bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clofarabine (CLO) Is Active in Patients (pts) with Refractory and/or Relapsed Non-Hodgkin’s Lymphoma (NHL): A Phase I/II Study.
Authors: Nabhan Chadi , Fried Walter , Galvez Angel G. , Venugopal Parameswaran , Gozun Phillip , Bitran Jacob D. 
Published: October 2019

Abstract
There is no known standard of care for pts with relapsed and/or refractory NHL who cannot undergo stem cell transplantation (SCT) or have relapsed after SCT. Such pts are candidates for new therapies. CLO is a novel nucleoside analogue with known activity in acute leukemia and myelodysplasia. Previous clinical trials with CLO have established safety and potential activity in a variety of tumors. We performed a phase I/II study of CLO in a heavily pretreated pt population with refractory and/or relapsed NHL regardless of cell type, histology, or grade. Eligible pts were adults over 18 years of age who have relapsed and/or refractory NHL with measurable disease. Pts were required to have adequate performance status, bone marrow function (unless cytopenias were related to disease involvement), renal, cardiac, and liver functions. Pts with bulky disease (>10 cm at any site), known HIV, or immune-related cytopenias were excluded. CLO was given as a 1-hour intravenous infusion for 5 consecutive days every 28 days for a maximum of 6-cycles. All enrolled pts received anti-viral and anti-pneumocystis carinii prophylaxis. Growth factors were administered at the investigator’s discretion. Pts were divided into cohorts of 3 each. CLO was given at 4 mg/m2 to the first cohort with escalated doses by 2 mg/m2 increments for each cohort. Once the dose-limiting toxicity (DLT) was reached, the phase II portion of this study was initiated at the dose below the DLT level. All pts were followed until disease progression. To date, 13 pts have been enrolled with 7 on the phase I portion and 6 on the phase II portion. For the phase I portion, the median age was 79 (range: 27–81); the median number of prior therapies was 5 (range: 2–6) with 3 pts having relapsed after prior SCT. The median number of given CLO cycles in the phase I portion was 2 (range: 1–5). The DLT at 6 mg/m2 was thrombocytpenia establishing 4 mg/m2 as the appropriate dose for phase II. For the phase II portion, the median age was 78 (range: 50–83), median number of prior therapies was 2 (range: 1–8). Taken all together (phase I and II pts), 9 out of 13 pts are evaluable for response. (All received at least 1 cycle). There was 1 complete response (CR) and 4 partial responses (PR) for an overall response rate (OR) of 55%. Four patients demonstrated stable disease (SD) with one of them progressing shortly after 2 months. Eight patients remain alive (overall survival: 61%) at a median follow up of 4 months (range: 1–13). Median times to progression and duration of response have not been reached in responding pts.

CLO is active in heavily pretreated refractory and/or relapsed NHL. The drug has an acceptable toxicity profile. Myelosuppresion is the major adverse event in this heavily pretreated population. The study continues to accrue patients and will be updated at the meeting.
Quality of Life in Patients with B-Cell Lymphoma during Maintenance Therapy with the Anti-CD20 Antibody Rituximab.
Authors: Witzens-Harig Mathias , Heiss Christiane , Benner Axel , Hensel Manfred , Neben Kai , Dreger Peter , Kraemer Alwin , Ho Anthony D. 
Published: October 2019

Abstract
The introduction of rituximab into the treatment of malignant lymphomas of the B-cell lineage has had a major impact on the management of these diseases. In diffuse large B-cell lymphomas (DLBCLs) and follicular lymphomas (FLs) several multicenter prospective randomized trials consistently demonstrated an improved outcome when rituximab was added to chemotherapy. In addition, prolonged exposure to rituximab as maintenance therapy has been benefical in patients with FL and mantle cell lymphoma (MCL). For patients, the effect of any prolonged antitumor therapy on the quality of life (QoL) is a very important question. However, so far the question whether rituximab maintenance therapy may impair QoL in patients with Non-Hodgkins-lymphoma remains unanswered. To investigate this subject, we have performed a prospective randomized trial of rituximab maintenance therapy (8 cycles rituximab 375 mg/m2 every 3 months) versus observation in patients with CD20+ B-cell Non-Hodgkins-Lymphoma in our institution. Between July 2002 and December 2005, 106 patients (pts) were included into the trial. QoL was assessed with the standardized questionnaires EORTC-QLQ-C30 and EuroQol-5D. After statistical analysis with the Wilcoxon signed-rank test, we found no significant differences of the QoL between the rituximab treatment group and the observation group. We conclude that rituximab maintenance therapy is safe and does not impair quality of life in this patient population.
Classification of HLA-Matching for Retrospective Analysis of Unrelated Donor Transplantation: Revised Definitions To Predict Survival.
Authors: Weisdorf Daniel J. , Spellman Stephen , Klein John , Haagenson Michael D. , Horowitz Mary , Lee Stephanie , Anasetti Claudio , Setterholm Michelle , Drexler Rebecca , Maiers Martin , King Roberta , Confer Dennis 
Published: October 2019

Abstract
Unrelated donor (URD) hematopoietic cell transplantation (HCT) is best performed using a donor who is allele-matched with the recipient at HLA-A,B,C and DR. Earlier reports analyzing outcomes of HCT have been limited by incomplete or lower resolution typing at some HLA loci. Excluding these incompletely typed pairs from studies decreases the power of analyses because of smaller sample size. If adjustment for known and unknown HLA-matching status could be accomplished, these patients could be retained in most analyses where HLA-matching is not the primary research focus. To understand the impact of incompletely characterized major histocompatibility antigens on the success of HCT, we analyzed 15,867 URD HCT using multivariable regression modeling adjusting for HLA and non-HLA factors affecting 1 year and 5 year survival. Of 26 independent matching groups defined by the completeness and resolution of donor:recipient pair matching we identified 3 distinct groups with significantly different outcomes: well matched, partially matched, and mismatched. Well-matched cases had no identified HLA mismatch and informative, though not necessary high-resolution data at all 4 loci or allele matching at HLA-A,B & DRB1 (n=7,753, 49% of the study population). Partially matched pairs had a defined, single locus mismatch at any of the 4 loci and/or missing HLA-C data [including 6/6 low/intermediate resolution A,B matched plus DRB1 allele matched] (n=5,396, 34%). Mismatched cases had 2 or more identified allele or antigen mismatches (n=2,692, 17%). Multiple-variable-adjusted one- and five-year survival estimates are shown in the Table. Using these HLA matching categories, we identified independently significant, 7–8% better 5 year survival using a better matched donor (between these 3 categories) stratified across patient subgroups of recipient age, disease stage, and using either myeloablative or non-ablative conditioning. Notably, the common term “6/6 antigen matched” [6/6 low/intermediate resolution A,B matched plus DRB1 allele matched] had survival outcomes within the partial matched cohort. We suggest that these HLA subgroups should be used in analyses of URD HCT outcomes when complete HLA typing is not available. This improved categorization of HLA matching status allows adequate adjustment for HLA donor-recipient HLA compatibility in retrospective studies and will help standardize interpretations of prior URD HCT experience.
HLA Matching Group 1 Year Survival (95% CI)* 5 Year Survival (95% CI)* Well Matched 53.5 (52.3–54.7) 34.9 (33.5–36.3) Partially Matched 41.5 (40.1–42.9) 27.0 (25.7–28.5) Mismatched 31.0 (29.3–32.9) 18.3 (16.7–19.9) * p<0.001
Biscoclaurine Alkaloid Cepharanthine Inhibits the Growth of Primary Effusion Lymphoma In Vitro and In Vivo and Induce Apoptosis Via Suppressing the NK-κB Pathway.
Authors: Okada Seiji , Makise Naoko , Hiyoshi Masateru , Suzu Shinya 
Published: October 2019

Abstract
Primary effusion lymphoma (PEL) is a unique recently identified non-Hodgkin’s lymphoma which was originally identified in AIDS patients. PEL is characteristically infected by the Kaposi sarcoma-associated herpesvirus (KSHV) and shows a peculiar presentation involving liquid growth in the serous body cavity with generally poor prognosis. As the NK-κB pathway is activated in PEL and plays a central role in oncogenesis, we examined the effect of biscoclaurine alkaloid, Cepharanthine, on PEL derived cell lines (BCBL-1, TY-1, and RM-P1) in vitro and in vivo. MTT assay revealed the cell proliferation of PEL cell lines was significantly suppressed by the addition of Cepahranthine (1–10μg/ml). Cepharanthine also inhibited NK-κB acitivation and induced apoptotic cell death in PEL cell lines. We established PEL animal model by intraperitoneal injection of BCBL-1 into the nobel immunodeficient NOD/Scid/Jak3null mice. Intraperitoneal injection led to the development of ascites and diffuse infiltration of organs, without obvious solid lymphoma formation, resembling the diffuse nature of human PEL. Intraperitoneal administration of Cepharanthine inhibited the ascites formation and diffuse infiltration of BCBL-1 without significant systemic toxicity in this model. These results indicate that NK-κB could be an ideal molecular target of PEL and Cepharanthine could a unique therapeutic agent for PEL.
Concomitant Diagnosis of Chronic Myeloid Leukemia and B-Cell Chronic Lymphocytic Leukemia in a 57-Year-Old Female Patient, with Good Therapeutic Response Exclusively to Imatinib in Both Myeloid and Lymphoid Clones.
Authors: Moellmann-Coelho Arthur , Otero Luise , Bigni Ricardo S. , Azambuja Denise , Stefanoff Claudio G. , Dobbin Jane A. , Zalczberg Ilana 
Published: October 2019

Abstract
We describe the clinical, cytogenetic, hystopathologic, immunophenotypic and molecular findings of a rare case of Philadelphia positive chronic myeloid leukemia (Ph+ CML) and B-cell chronic lymphocytic leukemia (B-CLL) occurring simultaneously at diagnosis, in a 57-year-old female patient. In the present case, the patient showed at diagnosis leukocytosis (48.000/ul) with myelocytes and metamyelocytes along with well-differentiated neutrophils, but also with well differentiated lymphocytosis (28.992/ul) in peripheral blood (PB) and also in bone marrow (BM) aspirate cytology. FACS cytometry exhibited clearly two predominant separated cellular populations and the immunophenotype profile of the lymphoid component in BM and PB was CD5+, CD20+, CD23+, with light chain clonal restriction. The BM hystopathological analysis showed two distinct cellular populations, one lymphoid well differentiated CD5+/CD20+, and other myeloid, in several stages of differentiation. Cytogenetic analysis with unstimulated bone marrow culture confirmed the presence of Philadelphia chromosome but with additional translocation involving chromosomes 9, 10 and 22. Molecular studies showed the evidence of BCR-ABL positivity and the B-cell clone was documented by the presence of a clonal heavy chain immunoglobulin rearrangement. The patient was treated with imatinib mesylate 400mg/day, achieving complete cytogenetic response at the fourth month, and complete molecular response (nested PCR) of the BCR-ABL component at the sixth month of treatment. Besides, the absolute lymphocytosis was gradually reduced during the treatment exclusively with imatinib, achieving normal absolute values at the sixth month. This seldom described case of simultaneous occurrence of these two rare chronic hematological malignancies, brings interesting questions about the possible cellular origin and the correspondent mechanisms of clonal expansion. The therapeutic response of the B-cell lymphoid clone exhibited, brings also a possible relationship with the observation that the c-Abl could have enhanced expression in B-CLL cells, as described by Ke Lin et al, in which the c-Abl kinase activity could be inhibited by imatinib mesylate.
The JAK2V617F Mutation in Blood Donors with High Haematocrit.
Authors: Tagariello Giuseppe , Di Gaetano Rosanna , Sartori Roberto , Belvini Donata , Radossi Paolo , Risato Renzo , Salviato Roberta , Tassinari Cristina , Toffano Nunzio , Zanotto Daniela 
Published: October 2019

Abstract
By the introduction for routine tests of automated counters it has become easy and extremely common the finding of abnormal or near normal laboratory results. During blood donations haematocrit (Htc) and haemoglobin level (Hb) are regularly tested to avoid a blood donation in the case of anaemia as this is the most frequent cause of exclusion from the donation. However it is not rare to observe a level of Hb or Htc upper or close the normal highest limit. Starting from the 1st of January 2006 to the 31st December 2006, we have collected 11240 donations in total from 5636 regular blood donors (total donation index 1.99) and selected on the basis of Htc, limit upper 50% for man and 46% for women, 84 males and 19 females. In this cohort, during a 1846 years donation period, the average of donations for males was 22.2 while for females was 11.4. We collected randomly and used as control group 79 donors (59 males and 20 females) with normal Htc levels in the last blood donation. For the identification of the V617F (1848 G>T) mutation within JAK2 we used the method published by Jones ed al. in 2005 named amplification refractory mutation system (ARMS). Among the 84 men with high haematocrit level we have been able to identify 1 blood donor positive for this mutation. This blood donor had Htc equal to 50.6 in the last donation, while the average Htc in the last year was 51.7. These results account for a total prevalence of the JAK2 mutation in 1% of the blood donor population with elevated Ht (1 out of 103) while it is 0.6% (1 out of 183) of the entire population of blood donors in this study or 0.02% of the entire cohort appertaining to our transfusion service. Our results seem also in keeping with the few studies evaluating blood donors (Zanella et al., Transfusion 1987) or normal population (Ruggeri et al., Ann Int Med 2003). In both these studies the prevalence of MPD was around 3% which is not so far away from that found in our cohort (asymptomatic patients) but much higher than that supposed in hospital based cohorts in previous studies (100 fold increased). The hypothesis that the prolonged myeloid stimulus from phlebotomies can induce inhibition of the feed-back control as well as blood donations triggered the onset of a pre-existing latent primary myeloproliferative disease needs further studies to be confirmed.
Higher Sensitivity and Detection of Homozygous/Hemizygous State of JAK2 Mutation Using Plasma.
Authors: Ma Wanlong , Zhang Xi , Sun Weimin , Schwartz Joyce , Buller Arlene , Jilani Iman , Kantarjian Hagop , Giles Francis , Albitar Maher 
Published: October 2019

Abstract
We recently reported that analysis of plasma rather than peripheral blood cells improves detection of the JAK2 V617F mutation, the most characteristic molecular abnormality in patients with non-chronic myeloid leukemia (CML)-myeloproliferative disease (MPD). To expand on these findings, we tested 634 consecutive paired plasma and cell samples for the V617F mutation and mutations in JAK2 exon 12. All patients were clinically suspected of having a non-CML MPD. Testing was performed using direct bidirectional sequencing. The V617F mutation was detected in the plasma of 151 (24%) patients but in only 140 (22%) paired cell samples. No patients were positive by cell analysis and negative by plasma analysis while 7% of patients positive by plasma were negative by cells. Of the 151 V617F-positive samples, 58 (38%) showed homozygous/hemizygous mutation by plasma analysis; 36 (24%) were homozygous/hemizygous by cell analysis. Upon quantifying the V617F mutant peak relative to wild-type peak, plasma exhibited significantly higher relative mutant JAK2 transcript than cell samples (P<0.001). None of the 634 paired samples had exon 12 mutations, nor did an additional 130 plasma samples from patients with confirmed MPD. However, two novel mutations, C618R and V617I, were identified. These data confirm that plasma is enriched with tumor-specific nucleic acid, allowing more sensitive detection of the JAK2 V617F mutation and homozygous/hemizygous state than cell analysis.
Chronic Lymphocytic Leukemia Complicated with Paraneoplastic Pemphigus and Glomerulonephritis in a Patient and Its Treatments: Report of One Case.
Authors: Xuan Qian Si , Yong Li Jian , Ming Hong , Ruan Changgeng 
Published: October 2019

Abstract
Objective To study chronic lymphocytic leukemia(CLL) in association with glomerulonephritis and paraneoplastic pemphigus, and discuss the possible etiology and appropriate therapy.
Methods We presented a rare case of this disease and analyzed the clinical features and therapy. A 41-year-old male was diagnosed with CLL He received one cycle of CHOP protocol, followed by two cycles of FCM protocol, and achieved the PR. After stopped the treatment, he had progression of disease, presented high level of creatinine and urea nitrogen. Then he received two courses of high dose of methyllprednisolone before the kidney biopsy was performed. He presented paraneoplastic pemphigus while his renal inadequacy was improvement. Skin biopsy was performed. He started with oral prednisone (60mg/d) and cyclophosphamide with improvement of blisteringl eruptions, but without improvement of oral leukoplakia and dysphonia. Rituximab was given in a dose of 375mg/m2 weekly for 4 weeks, and IV immunoglobulins 0.4g/kg/d for 5 days because of intermittence fever.
Results The patient with CLL appeared the proteinuria, hematuria and intraepithelial blister formation, refractory mucosal ulceration respectively. A kidney biopsy showed focal segmental sclerosing glomerulonephritis. The histologic and immunofluorescence examinantion of a skin biopsy was compatible with PNP. Conventional protocols were unsatisfactory, but recent developments in the use of cyclophosphamide, rituximab and intravenous immunoglobulin appeared to be more successful.
Conclusions Pathogenesis of CLL in association with autoimmunity diseases was unknown, Further clinical evaluation is required to define the role of treatment of CLL-associated autoimmunity.
Aggregation of Serum Free Light Chains (FLC) Causes Overestimation of FLC Nephelometric Results as Compared to Serum Protein Electrophoresis (SPE) While Preserving Clinical Usefulness.
Authors: Émond Jean-Pierre , Harding Stephen , Lemieux Bernard 
Published: October 2019

Abstract
Multiple myeloma is a disease characterised by the overproduction of monoclonal proteins. Whilst concentration of FLC correlates poorly with tumour burden at diagnosis, changes during treatment are considered to be an accurate and sensitive measure of response. Aggregation of FLC presents a problem for traditional means of FLC estimation, large aggregates will not pass through the kidney making urine unreliable.
Objectives : To report follow-up of 2 patients with discrepancy between SPE M-spike and serum FLC, one with serum free lambda, the other with serum free kappa. To analyze and confirm presence of multimer FLC aggregates in these 2 patients.
Methods : Routine SPE and immunofixation were performed by capillary electrophoresis (CZE). Serum FLC was measured by nephelometry. FLC polymerisation studies were undertaken by SDS-PAGE, Western blot and Sephadex S-200 gel filtration chromatography.
Results: First patient (free lambda) is a 80 y woman with IgA lambda multiple myeloma. Upon treatment, IgA lambda peak fell from 18 g/L down to < 0,4 g/L with a serum free lambda remaining at 10 700 g/L. Monoclonal free lambda peak at CZE was estimated to 1,5 g/L, a 7x discrepancy. High dose Decadron therapy was unsuccessful, serum free lambda remaining about 2500 to 4000 g/L for the next 6 months. Polymerisation studies revealed multiple aggregates of FLC with molecular weight (MW) ranging from 24 000 Da to > 200 000 Da. Second patient (free kappa) is a 70 y old man followed since 1985 for an IgG kappa indolent multiple myeloma. Treatment with melphalan in 1998 caused disappearance of M-spike at SPE and persistant hypogammaglobulinemia. Introduction of FLC testing in August 2006 revealed an unexpected serum free kappa of 2740 g/L which remained stable in the following months. This serum free kappa is not visible by CZE. Polymerisation studies revealed multiple aggregates of FLC with MW ranging from 24 000 Da to > 200 000 Da.
Conclusion : Serum FLC measurement is a new biological parameter for investigation and follow-up of monoclonal gammopathies with added value as showed here for 2 myeloma treated patients. One should be aware of well known interferences in FLC measurement such as renal dysfunction and polyclonal hyper-gammaglobulinemia. Here we demonstrated a less well documented confounding factor creating an unexpected discrepancy between this nephelometric technique and traditional CZE/SPE. We showed highly overestimated FLC by nephelometry. We revealed a profile of multiple complexes in 2 cases of FLC (one free lambda and one free kappa) of molecular weight up to > 200 000 Da. These multimers may well impact kidney function and interfere with standard urine investigation. It appears clear to us that an interpretation from an experienced professional should accompany any FLC measurement.
A High-Throughput Arrayed Lentiviral RNAi Screen To Identify Novel Oncogenes in Multiple Myeloma.
Authors: Schinzel Anna C. , Chapman Mike , Wittner Ben , Shrestha Yashaswi , Ramaswamy Sridhar , Golub Todd R. , Hahn William C. 
Published: October 2019

Abstract
Karyotypic complexity is one of the hallmarks of multiple myeloma, complicating efforts to identify the specific genetic alterations involved in the development of multiple myeloma. To identify genes essential for myeloma proliferation, we used a high-throughput loss-of-function approach using lentivirally delivered short hairpin RNA (shRNA) library targeting human kinases as part of a Multiple Myeloma Research Foundation sponsored pilot project. Three myeloma cell lines, MM.1S, RPMI8226 and INA6, were infected in an arrayed 384-well format. All infections were performed in quadruplicate; two replicates were treated with puromycin to select for infected cells and two were left untreated. Wells in which more than 25% of the cells survived puromycin treatment, as determined by a cell viability assay, were included in future analysis. Genes in which 2 or more hairpins scored below a defined threshold were considered as ‘hits’. To identify physiologically relevant hits, we have integrated these findings with whole genome analysis of copy number and gene expression of multiple myeloma. We have identified a number of genes that are both amplified in and required for multiple myeloma cell viability. These observations suggest potential new targets for therapeutic targeting in myeloma.