bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detecting Cryptic Neoplastic B-Cells: Flow Cytometric Analysis of B-Cell Lymphoma Concealed in Polyclonal B-Cells and Other Intense Reactive Components, with Emphasis on Large B-Cell Lymphoma in Fine Needle Aspirate (FNA)/ Body Fluid (BF).
Authors: Wang Endi , Etzell Joan E. 
Published: April 2020

Abstract
Flow cytometry is widely used in the diagnosis of lymphoma. In B-cell lymphoma, light chain restriction (LCR) is especially useful for distinguishing B-cell malignancy from a reactive lymphoid proliferation. Usually the neoplastic B-cell population predominates, and monoclonality is conspicuous as demonstrated by distinct LCR. However, if the specimen contains a large reactive component, especially polyclonal B-cells, a small number of neoplastic B-cells will be buried in the background, thus creating a diagnostic challenge. We retrospectively analyzed three/four-color flow cytometry by examining 12 cases of B-cell lymphoma with a small proportion of neoplastic B-cells hidden in polyclonal B-cells and other intense reactive components. These 12 cases (9 FNA, 1 BF, 2 tissues) comprised 7% of specimens diagnostic or suspicious for lymphoma by flow cytometry at our institution. Eight cases were diffuse large B-cell lymphoma (DLBCL) (18.6% of DLBCL and 27.6% of DLBCL in FNA/BF) while four were lymphoma of other types (3% of non-DLBCL). In all the cases, LCR was obscured by polyclonal B-cells (8/12) or absence of surface immunoglobulin (sIg) in neoplastic B-cells (4/12), and morphology resembled a reactive picture. The clues by flow cytometry prompting further analysis included increased forward angle light scatter(FSC)/side angle light scatter(SSC) (12/12), brighter CD20 (6/12), dim CD20 (1/12), absence of sIg (4/12), and a distinct population of B-cells co-expressing CD10 (2/12), CD5 (1/12), CD2 (1/12), CD23 (4/12) or CD38 (1/12). By backgating/regating suspected subpopulations, the concealed neoplastic B-cells were demonstrated by enriched LCR (5 to10 fold) or tight clustering on FSC/SSC. In conclusion, cryptic neoplastic B-cells, especially diffuse large B-cell lymphoma in FNA/BF, can be extracted, according to their altered immunophenotypic features, from background polyclonal B-cells and reactive T-cells via manipulation of gating strategies.
First-Line Treatment with R-Chop/21 for Patients with Disseminated Diffuse Large B-Cell Lymphoma (DLCL). Results of a Prospective Series of 128 Patients.
Authors: Gonzalez-Barca E. , Domingo-Domenech E. , Ribera J. M. , Briones J. , Salar A. , Gallur L. , Estany C. , Escoda L. , Gardella S. , Hernandez J. A. , Rodriguez J. , Ramila E. , Ramon O. , Garcia-Pinto M. , Español I. , Vivancos P. , Asensio A. , Encuentra M. , de Sevilla A. Fernandez 
Published: April 2020

Abstract
Purpose: to analize the response rate and survival of a series of patients with disseminated large B-cell lymphoma treated with R-CHOP/21 x 8 cycles and to evaluate the prognostic factors and the prognostic value of gallium-67 imaging.
Patients and Methods: 128 patients with DLCL have been prospectively treated with R-CHOP/21 from March 2002 to March 2004, ages between 18 and 85 years. Survival curves were expressed as Kaplan-Meier plots. Prognostic factors were evaluated by the Chi-square test. Survival curves were compared by the Log-rank test.
Results: the median age was 65 years (limits: 27–83), 31% older than 70 years. 59 (54%) patients were males. Gallium imaging was positive at diagnosis in 91%. Clinical presentation of DLCL was: bulky disease: 40%, extra-nodal disease: 66% (³ 2 sites: 33%), B symptoms: 41%, ECOG ³ 2: 53%, LDH&gt;N: 67%, IPI ³ 3: 60%. Chemotherapy cycles received were: &lt;6: 20%; 6: 34%; 8: 46%. The intention-to-treat response was: CR 72%, PR 11%, failures 11%, not evaluable: 6%. Survival, with a median follow-up of 13 months, was: OS: 74%, and EFS: 70%. There are no differences between patients who have been treated with 6 or 8 cycles. EFS of patients with normal gallium imaging at the end of treatment was 90% (p=0.03). EFS was not different between patients older or younger than 70 years. EFS of patients with age adjusted IPI 0 was 100%, IPI 1:70%; IPI 3: 82% and IPI 4: 48%. Three (5%) patients relapsed. Prognostic factors for OS and EFS were: LDH &gt; Normal (p=0.01 y p=0.005 respectively) and ECOG ³ 2 (p=0.0008 y p=0.02).
Conclusion: Rituximab associated with CHOP improves the results of historical series treated with CHOP for patients of all ages, but in patients with age-adjusted IPI=3 results have to be improved with other therapeutic strategies. Normalization of gallium-67 imaging at the end of treatment is predictive of a significantly better EFS. Age is not a prognostic factor in patients who receive the same treatment. For patients with disseminated disease, LDH and ECOG are the only significant prognostic factors.
Decrease of Bone Marrow Fibrosis in Hairy Cell Leukemia (HCL) after 2-CdA Therapy.
Authors: Zak Pavel , Dedic Karel 
Published: April 2020

Abstract
Different degree of bone marrow fibrosis is commonly described in patients with HCL. Hairy cells produce and assemble an insoluble matrix of fibronectin, which is responsible for the bone marrow fibrosis. Production of fibronectin is related to activity of the disease. The aim of our study was to evaluate the change of bone marrow fibrosis before and after 2-CdA therapy.
Patients and methods: 18 patients, who were treated with 2-CdA and achieved complete remission in 6 months, were included in this analyses. Trephin bone marrow biopsy were obtained before therapy and after therapy in 12 and 24 moths. The 3μm thick section were stained with Gomori reticulin stain. Grading of reticulin fibrosis (scale of 0 to IV): grade 0 - reticulin fibers (RF) absent, grade I - scattered RF or foci of fine reticular network (RN), grade II - diffuse fine RN, grade III - diffuse fine RN and scattered thick fibers, grade IV - diffuse thick reticular fibers and presence of collagen fibers.
Results: Before 2-CdA therapy: reticulin fibrosis was grade 0 in 0 p., I in 3p., II in 4p, III in 11p., IV in 0p.. Decrease of reticulin fibrosis in 12 months after 2-CdA was demonstrated in 51% of patients (grade 0 in 1, I in 8p., II in 5p., III in 4p., IV in 0p.), in 24 moths 77% of patients (grade 0 in 2, I in 10p., II in 4p., III in 2p., IV in 0p). Bone marrow fibrosis was increased by one grade in 3p. in 24 months after therapy.
Conclusion: Successful 2-CdA therapy in patient with 2-CdA leads to significant reduction of bone marrow fibrosis.
Poor Survival in ATL Patients Treated with CHOP Chemotherapy.
Authors: Shapira Iuliana , Feldman Joseph , Solomon William B. 
Published: April 2020

Abstract
The survival rate of Adult T-cell leukemia-lymphoma (ATL) patients, especially those who develop the acute leukemic or lymphomas forms, is very poor, and such clonal malignant CD4 expansion remains one of the most severe lymphoproliferations. We conducted a retrospective analysis of 31 consecutive patients diagnosed with HTLV-1 adult T-cell lymphoma-leukemia (ATL), treated at a single institution between 1995–2004. We used analysis of variance examining the mean survival of the patients. The patients were stratified according to the treatment conventional CHOP chemotherapy versus non-CHOP chemotherapy (CVP, no therapy or AZT and interferon). Twenty-two patients have received CHOP chemotherapy and 9 patients have not received CHOP chemotherapy. The mean survival for the entire group of patients was 22.7 weeks. The median survival was 16 weeks (range from 1–74 weeks). Most of the patients were at high IPI risk. (22 patients IPI=4, 8 patients IPI 5 and one patient IPI 3). If the patients presented without hypercalcemia their mean survival was significantly higher than the patients with hypercalcemia, 22.7 weeks versus 16 weeks p&lt;0.05.
The treatment with CHOP chemotherapy significantly improved survival mean 29.3+4.6 weeks versus 8.7 +2.5 weeks, p=0.01. The treatment with CHOP consistently improved survival in patients without hypercalcemia and in those with hypercalcemia 38.8+ 5.4 weeks versus 5.5+ 12.1 and in those with hypercalcemia 20.7+5.2 weeks versus 9.5+6 weeks. CHOP chemotherapy helped both groups of patients those who presented with hypercalcemia and those without hypercalcemia although there is a suggestion that it is less effective in patients with hypercalcemia. In this small retrospective study, no significant association was found between survival and presence or absence of pleural effusion, ascites, extensive liver or skin involvement. Hypercalcemia should be considered a poor prognostic factor in ATL patients.
Prospective multi-institution clinical trials are crucial to determine the most effective treatment regimens that will continue to improve survival rates in this aggressive disease.
Granulocyte Colony Stimulating Factor Preferentially Causes Proliferation of Pre-Existing Monosomy 7 Cells in Aplastic Anemia and Myelodysplastic Syndrome Because of Abnormal Truncated GCSF-Receptors on These Cells.
Authors: Sloand Elaine M. , Ramkissoon Shakti , Mainwaring Lori , Barrett John , Young Neal S. 
Published: April 2020

Abstract
Administration of granulocyte colony stimulating factor (GCSF) has been linked to development of monosomy 7 in some patients with aplastic anemia (AA) and congenital neutropenia. We assessed the effect of GCSF on monosomy 7 to determine if this chromosomal abnormality developed de novo or if GCSF simply favored expansion of a pre-existing clone. Bone marrow mononuclear cells (BMMNC) were co-cultured for 14 days with pharmacological doses of GCSF and examined by fluorescent in situ hybridization (FISH). No karyotypically healthy control, AA, or myelodysplastic syndrome (MDS) bone marrow showed development of monosomy 7. In BMMNC cultures from thirteen patients with MDS and monosomy 7, all developed substantial increases in numbers of monosomy 7 cells after prolonged exposure to GCSF. Experiments on stored AA samples obtained six months prior to the development of abnormal karyotype showed monosomy 7 on FISH ,with expansion of that clone on co-culture with GCSF. GCSFR mRNA was increased in BM from monosomy 7 patients as measured by real time PCR, and monosomy 7 cells expressed more GCSFR on the cell surface than did normal cells. As a truncated GCSFR isoform is associated with a hyperproliferative response to G-CSF and prolonged activation of signal transducer and activator of transcription (STAT) complexes, we sequenced the GCSFR DNA of monosomy 7 cells and measured the expression of the truncated GCSFR mRNA relative to full length GCSFR in patients with monosomy 7. While genomic GCSFR DNA showed no abnormalities, mRNA demonstrated increased proportions of the truncated isoform IV in all six patients tested. We examined GCSF-mediated GCSFR signal transduction of the Jak/Stat system in monosomy 7 CD34 cells. STAT-1 was increased and the STAT 5: STAT 3 rato was increased by ten-fold in all patients with monosomy 7 compared to normals and to MDS with normal cytogenetics. In conclusion, pharmacologic doses of GCSF appear to increase the proportion of monosomy 7 cells; this heightened sensitivity to GCSFmay be related to altered amounts of the truncated form of the receptor, with changes in GCSF signal transduction resulting in expansion of the monosomy 7 clone.
A Multi-Center, Open-Label, Non-Randomized Phase II Study of Elsamitrucin (SPI-28090) in Patients with Relapsed or Refractory Non-Hodgkin’s Lymphoma (NHL).
Authors: Mohrbacher Ann , Sanani Shamel , Irwin David , Espina Byron M. , Madrid Catherine , Lenaz Luigi , Rosales Rosamerlinda 
Published: April 2020

Abstract
Background: Elsamitrucin (SPI-28090) is a novel actinomycete fermentation product that induces single strand breaks in DNA and inhibits topoisomerase I and II. A previous Phase II trial showed evidence of promising anti-tumor activity with an acceptable toxicity profile in patients with relapsed/refractory NHL. The objectives of the current trial are to confirm and validate these earlier findings and to determine if elsamitrucin is efficacious in a particular pathologic NHL subtype(s).
Methods: Patients with relapsed or refractory NHL, indolent or aggressive, excluding HIV and Burkitt’s lymphoma were eligible for the study. Patients must have had measurable disease. All patients were given weekly Elsamitrucin 25 mg/m2 i.v. administered over 5–10 minutes x 8 weeks. All patients were treated until disease progression or toxicity. Treatment was given as an outpatient.
Results: To date, 8 patients (5 males/3 females) have been enrolled on study with a median age of 70 years (range 40–83). Pathologies include diffuse large B-cell (4), diffuse mixed large B-cell (1); mantle cell (1), follicular grade 2 (1) and aggressive T-cell lymphoma (1). All patients had stage III or IV disease. The median number of prior chemotherapy regimens received was 5 (range of 2–9). A median of 4 doses (range 2–11) of Elsamitrucin have been administered to date. Myelosuppression was absent or mild in majority of the patients except for one patients that had grade 4 ANC and grade 3 thrombocytopenia. All non-hematologic toxicities were mild to moderate in severity, limited to nausea and vomiting. There were no reported liver function toxicities which was the dose limiting toxicity noted on prior Phase I trials. No drug related serious adverse events have been reported. Five patients are evaluable for response; 3 are too early to evaluate. One patient with stage IV mantle cell lymphoma who had received five prior chemotherapy regimens and radiation therapy has had a confirmed partial response after eight weeks of treatment, lasting for 8+ weeks. Another patient had unconfirmed partial response. One patient had mixed response and the other 2 had progressive disease.
Conclusions: Elsamitrucin preliminarily appears to be safe and well tolerated in this patient population. There has been some early evidence of anti-tumor activity. Accrual is ongoing and further update will be presented at the meeting.
SDX-105 (Treanda™), Active in Non-Hodgkin’s Lymphoma Cells, Induces the Mitotic Catastrophe Death Pathway.
Authors: Leoni Lorenzo M. , Niemeyer Christina , Bendall Heather , Reifert Jack , Bailey Brandi 
Published: April 2020

Abstract
SDX-105 (Treanda™) is an alkylating agent with a distinct mechanism of action that has been shown to be active in clinical trials in NHL and CLL patients refractory to traditional DNA-damaging agents. SDX-105 induces unique changes in gene expression in NHL cells and displays a lack of cross resistance with other 2-chloroethylamine alkylating agents. Quantitative PCR analysis confirmed that the G2/M checkpoint regulators Polo-like kinase 1 (PLK-1) and Aurora A kinase (AurkA) are down-regulated in the NHL cell line SU-DHL-1 after 8 hours of exposure to clinically relevant concentrations of SDX-105. No changes in these same genes were observed when cells were exposed to equi-toxic doses of chlorambucil or an active metabolite of cyclophosphamide. Because our previous studies demonstrated that SDX-105 treatment can activate apoptotic cell death pathways, we examined the ability of SDX-105 to induce cytotoxicity in cells unable to undergo ‘classical’ caspase-mediated apoptosis. Multi-drug resistant MCF-7/ADR cells and p53 deficient RKO-E6 colon adenocarcinoma cells were exposed for two or three days to either 50 μM SDX-105 alone or 50 μM SDX-105 and 20 μM pan-caspase inhibitor zVAD-fmk. Although zVAD-fmk was able to inhibit SDX-105 induced increases in Annexin-V-positive cells, microscopic analysis of nuclear morphology using the DNA stain DAPI in cells treated with either SDX-105 alone or in combination with zVAD-fmk showed increased incidence of micronucleation. Multi/micro-nucleation and abnormal chromatin condensation are both hallmarks of mitotic catastrophe and have been observed in tumor cells exposed to microtubule-binding drugs such as the vinca alkaloids and taxanes. Activation of mitotic catastrophe may amplify the cytotoxicity of SDX-105 and its activity in tumor cells where classical apoptotic pathways are inhibited. This may explain, at least in part, the potent anti-tumor activity of SDX-105 in tumor cells refractory to conventional 2-chloroethylamine DNA-damaging agents. Additional studies are ongoing to further elaborate the role of mitotic catastrophe in SDX-105’s mechanism of action. The capacity to induce mitotic catastrophe may explain the anti-tumor activity of SDX-105 in chemotherapy relapsed and resistant patients.
Predicting the Risk of Neutropenic Complications and Reduced Dose Intensity in Patients with Malignant Lymphoma: Results from a Prospective Study.
Authors: Dale David C. , Crawford Jeffrey , Wolff Debra A. , Poniewierski Marek S. , Culakova Eva , Lyman Gary H. ,   for the ANC Study Group
Published: April 2020

Abstract
Background: Chemotherapy-induced neutropenia is frequently associated with neutropenic complications resulting in reduced relative dose intensity (RDI) potentially compromising clinical outcomes. Retrospective analyses have identified several factors but are limited by variable reporting and missing data.
Methods: Results from an ongoing prospective study of cancer chemotherapy patients based at more than 100 randomly selected US centers are reported. Demographic, clinical and treatment-related variables were obtained on 345 patients with malignant lymphoma (ML). Data are presented on the first 265 patients completing at least one cycle of chemotherapy. Planned and unplanned reductions in relative dose intensity (RDI) were estimated along with the risk of neutropenia and febrile neutropenia (FN) over the first four cycles of treatment are presented.
Results: Patients with Hodgkin’s disease (HD; N=43) received five different regimens including ABVD (84%) while patients with Non-Hodgkin’s lymphoma (NHL; N=222) received 33 different regimens the most common of which was CHOP (53%). Neutrophil nadirs &lt;1000 were reported in 54% of subjects, two-thirds of which occurred during the 1st cycle of treatment. One or more episode of FN occurred in 18% (29% HD; 16% NHL) with 60% in cycle 1. Overall average RDI was 90% with 25% receiving &lt;85%. Differences in delivered RDI were found based on practice setting (P=.07), geographic location (P=.007), age (P=.007), ECOG performance status (P=.065) and peripheral vascular disease (P=.021). Significant reductions in planned RDI but not unplanned RDI were observed for increasing age (P=.008). Over the first three cycles of treatment, patients with HD experienced a greater risk of FN (29%) than patients with NHL (16%) (P=.042). Correspondingly, HD patients received an average RDI of 93% with two-thirds of reductions unplanned compared to NHL patients who received an RDI of 90% with two-thirds were planned reductions (P=.03). In multivariate logistic regression analysis, significant predictors of reduced RDI were age, chemotherapy regimen, peripheral vascular disease and cerebrovascular disease (P&lt;.001; R2=.435).
Conclusions: This prospective study confirms previous retrospective surveys that showed a substantial proportion of patients with ML receive reduced RDI potentially compromising clinical outcomes. Predictive models based on the risk factors identified should enable clinicians to target supportive care efforts in a more cost-effective manner.
A New Mechanism of Communication between Stem Cells Involving Vertical Transfer of mRNA by Its Intracellular Delivery within Membrane-Derived Microvesicles.
Authors: Ratajczak Janina , Miekus Kasia , Kucia Magda , Dvorak Petr , Ratajczak Mariusz 
Published: April 2020

Abstract
Membrane-derived microvesicles (MV) are spherical membrane fragments that are released from eukaryoctic cells upon their activation. We reported that MV transfer cell membrane-derived receptors between cells and/or directly stimulate target cells by the ligands expressed on their surface (Blood2001:98;3143; AIDS2003:17;33). Recently we observed that embryonic stem cells (ES) shed MV into culture media and that co-culture of ES with hematopoietic stem cells enhances the latter’s expansion. Similarly, co-culture of ES with somatic cells induces their dedifferentiation. Although the mechanisms responsible for these phenomena are not clear, we hypothesized that ES-derived MV (ESMV) could play an important role. To address this we isolated ESMV from murine (ES-D3) and two human (CCTL-12 and CCTL-14) embryonic cell lines and focused on molecules that may be responsible for epigenetic changes of cells co-cultured with ESMV. We found that ESMV as compared to the ES cells from which they originated are highly enriched in mRNA. This increase in mRNA content suggested a segregation mechanism that enriches ESMV in cytoplasmatic mRNA during their shedding from ES. Using real-time RT-PCR we found that ES-MV are highly enriched (x 103−107) in mRNA for early transcription factors that regulate self-renewal of stem cells (e.g., Oct-4, Gata-4, Rex-1 and Nanog). Intrigued by these observations we hypothesized that ESMV could penetrate the cells and deliver ES-derived mRNA and that this could be a novel mechanism for reprogramming target cells. Supporting our hypothesis we found (i) by confocal microscopy that ESMV do indeed penetrate the cells (e.g., BM-derived CD34+ cells or ES themselves), and (ii) by Western blot analysis that mRNA delivered to the target cells by ESMV is not trapped in the endosomal compartment but is delivered to the cytoplasm and actively transcribed into appropriate proteins (e.g., Oct-4). Based on these data we postulate that MV may transfer mRNA between the stem cells and play a role in vertical transfer of genetic information. Our recent similar data on MV derived from other cell types (normal and malignant) lend further support to this novel hypothesis and mechanism of cell to cell signaling/communication.