bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined Chemotherapy and Radiation Is Associated with Improved Outcomes in Stage I Follicular Lymphoma.
Authors: Ganti Apar Kishor , Bociek R. Gregory , Bierman Philip J. , Lynch James C. , Bast Martin A. , Vose Julie M. , Armitage James O. 
Published: April 2020

Abstract
Follicular lymphoma (FL) is the second-most common subtype of non-Hodgkin’s lymphoma. However, data addressing the management of early-stage FL is sparse. Hence we conducted this study in order to try to assess the influence of initial treatment on outcome in patients with stage I follicular lymphoma. One hundred patients, 46 males and 54 females diagnosed with stage I FL and treated on various Nebraska Lymphoma Study Group protocols have been included in this retrospective study.
Thirty-eight percent of patients had grade 1, 22% had grade 2 and 40% had grade 3 FL. Sixty percent of patients were older than 60 years of age, 3% had a poor performance status (Karnofsky score &lt;80), 7% had an elevated LDH level, 19% had bulky disease (tumor size ≥5 cm) and 5% had B-symptoms at presentation. Twenty-five percent of patients were treated with radiation alone, 37% with chemotherapy alone and 37% received both chemotherapy and involved-field radiation. Patients who received chemotherapy alone were more likely to have extranodal disease (p&lt;0.01), but all other patient characteristics were similar across the three treatment groups. At a median follow-up of 8.4 years (range, 2.3 – 18.3 years), 45 patients are alive and disease-free, 39 patients have died while 16 patients are alive after progression. Of the 39 deaths that occurred, 13 were due to lymphoma progression, 4 were related to therapy, 11 patients died of unrelated causes (mainly coronary artery disease and its complications), while the cause of death was unknown in 11 patients. The median event-free survival (EFS) for this group of patients is 8.09 years and the median overall survival (OS) is 11.7 years. By multivariate analyses, only treatment with combination chemotherapy and radiation (HR: 0.3, 95% CI: 0.1 – 0.5, p&lt;0.001) as opposed to either modality alone, and surprisingly, presence of B-symptoms at presentation (HR: 0.2, 95% CI: 0.04 – 0.8, p=0.02) predicted for a better EFS. Older age (≥60 years) predicted for an adverse OS (HR: 2.9, 95% CI: 1.3 – 6.3, p&lt;0.01), while combination chemotherapy and radiation predicted for a better OS (HR: 0.4, 95% CI: 0.1– 0.9, p=0.02). However, there was no difference in the relapse rates between the older and younger patients (p=0.42), thereby suggesting that that poor OS in older patients was due to factors other than the disease itself. Patients who received both chemotherapy and radiation had a median EFS of 13.2 years and median OS was not yet reached in these patients. In contrast patients who received chemotherapy or radiation alone had an EFS of 5.54 years and 3.32 years respectively and an OS of 9.95 years and 10.7 years respectively. Thus, after accounting for known confounding factors, combined modality treatment with chemotherapy and radiation was associated with better EFS and OS than either modality alone in patients with Stage I follicular lymphoma.
Single Dose Per Cycle Pegfilgrastim Successfully Supports Full Dose CHOP-21 in Patients with Post-Transplant Lymphoproliferative Disorders (PTLD).
Authors: Papp-Vary Matthias , Oertel Stephan H.K. , Maschmeyer Georg , Riess Hanno 
Published: April 2020

Abstract
Background: PTLD is a life-threatening complication after transplantation of organs. There exists no common strategy for the treatment of patients with PTLD. Some patients benefit from reduction of immunsuppression or virostatic therapy, but most patients are treated by adriamycin based chemotherapy. Administration of chemotherapy is complicated by immunosuppressive therapy which induces bone marrow and renal insufficiency. Cytotoxic chemotherapy is frequently accompanied by febrile neutropenia and even lethal courses. Previous studies with CHOP 21 has demonstrated the need for growth factor (Filgrastim) to conduct chemotherapy in these patients. The aim of this study was to assess the ability of Pegfilgrastim, a pegylated form of Filgrastim, to support the 21 day CHOP chemotherapy. Pegfilgrastim has a sustained-duration effect relative to filgrastim, as a result of decreased renal clearance of the pegfilgrastim molecule.
Methods: Chemotherapy consisted of cyclophosphamide 750mg/m2, doxorubicin 50mg/m2 and vincristine 1,4mg/m2 at day 1 and prednisone 100mg day 1–5 and was administered at 21 days intervals for 4 cycles. Pegfilgrastim was administered by a single dose (6 mg s.c.) on day 3 of each cycle of chemotherapy
Results: In total 5 patients (4 after kidney- and 1 after liver-transplantation) were included in this study. The mean age of patients is 54 years (19–75) with two females and three males. A total of 15 cycles of CHOP has been administered. 14 of 15 cycles of CHOP could regularly be administered at day 21. In three patients five episodes of grade 4 neutropenia occurred, but none of the patients experienced infectious complications. Three patients experienced grade 3 neutropenia and two patients three episodes of grade 2 neutropenia. The lowest granulocyte count was 0.327 x 109/l. The rate of serious adverse events was low and no episode of febrile neutropenia occurred.
Conclusion: These results support the use of once-per-cycle pegfilgrastim (6 mg s.c.) for safe and effective on time delivery of a regimen with CHOP-21 in patients with Post-transplant Lymphoproliferative Disorders (PTLD).
A Stratified Risk-Adapted Approach to Lymphoma Salvage in an Outpatient Setting.
Authors: Spencer Andrew , Catalano John , Grigg Andrew , Leahy Michael , Underhill Craig , Ganju Vinod , Arthur Christopher 
Published: April 2020

Abstract
Aims: Interim analysis of the safety and efficacy of a risk-adjusted approach to lymphoma salvage therapy. Methods: Patients were stratified - Group 1 (G1) (good risk - first relapse following durable CR1); Group 2 (G2) (poor risk - primary refractory, &gt;1 relapse, or non-durable CR1); or Group 3 (G3) (relapse post-ASCT). Two regimens were evaluated: VGF (vinorelbine 25mg/sqm days 1 and 8, gemcitabine 1000mg/sqm days 1 and 8, pegfilgrastim 6mg SC day 9) (G1/3) and F-GIV (VGF plus ifosfamide 3000mg/sqm day 1) (G2). Following 2 cycles all patients were re-staged. Responsive patients (&gt;50% reduction in disease and functional imaging negative) received 2 further cycles of the same therapy, the remainder ‘escalated’ therapy to F-GIV (G1/3) or IVAC (G2) (inpatient ifosfamide, VP-16 and Ara-C). Results: 45 of a planned 90 patients, median age 56 years, are evaluable (G1 = 16, G2 = 23, G3 = 6). Diagnoses were Hodgkin’s lymphoma n = 9 and NHL, n = 36 (DLC = 24, follicular = 6, others = 6). To date G1 and G2 have received 127 cycles of VGF or F-GIV, with grades 3/4 neutropenia or thrombocytopenia in 31% and 17% (VGF) and 74% and 78% (F-GIV) of patients, respectively. Febrile neutropenia, admission, treatment delay or dose-reductions occurred with 13%, 28%, 12%, 6% of cycles, respectively. Based on ITT the ORR is 59% (CR 33%). Conclusion: VGF and F-GIV can be safely administered on an outpatient basis and show significant activity against advanced lymphoma.
Rituximab (Rituxan) Combined with ESHAP Chemotherapy Is Highly Active in Relapsed/ Refractory Aggressive Non-Hodgkin’s Lymphoma.
Authors: Venugopal Parameswaran , Gretory Stephanie A. , Showel John , Shammo Jamile , Enschede Sari , Larson Melissa , Obrien Teresa , Sokolovsky Tatiana D. , Means Aaron 
Published: April 2020

Abstract
Patients with relapsed/refractory aggressive lymphoma have limited options for achieving long-term remission other than stem cell transplantation. ESHAP is active in aggressive NHL and has the added advantage of being a non-anthracycline regimen. However, the response rate and remission duration with ESHAP chemotherapy alone are low in this group of patients. Encouraged by the increased efficacy of chemo-immunotherapy combinations like CHOP + Rituximab (Rituxan) in untreated aggressive lymphoma, and the in vitro synergy of Rituximab with cisplatin, cyclophosphamide and steroids, we studied the safety and efficacy of ESHAP + Rituximab combination in this group of patients. Standard ESHAP regimen (Etoposide 40 mg/m2/d IV/2h day1–4; Methylprednisolone 500 mg/m2 IV days 1–4; Cytarabine 2 g/m2 IV/3h day 5 and Cisplatin 25 mg/m2/d CIV days 1–4) was administered. Rituximab 375 mg/m2 IV was administered in the following manner: 2 doses separated by one week prior to the first cycle of ESHAP and 2 doses administered similarly after completion of the sixth cycle of ESHAP; one dose of Rituximab each was also given 48 hours prior to the third and fifth cycle of ESHAP. Treatment cycles were repeated every 28 days x 6. GMCSF (Leukine) and Erythropoietin (Procrit) were used at the discretion of the investigator. 14 patients were enrolled in the study. Median age was 55.5 years (range 37–70); there were 12 males and 2 females. 11/14 (71%) of patients had advanced disease (stage III/IV). Extranodal disease sites included kidney, lungs and adrenals. Histology was Diffuse Large Cell: 13 (93%) and Mantle Cell Lymphoma: 1 (7%). All patients had prior therapy: 1st relapse 11, 2nd relapse 1 and 3rd relapse 2. Prior therapies included CHOP, modified CHOP, Fludarabine-based regimen, Rituxan and Bexxar. 7 patients (50%) achieved CR, 2 PR, 1 stable disease and 4 PD. Among the 6 patients who received all 6 cycles of therapy, 4/6 (67%) achieved CR and 2/6 (33%) PR, (ORR 100%). Duration of response in patients who received all 6 cycles: All Responders: 26.3 months (1–53.3) and Patients who achieved CR: 35 months (24.1–53.3). Significant toxicity included grade III/IV hematologic in 43% and grade III/IV infection/febrile neutropenia in 21%.
Conclusion: ESHAP combined with Rituximab appears to be more active than ESHAP alone with no additional toxicity other than infusion-related adverse events in patients with relapsed/refractory aggressive lymphoma. Patients who achieved CR with this regimen appear to have longer remissions. Prospective, controlled trials are warranted.
Combined Effects of As4S4 and Imatinib on Chronic Myeloid Leukemia Cells and BCR-ABL Oncoprotein.
Authors: Yin Tong , Wu Ying-Li , Sun Hui-Ping , Sun Guan-Lin , Zhang Ji , Chen Guo-Qiang , Chen Sai-Juan , Chen Zhu 
Published: April 2020

Abstract
Imatinib is a tailored drug for chronic myeloid leukemia (CML), which has very good effects on patients at chronic phase (CP), but not on those at accelerated phase or blast phase. In addition, even among patients at CP, Imatinib seems unable to eradicate the malignant progenitors and a significant portion of patients develops drug resistance after long time use. Arsenic compounds were known as ancient remedies for CML with certain efficacy. The aim of this study was to investigate the potential benefit of combination therapy with Imatinib and arsenic sulfide (As4S4) on BCR-ABL+ K562 cells and fresh CD34+ hematopoietic progenitor cells isolated from CML patients and non-leukemic donors. Analysis of cell proliferation and clonogenic ability showed that As4S4 and Imatinib exerted synergistic effects on both K562 cells and fresh CML cells. The effective concentrations on fresh CML cells were pharmacokinetically available in vivo but had much less inhibitory effect on CD34+ cells from the non-leukemia donors. The synergistic effect of Imatinib/As4S4 combination in terms of anti-proliferation might be connected with their distinct but complementary roles in interfering with the cell cycle progression. Our data showed that Imatinib induced G1 arrest of K562 cells, while As4S4 induced G2/M arrest. In addition, Imatinib induces significant down-regulation of phosphorylated Rb and CDK1, which is in agreement with the G1/S but not G2/M arrest under this drug. However, As4S4 shows no obvious effect on these proteins in spite of a visible effect on G2/M block. Using a number of parameters such as morphology, Annexin V/PI, mitochondrial transmembrane potential, caspase3 activity and Fas/Fas-L, the synergistic effects were revealed on induction of cell apoptosis, largely through mitochondrial pathway. What’s more, the two drugs also exhibited synergistic effect in targeting BCR-ABL protein. While As4S4 triggered its degradation and Imatinib inhibited its tyrosine kinase activity, combined use of the two led to lower protein/enzymatic activity levels of BCR-ABL. In conclusion, our study suggests As4S4 and Imatinib have synergistic effects in inhibiting proliferation, inducing apoptosis of cells and reduction the tyrosine kinase activity of BCR-ABL. Our in vitro data thus strongly suggest a potential clinical application of Imatinib/As4S4 combination on CML.
PEG-Interferon for Chronic Phase CML - Still an Option in the Era of Imatinib?.
Authors: Scheid Christof , Draube Andreas , Holtick Udo , Cornely Oliver , Hacker Ulrich , Fuchs Michael , Berger Ute , Hochhaus Andreas , Hehlmann Rüdiger , Hallek Michael 
Published: April 2020

Abstract
Objectives
PEG-Interferon alpha 2b (PEG-IFN) is a new formulation of Interferon with a prolonged half-life and can therefore be given once weekly. It has shown efficacy in patients refractory or intolerant to IFN. Within a German multicenter study (SHG CMLIIIA) PEG-IFN (PEG-Intron, Essex) was used in our centre for patients with CML in first chronic phase.
Methods:
17 patients with newly diagnosed bcr-abl positive CML in chronic phase were included in our centre as part of the CML IIIA study. Median age was 42 yrs (range 24 – 78 yrs). After initial cytoreduction with hydroxyurea patients received 3–6 μg/kg PEG-IFN subcutaneously once a week. One patient received additional cytarabine at a dose of 20 mg/m2 10 days per month.
Results:
After 3 months 13/17 patients had a complete hematological response, 3 had a partial hematological response, 1 patient had a hereditary thrombocytopenia and therefor did not fulfill hematological CR criteria. Cytogenetics/FISH after 6 months were available in 12 patients and showed 1 complete cytogenetic response, 3 partial cytogenetic responses, 5 minor cytogenetic reponses and no response in 3 patients. 9 patients remained on PEG-IFN for at least 12 months and showed 2 complete, 1 partial and 2 minor cytogenetic responses and no response in 4 patients. Thus the rate of major cytogenetic responses was 33% at 6 months and at 12 months. PEG-IFN treatment was stopped in 14 patients due IFN-intolerance (n=6), patient decision (n=1), blast crisis (n=2), accelerated phase (n=1) or cytogenetic non-response (n=4). Relevant toxicities included acute pancreatitis in 1 patient, a grand mal seizure in a patient with a history of subdural hematoma, exacerbation of supraventricular tachycardia in 1 patient, transient elevation of GPT in 1 patient and a local abscess at the injection site in 1 patient. All patients experienced fever and flu-like symptoms in the first 4 weeks which gradually improved.
Conclusion:
PEG-IFN at a dose of 3–6 μg/kg was effective in producing complete hematological remissions after 3 months in the majority of patients and showed major cytogenetic responses in one third of patients. However there was a considerable toxicity. Still 53% of patients were able to continue treatment for at least 12 months and 4 of these (44%) are in continuous partial or complete cytogenetic response. This response rate is comparable to the results for conventional IFN in combination with Ara-C from the recent IRIS study. However in the IRIS study only 10.8% remained on IFN compared to 53% in our cohort. For patients able to tolerate this treatment PEG-IFN appears to be a valid alternative to IFN+Ara-C or imatinib in chronic phase CML.
Effects of Imatinib Mesylate and Interferon-alpha Combined with Granulocyte Colony-Stimulating Factor on Chronic Myelogenous Leukemia Cells In Vitro.
Authors: Ota Shuichi , Musashi Manabu , Kondo Keiichi , Toyoshima Nobuyasu , Toubai Tomomi , Iwao Noriaki , Tanaka Junji , Asaka Masahiro , Imamura Masahiro 
Published: April 2020

Abstract
Aim. In the treatment of patients with chronic myelogenous leukemia (CML), neutropenia is a dose-limiting factor on the combination therapy of imatinib mesylate (STI571) and interferon-alpha. If STI571 combined with interferon-alpha effects on decreasing BCR-ABL-positive cells and granulocyte colony-stimulating factor (G-CSF) has an effect on increasing normal neutrophils, the combination therapy may improve current remission rates in CML. We evaluated in vitro combined effect of STI571, interferon-alpha and G-CSF on primary bone marrow cells from patients with CML in chronic phase (CP).
Material and Methods. The primary bone marrow mononuclear cells (BMMNC) from patients with CML-CP were incubated in the medium containing STI571 (1 μM) and/or interferon-alpha (100 U/ml) with or without G-CSF (100 ng/ml). The viability of the cells was evaluated by trypan blue dye exclusion. Apoptosis was detected by the flow cytometry analysis with Annexin V (AV) and propidium iodide (PI) double staining. The colony formation assays of BMMNC were performed by methylcelulose. And then, BCR-ABL and normal cell colony rates were evaluated on14 days.
Results. Treatment of BMMNC with STI571 revealed a decrease of cell number in dose-dependent and time-dependent manner. Incubation with STI571 and interferon-alpha for 24 and 48 hours decreased viable cell number by 58% and 39%, respectively. G-CSF did not stimulate the BCR-ABL-expressing cells proliferation in the combination therapy. Cytometry analysis with AV and PI showed about 70–75% of AV-positive cells in the combination therapy and monotherapy. There were no significant differences in apoptosis between STI571 plus G-CSF and interferon-alpha plus G-CSF. Colony formation of BMMNC from patients with CML-CP in combination of STI571 and interferon-alpha was more strongly suppressed than STI571alone, and G-CSF did not abrogate the suppressive effect of the combination therapy. From these observations, it is concluded that combination therapy of STI571 and interferon-alpha with G-CSF can induce apoptosis effectively in BCR-ABL-expressing cells.
Conclusion. Obtained data provide an evidence for the effective and safe combination therapy of STI571 and interferon-alpha with G-CSF against CML-CP patients. Although further studies are needed to clarify whether combination therapy really increase normal cells or not, the combined therapy with G-CSF appears not to stimulate leukemic cell proliferation.
Prediction of Response to Imatinib by Prospective Quantitation of BCR-ABL Transcript in Late Chronic Phase Chronic Myeloid Leukemia PatientsBy GIMEMA Working Party on CML.
Authors: Martinelli Giovanni , Rosti Gianantonio , Pane Fabrizio , Amabile Marilina , Bassi Simona , Izzo Barbara , Poerio Angela , Giannini Barbara , Cilloni Daniela , Soverini Simona , Terragna Carolina , Ottaviani Emanuela , Grafone Tiziana , De Vivo Antonio , Testoni Nicoletta , Trabacchi Elena , Alberti Daniele , Salvatore Francesco , Saglio Giuseppe , Baccarani Michele 
Published: April 2020

Abstract
Imatinib mesylate (STI571), a specific Bcr-Abl inhibitor, has shown a potent antileukemic activity in clinical studies of chronic myeloid leukemia (CML) patients. Early prediction of response to imatinib cannot be anticipated. We used a standardized quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR) for bcr-abl transcripts on 191 out of 200 late-chronic phase CML patients enrolled in a phase II clinical trial with imatinib 400 mg/day. Bone marrow samples were collected before treatment, after 3, 6 and 12 months or at the end of study treatment (12 months) while peripheral blood samples were obtained after 2, 3, 6, 10, 14, 20 and 52 weeks of therapy. The amount of Bcr-Abl transcript was expressed as the ratio of Bcr-Abl to β2-microglobulin (β2M). We show that, following initiation of imatinib, the early Bcr-Abl level trends in both bone marrow and peripheral blood samples made it possible to predict the subsequent cytogenetic outcome after 6 and 12 months of treatment, and that these early trends were also predictive of progression-free survival.
Generating Human Immune Responses to Mutations in Bcr-Abl Kinase Selected by Imatinib.
Authors: Pinilla Javier , May Rena , Gomez Marta , Korontsvit Tanya , Barry Kappel , Zakhaleva Victoriya , Dao Tao , Scheinberg David A. 
Published: April 2020

Abstract
Imatinib mesylate is now standard treatment for chronic myelogenous leukemia. In spite of its high efficacy in controlling the disease, residual bcr-abl cells measured by RT-PCR are still detectable in more than 95% of the patients treated with this drug. In addition, recent reports describe the emergence of resistance to Imatinib mesylate. A major mechanism for the appearance of resistance, are point mutations changing amino acids in the bcr-abl tyrosine kinase that make imatinib ineffective. We hypothesized that some bcr-abl kinase mutations selected by imatinib would generate new immunogenic peptide-epitopes that could be recognized by the human immune system. For this purpose, we selected with predictive computer algorithms potentially immunogenic mutated amino acid sequences and synthetic analogues of mutated bcr-abl kinase sequences to study for immunogenicity and anti-leukemia activity in an in vitro human system. Initially we designed a number of synthetic peptides derived from the most frequent bcr-abl kinase mutations induced by imatinib in which single amino acid substitution was introduced at different MHC-binding positions. We investigated the most common mutations: E255V, E255K, Y253H, Y253F, F311L, T315I, M351T and H396P. Specific single and combined mutations improved the predicted binding of peptides to HLA A0201. Further additional single amino-acid substitutions on mutated peptides generated high predicted binding. Selected sequences were evaluated for eliciting MHC-restricted, peptide-specific CTL responses in an in vitro model using T-cells from different HLA A0201 healthy donors after stimulation with monocyte-derived DC. CTL lines were assessed by either IFN gamma ELISPOT or by a chromium51 release assay. Mutated derived peptides from E255K, E255V, Y253F and T315I were shown to be immunogenic in vitro by the specific release of IFN gamma. Furthermore, single amino-acid substitutions in key residues improved the immunogenicity of these peptides. Finally, T cell lines generated with optimized peptides derived from E255K and T315I (the most common imatinib-induced mutations) were able to kill peptide pulsed targets; more important, these T cell lines cross-reacted with the mutated peptides (a heteroclitic response). In conclusion, Imatinib-selected mutations of peptides from bcr-abl kinase have a better predicted binding than native kinase sequences. Selected peptides from the most common mutations are immunogenic in vitro in a HLA A0201 restricted manner. T cells generated with optimized peptides from these mutations are able to elicit heteroclitic peptide-specific cytotoxicity.