bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II Study of Alemtuzumab Treatment in Patients with Pretreated T-Cell Lymphoma.
Authors: Zinzani Pier Luigi , Tani Monica , Stefoni Vittorio , Alinari Lapo , Marchi Enrica , Gabriele Annalisa , Musuraca Gerardo , Fina Maria Paola , Pileri Stefano , Baccarani Michele 
Published: October 2019

Abstract
To evaluate the efficacy and toxcity of Alemtuzumab, an anti-CD52 monoclonal antibody in patients with relapsed or refractory cutaneous T-cell lymphomas and peripheral T-cell lymphomas. Between 2003 and March 2004, 10 previously treated patients with mycosis fungoides (MF; n=4) and peripheral T-cell lymphoma unspecified (PTCLU) with nodal involvement (n=6) were enrolled onto a phase II trial and treated with Alemtuzumab in our Institute. This monoclonal antibody was given at a dose of 10 mg 3 times a week for 4 consecutive weeks. Of the 10 patients, 2 (20%) achieved complete response (CR), 4 (40%) partial response (PR), and the remaining 4 showed no benefits from the treatment. In the MF subset were observed only PR (3/4, 75%), while in the PTCLU patients there were 2 (33%) CR and 1 (17%) PR, respectively. The durations of CRs were 3 and 8 months. Treatment was well tolerated; hematolgic toxicity was mild. In terms of infectious adverse events, cytomegalovirus reactivation occurred in 1 (10%) patient and none patient had additional suspect or manifest infection. The results of the present phase II study show activity of Alemtuzumab as a single agent in patients with pretreated CTCL and PTCL using a low dose schedule; at the same time, this efficacious reduced dose permitts to avoid treatment-related mortality and to curtail the CMV reactivation rate.
A New Multi-Parameter Flow Cytometric Assay for Monitoring Lymphoma Growth and Spread in a Pre-Clinical Murine Model for Human Lymphoma.
Authors: Neeson Paul J. , Paterson Yvonne 
Published: October 2019

Abstract
Murine lymphoma models are commonly used to test the efficacy of idiotype-based vaccines for B-cell lymphoma prior to human trials. Mouse survival has been used as an indirect measure of the tumor response to the vaccine. In this study, we describe a multiparameter flow cytometric (MPFC) assay that enables direct assessment of the tumor at the inoculation site and detection of lymphoma metastases. In initial experiments, we show that 38C13 mouse lymphoma cells expressed an aberrant phenotype compared to normal splenocytes. The combination of CD45, CD19, B220 and an anti-idiotypic antibody (S1C5) along with a sequential gating technique defined the 38C13 cells with high sensitivity and specificity. The specificity of the MPFC assay for 38C13 lymphoma cells was greater than a gating strategy using light scatter and idiotype antibody binding. The MPFC assay was used to monitor 38C13 tumor kinetics in the C3H/HeN mouse and demonstrated tumor growth at the inoculation site and metastases to the lymph nodes and bone marrow. The presence of 38C13 metastases in lymphoid organs and bone marrow predicted by the MPFC assay were confirmed by histology and immunohistochemistry (IHC). The MPFC assay will enable investigators to monitor 38C13 lymphoma tumor response to individual vaccines or other lymphoma therapy prior to clinical trials. Furthermore, the MPFC concept could be readily applied to other models of human B cell lymphoma.
Sigma 2-Agonist CB-64D Induces Apoptosis in Non Hodgkin’s Lymphoma Cells: Association with Decreased Akt Expression.
Authors: Dell’Agnola Chiara , Wojciechowski Wojciech , Marshall Shannon , Lopez Natalia E. , Li Huifen , Bowen Wayne D. , Espinoza-Delgado Igor J. 
Published: October 2019

Abstract
Background and aim: Sigma (σ) receptors are expressed at high density in a variety of tumor cell types, with an increased expression of σ2-subtype in rapidly proliferating tumors. CB-64D is a recently developed sigma agonist, showing a higher affinity for σ2- receptor subtype. We evaluated the cytotoxic activity of CB-64D in the extensively characterized Non-Hodgkin’s Lymphoma (NHL) cell lines DB, RL, and Ramos.
Materials and methods: Human DB, RL (both derived from patients with diffuse large cell lymphoma), and Ramos (Burkitt’s lymphoma) cells were exposed to increasing concentrations of CB-64D for various periods of time. Cells were harvested and stained with Annexin-V and PI and apoptosis was evaluated by flow cytometry. Expression of caspases, Akt and Bcl-2 was determined by Western blotting.
Results: CB-64D induced apoptosis in all NHL cells tested in both a time- and dose- dependent manner. Apoptosis was detected as early as 3 hours (7.5%) and reached its maximum at 12 hours (75%). As little as 5 μM CB-64D was able to induce apoptosis and maximum effects were noted with 40 μM CB-64D. To investigate the mechanisms responsible for the observed apoptosis, expression of caspases, Bcl-2, and Akt was evaluated. Western blot experiments revealed that CB-64D induced the expression of activated caspases 3, 8, and 9. Inhibitors of both caspase 3 and caspase 8 significantly decreased CB-64D-induced apoptosis. The induction of apoptosis was not associated with changes in Bcl-2 levels. In contrast, CB-64D induced a major decrease of Akt as determined by Western blot. Northern blot analysis demonstrated that Akt mRNA was not affected by CB-64D suggesting that the decreased expression of Akt was controlled at the post-transcriptional level. Treatment with the proteasome inhibitor PS-341 failed to prevent CB-64D-induced Akt down-modulation suggesting that the decreased expression of Akt is not due to proteasome degradation.
Conclusions: Our data demonstrate that the σ2-agonist CB-64D has a potent anti-lymphoma activity. CB-64D directly induces apoptosis through caspase-dependent mechanisms. Our data also show that CB-64D-induced apoptosis is associated with a decreased Akt expression that is controlled at the post-transcriptional level. The present results warrant the exploration of CB-64D in a pre-clinical model.
Investigation of FcγR Polymorphisms and Response to IL-2 (Proleukin®) and Rituximab Treatment in Rituximab-Resistant NHL Patients: Importance of the F/F Polymorphism at Position 158 of the Fcγ.
Authors: Milan Sandra , Wilson Susan E. , Kahn K.D. , Giordano Heidi 
Published: October 2019

Abstract
Background: Antibody-dependent cellular cytotoxicty (ADCC) is an important mechanism of rituximab activity. Genetic polymorphisms in FcγRIIIa have been reported to influence response to rituximab in follicular non-Hodgkin’s lymphoma (NHL) patients, and the F/F polymorphism at position 158 has been associated with decreased response (Cartron, et al. Blood 2004). IL-2 induces expansion and activation of FcR bearing cells, enhancing ADCC (Gluck, et al. Clin Cancer Res 2004).
Methods: The combination therapy of IL-2 and rituximab (IL-2+R) was evaluated in low grade NHL patients who were rituximab-resistant by standard criteria. Rituximab was administered weeks (wks) 1–4 at 375 mg/m2 IV; IL-2 was administered SC 3 times/wk at 14 MIU wks 2–5 and at 10 MIU wks 6–9.
Results: 57 patients (pts) were enrolled. Twenty-nine pts are evaluable with at least week 8 response data, all of whom have been genotyped. Best response to date: 4 responders (1 CR, 3 PR), 22 patients with stable disease (SD), and 3 pts have progressed (PD) on therapy. Follow-up is on-going. FcγRIIIa polymorphism analysis at position 158 from 36 pts typed to date shows a frequency of 53% F/F, 36% V/F, and 11% V/V as compared to 35%F/F, 45%V/F and 20% V/V in previously untreated pts (Cartron et al, 2004). To date, the data has shown a higher response rate for the F/F pts (4/17; 24%) than the overall population (4/29; 14%). Best response to date for 17 F/F pts: 4 responders and 13 SD; for the 9 V/F pts: 0 responders, 7 SD, and 2 PD; for the 3 V/V pts: 0 responders, 2 SD, and 1PD. In addition, 9 pts had responses lasting = 4 months with 6/9 being F/F and 3/9 being V/F. Patients will be followed periodically up to 2 years or until disease progression. The regimen was well tolerated and the majority of adverse events (AEs) were CTC grade 0, 1, or 2 (flu like symptoms, injection site reactions and rash). No grade 3 or 4 AEs occurred in 10% or more of pts.
Conclusions: These data support an association of the genetic polymorphism of FcγRIIIa 158F/F with prior failure to respond to rituximab. Immunotherapy with IL-2+R may achieve a critical threshold to drive ADCC more effectively in patients carrying the low affinity F/F IgG FcR polymorphism, restoring their response to monoclonal antibody therapy. All pts with this F/F polymorphism either responded to therapy or achieved SD as their best response to date. This outpatient regimen was generally well tolerated. The role of the FcγRIIIa F/F polymorphism is currently being evaluated in a prospective randomized trial comparing rituximab to rituximab + IL-2 in patients with follicular lymphoma.
Results of Multicentre Phase IV Study of Rituximab in Combination with CHOP Chemotherapy in Patients with Previously Untreated Non-Hodgkin’s Lymphoma.
Authors: Shen Ti , Guan Zhongzhen , Shen Zhixiang , She Yuankai , Zhu Jun 
Published: October 2019

Abstract
Purpose: Rituximab is a chimeric anti-CD20 monoclonal antibody that was the first antibody approved by the FDA in the United States of America and SDA in China for the treatment of B-cell non-Hodgkin’s Lymphoma (NHL). It has shown significant efficacy and good tolerability in refractory and relapsed NHL. We have conducted a multicenter phase IV trial to evaluate the efficacy and safety of rituximab combined with standard CHOP chemotherapy in patients with newly diagnosed B-NHL.
Methods: Patients with newly diagnosed, histologically proven CD20-positive NHL were eligible for the study. All patients received 4–6 infusions of rituximab (375mg/m2 per dose) in combination with CHOP chemotherapy, either concurrently (rituximab administered on the first day of each 21-day CHOP cycle) or sequentially (4–6 once-weekly infusions of rituximab followed by six 21-day cycles of CHOP). Each CHOP cycle consisted of cyclophosphamide 750 mg/m2, doxorubicin 50mg/m2, and vincristine 1.4mg/m2 (maximum 2.0mg/dose) given intravenously on day 1, and prednisone 100mg/day orally on days 1-5. Tumor responses were assessed at the end of treatment.
Results: A total of 347 patients were recruited between February 2002 and December 2003. Of these 235 (68%) were male and 94 (27%) aged >60. The main lymphoma subtypes were diffuse large B-cell 196 (56%), follicular 41(12%), small lymphocytic/chronic lymphocytic leukemia 13(4%) and MALT 11(3%). Ann Arbor staging was as follows: stage I, 52 (15%); stage II, 80 (23%); stage III, 90(26%); stage IV, 105(30%); twenty patients (6%) could not be assessed. Of the 347 patients enrolled, 314 were evaluable for response. An objective response was observed in 94% of evaluable patients with a complete response (CR) in 56%, stable disease in 3.8% and progressive disease in 2.5%. The complete response rate was 63% for patients receiving 6 cycles of rituximab and 54% for those receiving four cycles of rituximab. No difference in response rate was observed between the sequential and concurrent groups. The most common adverse events were leucopenia in 122 patients (35%), nausea and vomiting 66 (19%), fever 39 (11%), rash 15 (4%) and asthma 4 (1%).
Conclusion: The combination of rituximab and CHOP chemotherapy is an effective and well-tolerated treatment for patients with newly-diagnosed CD20-positive NHL. The safety and efficacy achieved in this study suggests that more than four doses of rituximab may be required for optimal efficacy.
Survival Benefits of Patients with Non-Hodgkin’s Lymphoma Treated with Rituximab Combined with Chemotherapy.
Authors: Shen Zhixiang , Li Junmin , Wang Aihua , Chen Yu 
Published: October 2019

Abstract
Purpose: Rituximab combined with chemotherapy has been recommended as first-line or second-line standard regimen in most subtypes of B-cell lymphoma in China by the 2004 National Comprehensive Cancer Network lymphoma therapy guideline. We have conducted a multicenter trial to evaluate the efficacy and safety of rituximab in combination with standard chemotherapy (CHOP) in patients with previously untreated or relapsed indolent and aggressive NHL.
Methods: Patients received 4–8 cycles of rituximab plus CHOP every 21 days. For each cycle, rituximab (375mg/m2) was given on day 1 and CHOP started on day 3. CHOP consisted of cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, and vincristine 1.4mg/m2 (maximum 2mg/dose) given intravenously on day 3, and oral prednisone 100mg on days 3–7.
Results: A total of 221 patients were enrolled on the trial, 128 males and 93 females with a mean age of 49 years (range 10–83 years). The main lymphoma subtypes were small lymphocytic (15 patients, 7%), follicular (27 patients, 12%), and diffuse large B-cell (160 patients, 72%). In total, 56 patients had indolent NHL and 165 aggressive NHL. The overall response rate for all patients was 86% with 57% complete responses. In patients with indolent NHL the overall and complete response rates were 95% and 55% respectively. After a median 12 months follow up, progression-free survival in patients with indolent NHL was 88%±5% at 1 year and 83%±6% at 2 years. In the 160 patients with diffuse large B-cell lymphoma, the overall response rate was 88% with 61% complete responses, and after a mean follow-up of 6 months, predicted 1-year and 2-year progression-free survival were 88%±5% and 83%±7% respectively. Infusion-related adverse events occurred in 4% of patients, associated with the first infusion of rituximab. Subanalyses according to subtype, stage, IPI and other factors will be presented.
Conclusion: Rituximab plus chemotherapy is an effective, well-tolerated treatment that achieves high response rates and long progression-free survival in both indolent and aggressive NHL.
Analysis of Histone Deacetylase Inhibitor, FK228, Effect on Chronic Myelogenous Leukemia Cell Line.
Authors: Okabe Seiichi , Tauchi Testuzo , Nakajima Akihiro , Sashida Goro , Sumi Masahiki , Gotoh Akihiko , Ohyashiki Kazuma 
Published: October 2019

Abstract
Chronic myelogenous leukemia (CML) results from transformation of hematopoietic cells by the BCR/ABL gene. Although high rates of hematologic responses to imatinib therapy, the acquired resistance to imatinib has been recognized as a major problem in the treatment of CML Histone deacetylases (HDACs) and histone acetyltransferases (HATs) regulate gene expression and cell growth. Recently, HDAC inhibitors have known as a new class of anti-cancer drugs. One of the HDAC inhibitor, FK228 (FR901228, depsipeptide) is now doing the clinical trial for the treatment of patients, such as peripheral T-cell lymphoma, but there was not known to the CML. In this study, we used the TF-1 BCR-ABL cell line, which were transfected BCR/ABL gene to the leukemia cell line, TF-1. We show here that FK228 potently induced apoptosis of TF-1 BCR-ABL cells, compare to the parental cell line, TF-1, in a dose and time depend fashion. BCR-ABL, intracellular molecular chaperone, heat shock protein 90 (HSP90), and p53 which regulate cell cycle, were acetylated after FK228 treatment, but not glycogen synthase kinase-3 β(GSK-3β) and signal-transducing activators of transcription 5 (STAT5). Histone H4 is also acetylated after FK228 treatment. In a cell cycle analysis, TF-1 BCR-ABL cells were stopped at G2-M phase after FK228 treatment. The activity of MAPK and Src kinases were blocked after FK228 treatment in a time and dose depend fashion, but p38 was activated. Inhibitor of apoptosis proteins (c-IAPs) have prevented cell death by inhibiting effectors caspases. IAPs were inhibited by FK228 and caspase3, caspase9 and poly (ADP-ribose) polymerase (PARP) were activated in a time and dose depend manner. Histone acetylation and caspase activitation were not blocked by treatment of p38 inhibitor, SB203580. Our study supports the future clinical trial of FK228 in the management of CML patients.
Quantitative Polymerase Chain Reaction (qPCR) at Diagnosis and Follow-Up of Patients with Chronic Myeloid Leukemia in Treatment with Imatinib.
Authors: Vallespí Teresa , Borrego Mildred , Colomé Doulous , Jaen Ana , Rozman Maria , Massagué Isabel 
Published: October 2019

Abstract
Imatinib, a selective inhibitor of tyrosin-kinasa BCR/ABL fusion protein, produces high response rates in patients with chronic myeloid leukemia (CML) in the chronic phase. The behavior of the levels of the BCR/ABL transcript by qPCR technique was studied in 24 patients (13M/11F; median age: 49.6 years, range: 23–73), diagnosed of CML in chronic phase, before and after the treatment with imatinib (at the 0, 3, 7, 11 and 15 months). Eight patients had previously received interferon alpha or busulphan and 16 hidroxiurea. The amplification of BCR/ABL with the qPCR technique, according to protocol BIOMED-2, was carried out in samples of bone marrow (n = 23) and peripheral blood (n = 48). Results were calculated in relation to a control gene of the glucuronidasa (GUS) and expressed in logarithmic scale (log10). Median time from the diagnosis was of 28 months and median treatment time with imatinib was 14 months. The median reduction of BCR/ABL transcripts was 1,98 log after three months and decreased further (2,71 log) during follow-up. Both of them were significative when compare with base line levels (P &lt;0.001). The reduction was greater in patients who received a dose ³ 400 mg/day (n=16) than those with 300 mg/day (n=8). Three patients reached a major molecular response (ratio BCR-ABL/GUS &lt;0.005) up to 15 months of treatment. In conclusion: the determination of the BCR/ABL transcripts by qPCR contributes with valuable information about the effect of imatinib in patients with CML. The logarithmic reduction is higher in the beginning of the treatment and doses ³ 400 mg/day are associated with a greater reduction of the tumoral load.
Figure Figure
Use of Single Course IV Fludarabine in Treatment of Hypocellular Bone Marrow (Aplastic Anaemia and MDS) Patients.
Authors: Apte Shashikant J. , Vaidya Sujata U. , Shah Nikhil , Bhatwadekar Seema , Kalro Akash , Sayaji Bhavna , Suryavanshi Prashant , Kelkar Anjali J. 
Published: October 2019

Abstract
Young patients with Hypocellular Bone Marrow ideally need Allogenic Stem Cell Transplant or ATG + CYA + Steroids. In country like India these two treatment modalities are very expensive and very few can afford. We tried to study effect of single course of IV FLUDARABINE 30 mg/m2 x 5 days as an upfront immunosuppressive therapy for these patients.
Study period: January 2001 – April 2004.
Total patients – 29.
Age group: 17 – 47 years
Follow up: 4–37 months. Median follow up 15 months.
Haemogram range at diagnosis
Hb: 3–7.2 gm%, ANC: 100 – 600/cmm, Platelet: 3 – 11 x 10 9/L
Bone marrow aspirate & trephine biopsy showed Hypocellularity on all patients.
8/29 patients had dysplastic features on morphology.
3/29 patients had cytogenetic anamoly, two: del 7 & one: del 7q.
14/29 patients had normal cytogenetics.
12/29 patients no metaphases seen on Cytogenetics.
All cellular transfusions were 2500 rads irradiated.
11/29 ( 38 %) patients died in first six months, causes of mortality being infection and intracranial bleed.
10/29 ( 34 %) patients responded to treatment. They are transfusion independent ( Hb > 9 gm%), platelet > 50000/cmm and ANC > 1500/cmm. All three patients with cytogenetic anamoly responded.
8/29 ( 28 %) patients showed no response.
Larger data is needed to asses the efficiency of single course IV Fludarabine in patients with Hypocellular bone marrow. Single five day course of IV Fludarabine can be a cheaper immunosuppression, for these patient.
Cost: ALLO SCT - Rs. 10 lakh ( $ 20000), ATG + CYA + Steroid - Rs. 4 lakh ($ 3000)
IV Fludara 30 mg/m2 x 5 day – Rs. 40000/- ( $ 800)
Autoimmune Disease (AD) in Patients with Myelodysplastic Syndrome (MDS): A Retrospective Single Institution Study.
Authors: Ramanarayanan Jeyanthi , Baer Alan N. , Battiwalla Minoo , Ford Laurie A. , Wetzler Meir , Baer Maria R. 
Published: October 2019

Abstract
Autoimmune disease (AD) can manifest uncommonly either at the time of diagnosis of MDS or during its course. When present, AD generally responds to immunosuppressive therapies, but cytopenias and immunosuppression associated with MDS compromise delivery of these therapies. Few studies have investigated the impact of co-existing AD on the course and outcome of patients with MDS. Our objective was to evaluate the clinical manifestations, laboratory characteristics, response to therapy and survival of MDS patients with AD. Records of patients evaluated at Roswell Park Cancer Institute with pathologically demonstrated MDS between 1993 and 2003 (n=277) were reviewed and patients with evidence of AD were identified. Patients with laboratory abnormalities without disease manifestations were excluded, as were patients with therapy-related MDS following treatment for AD. 13 patients (4%) were identified with co-existing MDS and AD. The initial presentation was AD in 6 (46%) and MDS in 4 (31%), while 3 patients (23%) had near-simultaneous diagnoses of both conditions. The spectrum of AD in these patients included systemic vasculitis in 3 patients, systemic lupus erythematosus in two and rheumatoid arthritis, temporal arteritis, cryoglobulinemia, aphthous stomatitis, pyoderma gangrenosum, inflammatory bowel disease, erythema nodosum and Evans syndrome in one patient each. Anti-double stranded DNA (levels ≥ 40.0 u/ml; normal range 0.0–3.5u/ml), ANA (≥1:160), cold agglutinins, low C3 and elevated ESR (≥100mm/hr) were the serological abnormalities detected at the time of AD diagnosis. Eleven of 13 patients were female, and median age at diagnosis of MDS was 65 years, while the entire cohort was 44% female (p=0.005) and had a median age of 71 yrs at diagnosis. FAB subtypes were RA (n=7), RAEB (n=3), CMMoL (n=2) and RARS (n=1). Cytogenetics were normal in 5 patients; abnormalities in the other 8 patients included −7, +8, and del(5q). The median survival of patients from diagnosis of MDS was 48 months and the survival from diagnosis of AD was 46 months. Known causes of death in 6 patients included sepsis, intracranial hemorrhage, lung cancer and transplant-associated multiorgan failure. Based on this study, AD occurs in 4% of MDS patients, predominantly affects female patients, and has heterogeneous clinical manifestations.The pathobiologic implication of the occurrence of AD at the same time or after the diagnosis of MDS is that the dysplastic clone might be responsible for the induction of immune dysregulation.