bluuebunny/crossref_metadata_2025_split huggingface dataset:
TOP-M Chemotherapy (Thiotepa, Oncovin [Vincristine], Prednisone, Mitoxantrone) Plus Rituximab for Marginal Zone Lymphoma.
Authors: Coleman Morton , Furman Richard R. , Niesvizky Ruben , Ashe Michelle , Mathews Lena , Fiore Jennifer , Ketas Jamie , Leonard John P. 
Published: April 2020

Abstract
Although considered an indolent disease, marginal zone lymphoma (MZL) often requires treatment. No standard therapy has been clearly established. Mitoxantrone has been effective in combination for indolent lymphomas, and is associated with considerably less cardiotoxicity and alopecia than doxorubicin. Thiotepa likewise does not induce alopecia, and does not display the immunosuppressive properties of fludarabine, which is also frequently employed as therapy for indolent lymphoma. The combination of thiotepa, vincristine, prednisone and mitoxantrone chemotherapy, with a scope similar to CHOP, has been demonstrated to be useful in elderly patients with diffuse large cell lymphoma (Lichtman, et al, Am J Clin Oncol, 24(4):360–2, 2001). The TOP-M regimen consists of thiotepa 7.5 mg/m2, mitoxantrone 7.5 mg/m2, vincristine and prednisone as per the CHOP regimen, with rituximab 375 mg/m2 all given on day 1 with a 21–28 day cycle (in accordance with resolution of cytopenias). Thiotepa and mitoxantrone doses were escalated by a total of 2.5 mg/m2 to a maximum of 20 mg/m2, respectively, based on nadir blood counts. We have retrospectively reviewed data on 12 patients with disseminated MZL treated with TOP-M either alone (n=4) or with rituximab (n=8). All subjects had advanced stage disease (4 with stage III, 8 with stage IV), 4 had B symptoms, and all patients clinically required treatment. Median age was 69, and 4 (33%) had an elevated LDH. Myeloid growth factor support was routinely applied, and anti-emetics were generally unnecessary. Central venous access was not required since neither thiotepa nor mitoxantrone are associated with tissue injury in the event of extravasation. Treatment was well tolerated, with only two episodes of hospitalization for fever. There was no cardiac toxicity. Eleven of 12 patients (92%) demonstrated clinical responses, with 9 CR/CRu (75%) and 3 PR (17%). Median duration of response has not been reached at with a range of 11 to 40 months of followup. TOP-M with rituximab is an easily administered, well tolerated and active regimen for disseminated marginal zone lymphoma, and may have utility for other indolent lymphomas.
Quantitative Pharmacogenetics of Cyclophosphamide in Patients with Hematological Malignancies.
Authors: Hassan Moustapha , Xie Hanjing , Ståhle Lars , Hassan Zuzana , Kimby Eva 
Published: April 2020

Abstract
A high degree of interindividual variation in cyclophosphamide (CPA) pharmacokinetics was reported in certain cancer patient groups. To better understand the mechanisms underlying the variation in CPA metabolism, the pharmacokinetics of CPA and its active metabolite 4-OH-CPA were estimated in patients with hematological tumors and related to the genotype of CYP2B6, CYP2C9 and CYP2C19. The influence of liver function on CPA metabolism was also evaluated.
Twenty-nine patients with hematological malignancies (MM, ALL or NHL) treated with a conventional CPA dose (1 g/m²) were recruited to this study. Blood samples were collected before, during and after CPA treatment. HPLC was used to measure plasma concentrations of CPA and 4-OH-CPA. Patients were genotyped for the CYP2B6 G516T, CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 alleles. Serum bilirubin levels were measured before the treatment. Data was analyzed individually and by population pharmacokinetic methods, using non-linear mixed effect modeling. The interindividual variability in exposure to CPA, 4-OHCPA and 4-OH-CPA/CPA was 5.8-, 3.3- and 10.3- fold, respectively. A positive correlation was found between half-lives of CPA and 4-OH-CPA (p&lt;0.05) and there was a significant negative correlation between AUCs of CPA and 4-OH-CPA. In the population analysis the clearance contribution of the CYP2B6 G516T variant allele was about twice the wild type gene while the genotype of CYP2C9 did not influence clearance. A negative correlation was observed between bilirubin level and CPA bioactivation. There is a considerable variation in CPA formation of 4-OH-CPA among patients. The liver function influences CPA metabolism. Presence of the CYP2B6 G516T mutation increases the rate of 4-OH-CPA formation, a substantial variation among patients remain to be explained.
Prognostic Molecular Features in Diffuse Large B-Cell Lymphoma from Saudi Arabia.
Authors: Al-Kuraya Khawla S. , Siraj Abdul Khalid , Nayanappa Rajeswari , Al-Dayel Fouad , Ezzat Adnan , Al-Jommah Naif , Sauter Guido , Simon Ronald 
Published: April 2020

Abstract
Molecular features that can classify diffuse large B cell lymphoma (DLBCL) in clinically relevant subgroups have recently been demonstrated in studies investigating Western Patients. Different etiologic factors and potentially also varying genetic predispositions have been demonstrated for lymphoma patients from developing countries. To investigate whether proposed molecular classifiers are equally important for Middle East as for Western populations, we analyzed coexpression of CD10/bcl6 (by immunohistochemistry), IgH/Cyclin D1 translocations (by fluorescence in situ hybridization) and methylation of the gene encoding the DNA repair enzyme O6 methyguanine -DNA methytransferase gene (MGMT) in a series of 236 DLBCL patients from Saudi Arabia. Clinical follow up data were available from 190 patients. Coexpression of CD10/bcl6 was found in 21%, IgH/Cyclin D1 translocations in 18.3%, and MGMT methylation in 70% of cases. With the exception of MGMT methylation which was reported in only 20–35% of European patients, these numbers were in the range expected from the Western literature. Despite the markedly higher number of MGMT methylation in Saudi cases, its proposed positive effect on DLBCL prognosis could be confirmed (p&lt;0.05). IgH/Cyclin D1 translocations were significantly more frequent in DLBCL with CD10/bcl6 coexpression (12 of 41) than in DLBCL without CD10/bcl6 coexpression (4 of 36; p&lt;0.05). However, neither CD10/bcl6 coexpression nor IgH/Cyclin D1 translocation was related to clinical outcome in our study. In summary, our data do not suggest major molecular differences between Saudi and European DLBCL. Methylation of MGMT gene is a strong prognostic factor in DLBCL. IgH/Cyclin D1 translocations are predominantly found in DLBCL of germinal center (CD10/bcl6 positive).
Impaired Clonogenic Capacity Contributes to Bone Marrow Hypoplasia and Late Hematological Recovery after Zevalin in the Low-Grade NHL Patients.
Authors: Jurczak Wojciech , Szostek Marta , Rudzki Zbigniew , Krochmalczyk Dorota , Wegrzyn Joanna , Czyz Jaroslaw , Skotnicki Aleksander B. 
Published: April 2020

Abstract
Chemoimmunotherapy with Zevalin (anty CD20,90Y) is a new therapeutic approach in the resistant or relapsed low grade malignant lymphoma patients. The most important side effect observed in the up to date studies is related to transient peripheral blood cytopenias.
In an attempt to evaluate the involved pathogenetic mechanisms of the above findings, the blood and bone marrow samples from 8 low grade NHL patients were prospectively tested for the peripheral blood count, the clonogenic capacity and the histopathology abnormalities (trephine biopsies) before and every 14 days after Zevalin administration until recovery. In the majority evaluated patients the mild thrombocytopenia (30-55000/μl) was observed 4 weeks after Zevalin therapy. Bone marrow mononuclear cells were cultured in methylcellulose assay using combination of recombinant CSF (IL-3, IL-6, stem cell factor, erythropoietin; Methocult, StemCell, Canada), at a concentration of 1x10^5 cells, in 35 mm gridded Petri dish and incubated at 37°C, in a humidified atmosphere of 5% CO2. The hematopoietic colonies (CFU-GM, BFU-E and CFU-GEMM) were evaluated on 14th d. of the culture. The in vitro CFU-Meg formation in the serum-free collagen-based semisolid culture (Megacult, StemCell, Canada) were also studied, stained after 12 days with a monoclonal antibody against CD 41.
In the results of our studies the significant inhibition of colony formation was found already in 7th day for CFU-GM and BFU-E and starting from 14th day after Zevalin administration for CFU-Meg. In the subsequent cultures evaluated during 4–8 weeks after Zevalin therapy the three lineages hematopoietic clonogenic capacity returned to the pre-radiotherapy values. In the repeated trephine biopsis several morphological changes were observed: oedema of stromal cells, the relative increase of erythropoietic components with inverted proportion of granulo- to erythropoiesis.
In conclusion, chemoimmunotherapy with Zevalin resulted in the reversible peripheral cytopenia parallely with transient damage to bone marrow hematopoiesis and in vitro clonogenic capacity.
Rituximab Plus CHOP Followed by Maintenance Rituximab as Initial Therapy for Advanced Stage Indolent Non-Hodgkin’s Lymphoma (NHL); Initial Results of Induction Therapy in a Phase II Study.
Authors: Huang Jane E. , Hart Lowell , Polikoff Jonathon , Langmuir Virginia , Zhang Fan , Fehrenbacher Louis 
Published: April 2020

Abstract
Background: This study was designed to investigate the activity and safety of rituximab (Rituxan®, R) plus CHOP induction therapy followed by maintenance R in patients with previously untreated advanced stage indolent NHL. The initial results of R-CHOP induction treatment are reported here.
Methods: 102 patients with Ann Arbor Stage III or IV indolent NHL (follicle center/follicular grade I/II or nodal marginal zone B-cell by REAL; Type B or C by IWF) were enrolled into this open-label, multi-center, community-based, Phase II, single-arm trial. Patients received 6 cycles of standard R-CHOP induction therapy (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, doxorubicin 50 mg/m2 all IV on Day 1; prednisone 100 mg/day Days 1–5). R 375 mg/m2 was given on Day 1 of each cycle except for cycle 1, when it was administered 2–3 days prior to CHOP chemotherapy. Subjects with an ongoing response (CR/CRu or PR) after induction receive maintenance R (4 weekly infusions) within 28 days after the completion of induction and repeated every 6 months for 2 years for a total of 16 maintenance R doses. The primary endpoints were CR/CRu after 6 cycles of induction and the incidence of R infusion-related toxicity during induction and maintenance therapy. Secondary endpoints included overall response rates (ORR), infusion times, serious adverse events (SAE) in induction and maintenance, and rituximab pharmacokinetics in maintenance therapy.
Results: Baseline characteristics were: median age 57y (33.3% ≥60y); 40.2% female; ECOG performance status 0: 70.6%; Ann Arbor stage III: 28.4% and IV: 71.6%. Serum β2-microglobulin and LDH at baseline were above normal in 66.3% and 20.6%, respectively. CR/CRu at the end of induction in 102 patients was 51.0% (ORR 86.3%). 1% had progressive disease (PD) during induction. 2 subjects died during the induction period, both due to SAEs (probable pulmonary embolus, acute respiratory distress). SAEs occurred in 22.5% of subjects during induction with the most common event being febrile neutropenia (7.8%). Grade 3–4 R infusion-related toxicity occurred in 4.9% of patients in cycle 1; this decreased to 1% by cycle 2 of induction. Two subjects discontinued R for infusion-related toxicity. 44% of patients were able to receive their R dose within 3 hrs at cycle 2 and 69.2% of patients at cycle 6.
Conclusion: Patients with advanced stage indolent NHL treated in the community setting with R-CHOP induction tolerate therapy well and have an excellent response rate. The outcomes of maintenance therapy and rituximab pharmacokinetics in maintenance await further follow-up.
MTOR (Mammalian Target of Rapamycin) Inhibition with RAD001 Induces Cell Cycle Arrest in Diffuse Large B Cell Lymphoma (DLBCL) Cells and Sensitizes DLBCL Cells to Rituximab Therapy.
Authors: Wanner Kathrin , Hipp Susanne , Peschel Christian , Decker Thomas 
Published: April 2020

Abstract
Purpose: DLBCL is a common lymphoma entity. Although a significant amount of patients can be cured with modern chemotherapeutic regimen, a substantial proportion of patients die due to progressive disease. Therefore, new therapeutic strategies are clearly needed. Inhibitors of MTOR (mammalian target of rapamycin) represent a new class of antiproliferative drugs with applications as immunosuppressive and anticancer agents. Extensive safety data exist on RAD001 which is already approved as an immunosuppressant in organ transplant recipients.
Methods: We have analyzed the effects of MTOR inhibition in three DLBCL cell lines: SUDHL-4, DB, DOOH-2. Propidium Iodide staining, MTT- and Annexin-V assays were performed to test the effects on viability, cell cycle distribution and apoptosis. Expression of cell cycle regulatory and phosphorylation of p70 s6 kinase and 4-EBP-1 molecules was revealed in western blot experiments
Results: Rapamycin and RAD001 inhibited cell cycle progression in DLBCL cells by inducing a G1 arrest without inducing apoptosis. Phosphorylation of the main targets of MTOR, p70s6 kinase and 4-EBP-1 was reduced in cells cultured in the presence of RAD001.Cell cycle arrest was accompanied by reduced phosphorylation of the Retinoblastoma protein (RB) as well as reduced expression of cyclin D3, E and A in all cell lines. Although the effect of chemotherapeutic agents like Vincristin or Doxorubicin was not enhance by Rad001, Rituximab induced cytotoxicity was augemted in both Rituximab sensitive cell lines.
Conclusion: MTOR Inhibition is a promising therapeutic strategy in DLBCL of the germinal center like subtype by inducing a G1 arrest and augments Rituximab induced cytotoxicity. Therefore, combination of these drugs might be an interesting new therapeutic approach in DLBCL patients.
In Search for the Specificity of Clonal CTL in T-LGL Leukemia - Generation of Soluble LGL-Derived T Cell Receptor.
Authors: Wlodarski Marcin , Howe Evan , Maciejewski Jaroslaw P. 
Published: April 2020

Abstract
Large granular lymphocyte leukemia (LGL) is a clonal lymphoproliferation of CTL associated with immune cytopenias. Hematopoietic progenitor cells may be targets for the immune attack by clonal CTL. The rearranged unique portion of the T cell receptor (TCR), the complementarity determining region 3 (CDR3) of the variable beta chain can serve as molecular marker of the clonal process. Previously, we applied molecular analysis of TCR repertoire to the analysis of CDR3 regions of the variable beta-chain in LGL leukemia and obtained 70 individually specific CDR3 clonotypes. Moreover, using clonotype-specific PCR clonal size was determined. Shared or highly homologous clonotypic CDR3 sequences in some patients provide evidence for the non-random nature of the clonal transformation in LGL and the presence of a common antigenic target. Such an antigen may constitute a drive for the expansion of LGL and its distribution may explain lineage-specificity of the LGL CTL. Identification of the target antigen is essential for understanding of immune-mediated hematologic disorders, including autoimmune cytopenias such as those observed in LGL. T-LGL has inherent advantage of the availability of clonal CTL for experimentation. We hypothesized here that generation of a soluble TCR (sTCR) derived from T-LGL clone could facilitate identification of target cells and analysis of the cellular distribution of peptide presentation. For cloning of sTCR we selected 4 patients with extreme clonal CTL expansion and profound neutropenia. Flow cytometry with VB specific antibodies was applied to determine VB family utilization by the clonal TCR. B-chains were amplified with specific primers so that C region is truncated and the transmembrane and intracellular portions are deleted. Due to the lack of VA specific antibodies, a 5′RACE RT-PCR with a constant A primer was applied. Expanded LGL-specific A chain was determined and cloned in its truncated form as described for B-chain. For example, clonal TCR for patient #1 had a structure VB1/JB1.6/CB1 and VA9-2/JA41*01/CA. To construct a sTCR truncated VA and VB products were subcloned into a dual promoter baculovirus expression vector containing the k and H-chain cassettes (pAC-k-CH3 or alternatively pAC-Fc). This vector allows for expression of a bivalent TCR:Ig protein that can be produced in a baculovirus system. A flow cytometry on fluorochrome conjugated sTCR after co-culture with HLA matched normal bone marrow cells allows for the detection of cells expressing target peptides. Therapeutically, malignant T cell clone-specific sTCR may be used as a potential idiotypic vaccine for T cell lymphomas/leukemias expressing TCR.
Figure Figure
Percentage of CD34 + Cells in a Minimum 500-Cell Count in Bone Marrow Trephines of Patients with Chronic Myeloid Leukaemia Provides the Best Correlation with Aspirate Blast Count.
Authors: Elliot Victoria J. , Marin David , Horncastle Donna , Elderfield Kay , Apperly Jane F. , Lampert Irvin A. , Naresh Kikkeri N. 
Published: April 2020

Abstract
We studied the expression of CD34 in 169 bone marrow trephines of 53 patients with CML in chronic, accelerated and blastic phases. The bone marrow blast count ranged from 0–82% (median: 4.5%). All were receiving imatinib treatment. We aimed to establish which counting method in bone marrow trephines provided the best correlation with the blast count of the corresponding bone marrow aspirate in all phases of the disease. Paraffin embedded sections were stained with the monoclonal antibody QBEND10.
CD34 expression in each marrow trephine was evaluated by three counting methods. The first method, established in our department for several years, expressed the percentage of CD34 positive cells vs. all nucleated cells in a minimum 500-cell count (% CD34+/500 cells). The second recorded the total number of CD34 positive cells in ten high power fields (CD34+/10hpf) using x 40 magnification /numerical aperture 0.65. The third method evaluated the highest number of CD34 positive cells present in a single high power field (CD34+/hpf), this value being taken from the previous 10 hpf count. The two latter methods were employed because they may be more applicable for general use by practicing histopathologists. In addition, counting over 10 hpf provides a much larger sample size than a 500-cell count. CD34 expression in endothelial cells served as a positive internal control.
All three methods showed significant positive correlation with blast count (% CD34+/500 cells: Pearson’s Correlation - 0.723, sig - &lt;0.001; CD34+/10hpf: Pearson’s Correlation - 0.434, sig - &lt;0.001; CD34+/hpf: Pearson’s Correlation - 0.372, sig - &lt;0.001). In conclusion, our previously established method of recording the percentage of CD 34 positive cells vs. all nucleated cells in a minimum 500-cell count provided the best correlation with the blast count.
Total Number of CD34 + Cells Per Ten High Power Fields in Bone Marrow Trephines of Patients with Chronic Myeloid Leukaemia Correlates with Probability of Complete Cytogenetic Response during the First Year of Treatment with Imatinib.
Authors: Elliot Victoria J. , Marin D. , Horncastle D. , Elderfield K. , Howard J. , Apperly J. F. , Lampert I. A. , Naresh K. N. 
Published: April 2020

Abstract
We studied expression of CD34 positive cells in the bone marrow trephines of two groups of patients with CML treated with imatinib. In the first group (n=17), patients went on to achieve sustained complete cytogenetic response during their disease course. In the second group (n =33) complete cytogenetic response was not achieved and patients later developed either accelerated or blastic phase disease. We studied paraffin embedded bone marrow trephines stained with the monoclonal antibody QBEND10 during an eighteen month period following initiation of imatinib therapy and recorded the highest CD34 positive cell counts and aspirate blast counts in three six-month intervals. CD34 positive cells were evaluated using three counting methods. The first method, established in our department for several years, expressed the percentage of CD34 positive cells vs. all nucleated cells in a minimum 500-cell count (% CD34+/500 cells). The second recorded the total number of CD34 positive cells in ten high power fields (CD34+/10hpf) using x 40 magnification /numerical aperture 0.65 and the third method utilised the highest number of CD34 positive cells expressed in a single high power field (CD34+/hpf), the value being taken from the previous CD34+/10 hpf count.
We hypothesised that the overall CD34 positive cell burden and absolute CD34 positive numbers would be more important in predicting the likelihood of complete cytogenetic response and this would be better assessed by volumetric evaluation than percentage calculation relative to other nucleated cells.
CD34 expression in endothelial cells was taken as a positive internal control. We aimed to establish which variable: % blast count, % CD34+/500 cells, CD34+/10hpf and CD34+/hpf provided better correlation with subsequent cytogenetic response to treatment. Values for each variable were dichotomised at the following levels; aspirate blast count &lt;5 and &gt; 5, % CD34+/500 cells &lt; 2 and &gt; 2%, CD34+/10hpf &lt; 60 and &gt; 60 cells and CD34+/hpf &lt; 10 and &gt; 10 cells. Univariate analysis was performed on samples within the first six months, seven to twelve months and thirteen to eighteen months. Only CD34+/10hpf showed significant discriminatory ability throughout the entire eighteen month period (Pearson’s Chi-square 2-sided sig: 0.031, 0.003 and 0.007 in the first six months, seven to twelve months and thirteen to eighteen months samples respectively). By logistic regression, we confirmed that CD34+/10hpf had the best correlation with cytogenetic response during the first year following initiation of imatinib therapy. Larger studies are required to confirm these initial findings and to establish volumetric assessment of CD34 positive cells as a predictor for cytogenetic response.