Further statistical analyses are on the way to substantiate our conclusions.
Targeting BH3-Domain Anti-Apoptotic Proteins with GX15-070 Decreases DNA Synthesis, Induces Cell Death and Sensitizes Rituximab-Sensitive and Resistant Non-Hodgkin’s Lymphoma Cell Lines to the Anti-Tumor Activity of Chemotherapy Agents.
Authors: Hernandez-Ilizaliturri Francisco J. , Iqbal Arshad , Alam Naheed , Bhat Seema , Olejniczak Scott , Knight Joy , Czuczman Myron S. 
Published: October 2019

Abstract
GX15-070 is a potent pan-bcl-2 inhibitor with known activity against chronic lymphocytic leukemia (CLL) cells and mantle cell lymphoma (MCL) cell lines, currently undergoing phase I testing. Bcl-2 over-expression is associated with chemotherapy resistance and correlates with a poor clinical outcome in diffuse large B-cell lymphoma. Recently, we demonstrated that acquisition of rituximab resistance is associated with deregulation of BH3-domain pro- and anti-apoptotic proteins. This leads to concomitant resistance to multiple chemotherapy agents. Targeting BH3-domain anti-apoptotic proteins with GX15-070 is an attractive strategy to potentially overcome acquired biologic and/or chemotherapy resistance. To this end we studied the effects of GX15-070 in a panel of rituximab-sensitive (RSCL) and rituximab-resistant cell lines (RRCL). Resistant clones were generated by chronic exposure of Raji, RL or DHL-4 cells to escalating doses of rituximab with (4RH) or without (2R) human complement. Functional assays (e.g. ADCC and CMC assays) demonstrated a significant decrease in rituximab sensitivity in RRCL. In addition, resistance to chemotherapy agents (CDDP, doxorubicin, vincristine, etc.) was demonstrated in RRCL. Lymphoma cells were exposed in vitro to GX15-070 (0 to 20mM) with or without CDDP (0 to 10mM) or Doxorubicin (0 to 1mM). Following a 24 and a 48 hour period of drug exposure: induction of apoptosis and the percentage of viability was determined by flow cytometric analysis, Western blotting and trypan-blue staining techniques. In addition, changes in DNA synthesis and cell proliferation following drug exposure were performed using standard [3H]-thymidine incorporation assays. GX15-070 induced a dose-dependent cell death and decrease in DNA synthesis in all the cell lines tested (both RSCL and RRCL). Up to 75% of cell death was observed in all cell lines exposed to 20mM of GX15-070. Anti-tumor activity was seen even at the lowest tested dose of GX15-070 (2mM, 20–25% death cells). Incubation of RSCL and RRCL with 2 or 5mM of GX15-070 induced synergistic cytotoxic and anti-proliferative effects when combined with CDDP and doxorubicin. The IC50 of CDPP and doxorubicin was decrease ten-fold by the concomitant in vitro exposure to GX15-070 in all cell lines tested, including RRCL. Our data demonstrates that GX15-070 is active against both RSCL and RRCL and augments the anti-tumor activity of chemotherapy agents. These results strongly suggest that GX15-070 added to systemic chemotherapy is a potentially valuable and novel therapeutic strategy in the treatment of B-cell NHL.
Monocyte Colony-Stimulating Factor Enhances Rituximab-Dependent Cellular Cytotoxicity by Monocytes.
Authors: Takami Akiyoshi , Shimadoi Shigeru , Kondo Yukio , Okumura Hirokazu , Nakao Shinji 
Published: October 2019

Abstract
[Introduction]
Recent data suggest that monocytes are the dominant effector cells during immunotherapy using the anti-CD20 monoclonal antibody rituximab, depleting B cells through FcγR-dependent pathways. Because monocyte colony-stimulating factor (M-CSF) enhances the antibody-dependent cellular cytotoxicity (ADCC) of monocytes, the clinical efficacy of rituximab might be improved by the addition of M-CSF. We have studied the effect of M-CSF in the enhancement of rituximab-mediated ADCC against B-cell lymphoma.
[Methods]
Monocytes were isolated by negative selection of PBMCs from healthy individuals for the absence of T-cell, B-cell, and NK-cell markers. Cytotoxicity was determined by a flow cytometry using two fluorescent dyes, calcein-AM and ethidium homodimer to specifically stain living and dead cells respectively. Monocytes were cultured for 48 hours in the presence or absence of human recombinant M-CSF (66 ng/ml). The B-cell lymphoma cell line Daudi was used as target in the presence of rituximab (5 μg/ml) or human IgG1 as control for 30 min at room temperature. Effector cells and target cells were incubated at different ratios ranging from 1:1 to 15:1 for 4 hours at 37°C. The expression of FcγRl, FcγRII, and FcγRIII on monocytes was determined using a flow cytometry.
[Results]
Monocytes treated with M-CSF showed a significant increase in rituximab-mediated cytotoxicity against B lymphoma cells: specific lysis at an E:T ratio of 15:1 was 39% ± 7% (mean ± SD) vs. 21% ± 5%, M-CSF-treated monocytes vs. non-treated monocytes. Lysis of lymphoma cells treated with rituximab alone was 8% ± 4%. Treatment with M-CSF led to a 1.5- to 2.0-fold increase of FcγRI and FcγRIII expression in monocytes, while FcγRII expression remained unchanged.
[Conclusion]
Pretreatment of monocytes with M-CSF enhances their rituximab-mediated ADCC against B-cell lymphoma, which may partly result from increasing expression of FcγRI and FcγRIII on monocytes via M-CSF stimulation. These in vitro results may provide a new approach to improve the therapeutic activity of rituximab.