bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unbalanced Chromosome Rearrangements Involving the 20q11.2 Region in Myeloid Malignancy.
Authors: Howard-Reeves Julie , Valgañón Mikel , Mazzullo Helen , Grace Colin , Campbell Lynda , Nacheva Elisabeth 
Published: April 2020

Abstract
Deletions of the long arm of chromosome 20 (del 20q) are a recurring abnormality associated with haematological malignancy (Mitelman 1995, Sandberg 1991, Heim and Mitelman,1995, Asimakopoulos & Green, 1996). The 20q deletions are seen in approximately 10% of the cases with PV and IMF, 4% of cases with myelodyspalstic syndrome (MDS) (Fenaux et al., 1996), 1–2% of patients with acute myeloid leukaemia (AML) as well as other myeloproliferative disease (MPD) (Bench et al. 2000). Deletions of chromosome 20q are well recognised in myeloid disorders and have been seen alone or as part of a complex karyotype (Johansson et al, 1993, Schoch et al 2002). A common deleted region (CDR) of chromosome 20q was observed by fluorescence in situ hybridization (FISH) mapping within 20q11.2/q12 region (Roulston et al., 1993, Bench et al, 2000). The breakpoints within this CDR have been shown to be heterogeneous (Asimakopoulos et al., 1994) and more recently a considerable overlap of this region has been observed in myeloid malignancy (Douet-Guilbert et al, 2008). Previous studies have been performed on cases with simple deletions of chromosome 20q as assessed by G-banding and confirmed by FISH, to be interstitial and no other rearrangements involving 20q have been reported so far. Here we present 43 patients with non-random translocations of chromosome 20q that appear to have a common breakpoint within the 20q11.2 region. Karyotypically some of the cases presented with the classical del(20q) morphology while in other cases translocations were identified, such as t(1;20)(q21;q11.2). Of these cases 44% have been shown to carry an unbalanced chromosome rearrangement with loss of material at the region of the breakpoint at 20q11.2 both with and without loss material on the partner chromosome. An example of the latter is the rearrangement t(17;20)(p13;q11.2) where 20q11.2 loss was accompanied by a p53 deletion (17p13). FISH mapping located the 20q11.2 breakpoint to be within the BAC clone RP1-1J6, which covers only the sequences of one gene, Topoisomerase 1 (TOP1). This gene is reported to form a fusion with NUP98 in therapy related MDS. Indeed we confirmed by FISH the presence of this fusion in 6 of our cases, all of which carried the t(11;20)(p15;q11.2). Unexpectedly, the rest of the cases also showed breaks within the same BAC clone, where the partner chromosomes were Yp11, 1q21, 17p11 and 21q11. These findings highlight the consistent involvement of the TOP1 gene at 20q11.2 in rearrangements occurring in MDS and MPD.
Protein Kinase C-Epsilon Is An Important Component of the Lyn Kinase Signaling Pathway in the Apoptotic Resistance of B- Chronic Lymphocytic Leukemia Cells.
Authors: Velcheti Vamsidhar , Tamma Srikanth , Larned Zoe L , Fuloria Jyotsna , Li Li , Rodwig Francis R , Cole John T. , Samaniego Felipe , Prakash Om 
Published: April 2020

Abstract
Although several mechanisms of apoptotic defects have been implicated in B- chronic lymphocytic leukemia (CLL) cells, the exact signaling pathways underlying these defects remain unresolved. Lyn kinase and protein kinase C (PKC)-epsilon play a critical role in B-cell antigen receptor signaling. They are also known to be negative regulators of apoptosis, and are linked to chemo-resistance. Because activation of PKCs results in their translocation from the cytosol to distinct subcellular locations in which they perform their specific functions, we examined the role of Lyn kinase in the cellular localization of PKC-epsilon in B-CLL cells and its link to the apoptotic defects. Untouched peripheral blood B-CLL cells or nonmalignant B cells were isolated from PBMCs of B-CLL patients or normal blood donors. Cytoplasmic and nuclear fractions of B-CLL cells and nonmalignant cells were prepared and examined for PKC-epsilon localization by Western blot analysis. Unlike the cytoplasmic localization in nonmalignant cells, a large fraction of PKC-epsilon in B-CLL cells was located in the nuclear fraction. Nuclear localization of PKC-epsilon in B-CLL cells was linked to the transcriptional activation of the antiapoptotic genes such as Mcl-1, XIAP, and Bcl-2, as well as NF-kappaB activation and VEGF production., both strongly implicated in the apoptotic resistance of B-CLL cells. Treatment of B-CLL cells for 16-20 hours with 10 micromolar Lyn-specific inhibitor peptide targeting a unique interaction site within Lyn (Cancer Res.2004;64:1058) resulted in redistribution of PKC-epsilon from the nuclear to the cytoplasmic fraction, decreased expression of the antiapoptotic genes as much as 60%, and decreased the viability of the leukemic cells. In addition, the Lyn-specific inhibitor peptide induced more than 50% inhibition of NF-kappaB p65 nuclear translocation and VEGF production in B-CLL cells but not in nonmalignant B cells. Similar results were obtained when a selective inhibitor peptide of PKC-epsilon translocation but not the negative control peptide was used. Our results suggest that PKC-epsilon is a downstream target of Lyn kinase, and that inhibition of PKC-epsilon nuclear translocation may have therapeutic potential by targeting Lyn kinase signaling pathway for the treatment of B-CLL.
Rituximab, Fludarabine, Cyclophosphamide, and Mitoxantrone (R-FCM) Is a Highly Active Chemoimmunotherapy Regimen for Chronic Lymphocytic Leukemia.
Authors: Bosch Francesc , Abrisqueta Pau , Villamor Neus , Terol Maria Jose , Ribera Josep-Maria , Gonzalez-Barca Eva , Gonzalez Marcos , Abella Eugenia , Delgado Julio , Gonzalez Yolanda , Ferrer Secundino , Carbonell Felix , Escoda Lourdes , Jarque Isidro , Monzo Encarnacion , Muntañola Ana , Salamero Olga , Montserrat Emili 
Published: April 2020

Abstract
The addition of monoclonal antibodies to chemotherapy has significantly improved treatment of patients with CLL. Based upon the excellent results obtained with our chemotherapy-only regimen fludarabine, cyclophosphamide and mitoxantrone (FCM) (Bosch et al. Clin Cancer Res, 2008) we have build up a new chemoimunotherapy combination, R-FCM (rituximab plus FCM). In November 2005 we initiated a multicentric phase II clinical trial that includes R-FCM as initial treatment followed by a maintenance therapy phase consisting of rituximab (375 mg/m2 every there months for 2 years). We report here the final results of the initial phase of this study, namely R-FCM treatment. From November 2005 to November 2007, 72 patients under the age of 70 with active CLL according the NCI and IWCLL criteria (Cheson et al. Blood, 1996; Hallek et al. Blood, 2008) were treated. Patients received rituximab 500 mg/m2 on day 1 (375 mg/ m2 in the first cycle), fludarabine 25 mg/ m2 i.v. on days 1 to 3, cyclophosphamide 200 mg/ m2 on days 1 to 3, and mitoxantrone 6 mg/ m2 i.v. on day 1, given at 4-week intervals up to six cycles. Treatment outcome was correlated with clinical and biological parameters. Minimal residual disease (MRD) was evaluated by four-color flow cytometry (Rawstron et al. Leukemia, 2007). Median cycles of R-FCM administered were 5 (range, 3–6), with 91% of patients completing all planed treatment. Response was evaluated three months after finishing therapy. Altogether, the overall response, MRD-negative CR, MRD-positive CR, and PR rates were 93%, 46%, 36%, and 10%, respectively. Variables correlated with a lower CR rate were del(17p) (25% CR) and increased β2-M serum levels (72% CR). No differences in response were observed according to the age of the patients. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Treatment-related mortality was 1%. With a median follow up of 24 months no cases of secondary MDS/AML have been observed.. Although based in two different phase II studies that preclude a completely valid statistical comparison, the CR rate obtained with R-FCM (82%, of which 46% MRD-negative CRs) favorably compares with that achieved with FCM (CR 64%, MRD-negative CRs 38%). In summary the 82% CR rate obtained with R-FCM is among the highest ever reported for any form of therapy for CLL. Both high β2-M serum levels and del(17p) predicted lower CR rate. Treatment toxicity was acceptable and manageable. Based on these results, R-FCM warrants further investigation, particularly in randomized clinical trials.
Randomized Comparison of Cladribine Plus Cyclophosphamide with Fludarabine Plus Cyclophosphamde in Untreated Patients with Chronic Lymphocytic Leukemia: Report of the Polish Adult Leukemia Group (PALG-CLL3).
Authors: Robak Tadeusz , Blonski Jerzy Z , Jamroziak Krzysztof , Gora-Tybor Joanna , Stella-Holowiecka Beata , Konopka Lech , Ceglarek Bernadeta , Warzocha Krzysztof , Seferynska Ilona , Kloczko Janusz , Piszcz Jaroslaw , Calbecka Malgorzata , Kostyra Aleksandra , Dwilewicz-Trojaczek Jadwiga , Wiater Elzbieta , Dmoszynska Anna , Kowal Malgorzata , Zawilska Krystyna , Grzywacz Alina , Hellmann Andrzej , Mital Andrzej , Zdunczyk Andrzej , Dybowicz Jacek , Kuliczkowski Kazimierz , Potoczek Stanislaw , Skotnicki Aleksander , Nowakowska-Domagala Maria , Lewandowski Krzysztof , Sulek Kazimierz 
Published: April 2020

Abstract
Purine nucleoside analogues, cladribine(2-CdA) and fludarabine (FA), especially combined with cyclophosphamide (CY) are potent cytotoxic drugs for the treatment of chronic lymphocytic leukemia (CLL). In this randomized study we aimed to establish whether combination of 2-CdA plus CY (CC) with FA plus (FC) provide similar benefit to previously untreated patients with CLL. The trial was started in January 2004 and the recruitment was ended in May 2007. The study primary endpoints were overall response (OR) and complete response (CR). The secondary endpoints included progression free survival (PFS), overall survival (OS), minimal residual disease negativity (MRD/-/) and treatment related toxicity. Eligible patients were randomly assigned to receive 6 courses of either 2-CdA 0.12 mg/kg/d i.v. + CY 250 mg/m2/d i.v. or FA 25 mg/m2/d i.v. + CY 250 mg/m2/d, both combinations for 3 consecutive days. The treatment response and toxicity were evaluated according to NCI-WG guidelines. MRD was evaluated in patients with CR using four-color flow cytometry assay.
There were no significant difference in the rates of OR, CR, MRD negativity, grade 3/4 neutropenia, thrombocytopenia and infections. PFS and OS were also similar in both groups. In conclusion, CC and FC regimens are similarly active and toxic in previously untreated CLL, however trend of longer OS in CC group is observed.
Characteristic CC arm FC arm P value Pts enrolled 212 211 - Pts evaluated 184 187 - No of courses (median, range) 6 (2–6) 5 (2–6) 0.56 OR (%) 163 (88.6) 159 (85.0) 0.31 CR (%) 86 (46.7) 91 (48.7) 0.43 MRD/–/ (%) 33 (68.8) 44 (72.1) 0.70 PFS (median, years) 2.195 2.361 0.86 Thrombocytopania gr 3/4 (%) 23 (12.6) 22 (11.6) 0.77 Neutropenia gr 3/4 (%) 39 (21.4) 43 (22.8) 0.76 Infection gr 3/4 (%) 53 (29.1) 54 (28.6) 0.91 OS (median, years) 4.066 2.531 0.10 Death (%) 37 (20.2) 53 (27.9) -
Retention but Significant Reduction of BCR-ABL Transcript in Hematopoietic Stem Cells in Chronic Myelogenous Leukemia after Imatinib Therapy.
Authors: Abe Akihiro , Minami Yosuke , Kitamura Kunio , Hayakawa Fumihiko , Nomura Yuka , Murata Makoto , Katsumi Akira , Kiyoi Hitoshi , Jamieson Catriona H.M. , Wang Jean Y.J. , Naoe Tomoki 
Published: April 2020

Abstract
Chronic myeloid leukemia (CML) is effectively treated with imatinib mesylate (IM), a small molecule inhibitor of the BCR-ABL tyrosine kinase that is expressed in the entire hematopoietic compartment including stem cells (HSC) and progenitors in CML patients. While IM induces disease remission, it does not appear to eradicate BCR-ABL-positive stem cells. We analyzed the HSC/Progenitors profiles using fluorescence-activated cell sorting (FACS) and investigated the minimal residual disease (MRD) in HSC and myeloid progenitors from patients with CML chronic phase (CP) after IM-therapy. HSC identified as CD34+CD38–Lin–, were separated to Thy-1+ (HSC/Thy-1+) and Thy-1– (HSC/Thy-1–) cells. HSC/Thy-1+ (CD34+CD38–Thy-1+Lin–), HSC/Thy-1– (CD34+CD38–Thy-1–Lin–), common myeloid progenitors (CMP: CD34+CD38+IL-3Rα+CD45RA–Lin–), granulocyte–macrophage progenitors (GMP: CD34+CD38+IL-3Rα+CD45RA+Lin–), and megakaryocyte–erythroid progenitors (MEP: CD34+CD38+IL-3Rα–CD45RA– Lin–) were isolated by cell sorting and MRD was quantified with real-time polymerase chain reaction detecting BCR-ABL transcripts. FACS analysis revealed higher levels of the HSC/Thy-1– cells and progenitors (CD34+CD38+Lin– cells) in bone marrow from patients with CML CP than in normal bone marrow although the level of long-term HSC in CML CP was similar with normal bone marrow. After the IM-therapy the proportion of progenitor pools (CD34+Lin– cells) within Lin– were remarkably reduced, especially that of HSC/Thy-1– cells and progenitor cells. The proportion of MEP was increased and that of GMP was decreased in bone marrow from patients with CML CP as compared with their normal counterparts. BCR-ABL positive progenitors in bone marrow were eradicated within 12 month in 5 out of 9 patients. BCR-ABL positive cells, however, remained in the stem cell population. They were positive even after achieving undetectable levels of BCR-ABL transcript in total RNA isolated from the bone marrow. The ratio of BCR-ABL to BCR was significantly decreased with the continuation of imatinib, however the retention of BCR-ABL-positive cells was observed in HSC/Thy-1– or HSC/Thy-1+ populations except one out of 9 cases. These results indicated retention but significant reduction of BCR-ABL positive stem cells in CML during IM-therapy. They also implicate that the sorted and purified stem cells are useful for more sensitive quantification of BCR-ABLpositive MRD.
Pulmonary Function in Pediatric survivors of non-Malignant Disorders after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Motosue Megan S , Inaba Hiroto , Pan Jianmin , Stokes Dennis C. , Srivastava Deo Kumar , Kasow Kimberly A. , Hale Gregory A. , Leung Wing 
Published: April 2020

Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is used to treat children with non-malignant disorders. As the number of survivors of non-malignant disorders after allogeneic HCST rises, monitoring late sequelae becomes increasingly important. However, no studies have solely targeted this population especially on pulmonary function. We therefore performed a long-term prospective study of pulmonary function in 38 pediatric survivors of non-malignant disorders after allogeneic HCST, including aplastic anemia (n = 15), sickle cell anemia (n = 13), immunodeficiency syndromes (n = 8), Hurler syndrome (n = 1), and osteopetrosis (n = 1). A total of 260 pulmonary function tests were conducted on the patients. Older age of recipients was associated with poorer pulmonary function; lower ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC; p &lt; 0.0001); lower percent predictives in FEV1 (p = 0.0178), forced expiratory flow (FEF25–75%; p &lt; 0.0001), FVC (p = 0.0299), and diffusion capacity corrected for hemoglobin (DLCOcorr; p = 0.0079); higher ratio of residual volume and total lung capacity (RV/TLC; p = 0.0193); and higher percent predictives in RV (p = 0.0308) and functional residual capacity (FRC; p = 0.0489). The following percent predictive values declined over time (median follow-up: 8 years): FEF25–75% (p = 0.0064), RV (p = 0.0134), FRC (p = 0.003), FVC (p = 0.0004), TLC (p = 0.0248), and DLCOcorr (p = 0.0077). Also, busulfan use was associated with lower FEV1 (p = 0.026), FVC (p = 0.0194), and DLCOcorr (p = 0.0105). This study underscores the need to monitor risk-adapted long-term lung function and provide early interventions in this vulnerable population, especially for those who received HSCT at an older age or had been administered busulfan.
Long Term Molecular Remissions after Autologous Haematopoietic Stem Cell Transplant in Follicular Lymphoma.
Authors: Lissandre Séverine , Vourch Patrick , Desbois Isabelle , Benboubker Lotfi , Dartigeas Caroline , Delain Martine , Senecal Delphine , Colombat Philippe , Gyan Emmanuel 
Published: April 2020

Abstract
Background and aim of the study: Autologous stem cell transplant (ASCT) has been shown to be an effective treatment for first-line and relapsed follicular lymphomas (FL). But no long term molecular remission was described. The aim of this retrospective study was to determine the clinical and molecular outcome of patients with FL who received ASCT during a 12-year period.
Method: All patients who underwent ASCT for first-line or relapsed FL between January 1992 and December 2004 were included. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method and cumulative incidence of nonrelapse mortality (NRM), with relapse as a competing event, by Fine and Gray method.
Patient characteristics: Seventy-one patients with a median age of 45 years and a median follow-up of 108 months were analysed. The majority were of the subtype grade 1 (57 %), had a high tumour burden (50 %) and were treated in firstline (52 %). After an anthracyclin-based induction regimen, 12 patients were in first complete remission (CR), 25 in first very good partial response (VGPR), 8 in second CR and 26 in second VGPR. They received BCNU, Etoposide, Aracytine, Melphalan (BEAM in 58 %) or Cyclophosphamide, total body irradiation (42 %) as conditioning for the ASCT. The majority of them received an unpurged graft (58%).
Results : Thirty-eight patients were alive, 24 without progression between 4 and 12 years; 31 patients had died, 7 without progression. A total of 38 patients (55 %) developed recurrent lymphoma. Median OS was estimated at 8 years and 4 months. The ten-year PFS and the ten-year OS were 33 % and 47 %, respectively and the tenyear molecular PFS was 37 %. There was an apparent plateau on the remission duration curve at 32 % at 72 months and on the molecular remission duration curve at 37 % at 80 months. A plateau on the OS curve seemed to emerge at 41 % from the tenth year. Patients who received a purged graft had better OS and better PFS (median OS not reached versus 50 months, p = 0.08; median PFS not reached versus 22 months, p = 0.035) Three patients developed a secondary neoplasm and two a secondary myelodysplastic syndrome. The 10-year non-relapse mortality (NRM) was 20 %.
Conclusion : This long follow-up study showed a plateau on the PFS and on the molecular PFS curves, suggesting that a selected group of patients might be cured by ASCT.
Increase in Proportion of Th-17 Lymphocytes in Blood Heralds Overt Acute Graft Versus Host Disease in HSCT Patients.
Authors: Lange Andrzej , Dlubek Dorota , Jaskula Emilia , Drabczak-Skrzypek Daria , Sedzimirska Mariola , Lange Janusz 
Published: April 2020

Abstract
IL-17 is involved in chronic inflammation and autoimmunity, this cytokine producing cells are well characterized in the mouse model. In man, situation is more complex due to the genetic variability, co-morbidities and environmental factors influencing the immune response. In patients post HSCT alloreactivity with the presence of aGvHD is a major factor affecting the outcome of transplantation. Understanding of the role of cells involved in regulation of the immune system is crucial for the treatment tailoring to favour tolerance but not making the recipient more prone to opportunistic infections and leukaemia relapse.
In this study 27 patients post HSCT were investigated for the presence of regulatory cells and those producing IFNgamma and IL-17 in blood. Blood was collected at the time of haematological recovery or when the first clinical symptoms of aGvHD became apparent and then in one week intervals until +60 day post transplantation. PBMC were stimulated for 4 hrs with BD Leukocyte Activation Cocktail in the presence of Golgi Stop (BD, Erembodegen, Belgium) and then stained extracellularly with anti-CD4, permeabilized with Fixation/Permeabilization Concentrate and Diluent (eBioscience, San Diego, CA) and finally stained with anti-IFNgamma (BD), anti-IL-17 (eBioscience) anti FoxP3 (eBioscience). CD4+ cells subpopulations were analysed according to the expression of the stained features.
It was found:
FoxP3+CD4+ cells were in higher proportions in pts with aGvHD (results from all time-points taken together) (9.93%±0.61 vs 8.2%±0.50, n=98, p=0.040, U Mann-Whitney test)
IFNgamma producing CD4+ lymphocytes were in higher proportions (0,34 vs 0.14, ns) in blood samples taken from patients lacking as compared to those having aGvHD.
CD4+IL-17+ lymphocytes proportions increased from 1.39%±0.42 to 5.33%±2.45 (p=0.04, Wilcoxon Test for pairs) one week before aGvHD.
Notably, at the time of full blown aGvHD the proportions of CD4+IL-17+ cells were lower as compared to the results of previous measurements (0.74%±0.29, p=0.008, Wilcoxon Test for pairs). Taking all results together the proportion of CD4+IL17+ lymphocytes were lower in patients having as compared to those lacking aGVHD (0.93%±0.27 vs 1,53%±0,41, p=0.05, U Mann-Whitney test).
It appears that:
FoxP3 positive cells expand during aGvHD likely as a response to alloreactive stimulation.
INFgamma+ CD4+ cells benefit the course post HSCT making the patients less susceptible to aGvHD.
CD4+IL17+ cells are likely involved at the early stage of aGvHD patho-mechanism heralding the clinical manifestation of this complication, but then they disappear from blood, possibly being marginalized in the inflamed tissues.
Apoptosis-Independent Activation of Caspase-3 in CD34–Positive (CD34+) Mobilized Cells.
Authors: Augeul-Meunier Karine , Crampé Carine , Farce Philippe , Mounier Christiane , Guyotat Denis , Campos Lydia 
Published: April 2020

Abstract
G-CSF mobilized peripheral blood CD34+ cells are now the preferred and major source of hematopoietic stem and progenitor cells harvested for both autologous and allogeneic transplantation. Several mechanisms, like SDF-1/CXCR4 interactions or degradation of adhesion molecules by proteolytic environnement, are involved in the mobilization process. However this phenomenon is still partially understood. Gene expression analysis has identified an overexpression of the caspase-3 gene in CD34+ mobilized cells, compared to CD34+ from normal bone marrow. Caspase-3 is the main effector of the terminal phase of apoptosis. However recent studies have provided evidence of its implication in non apoptotic cellular processes, such as differentiation, migration and cytoskeleton modelling. We evaluated by multicolour flow cytometry the expression of activated caspase-3 in G-CSF mobilized CD34+/CD45+ cells from blood (n=16), and from apheresis products (n=10). CD34+/CD45+ cells from normal bone marrow (n=4) served as control. Caspase-3 activity on fluorescent substrate (PhiPhiLux method) and apoptosis (Annexin V assay) were also evaluated. Finally we analysed the expression of anti apoptotic proteins Bcl-2, Bcl-Xl, and of Heat Shock Proteins HSP27, HSP70 and HSP90 in the same cell population. There was no significant difference for apoptosis between mobilized and bone marrow CD34+ cells (26% versus 33% apoptotic cells). Activated caspase-3 levels were significantly higher in mobilized CD34+ cells (mean fluorescence intensity 3.64 fold higher). This was consistent with cleavage of caspase-3 substrate observed in mobilized cells, but not in bone marrow CD34+ cells. An increased expression of HSP90 (of which caspase-3 is a client protein) was observed in peripheral CD34+ cells, but there was no variation of BCl-2 and Bcl-Xl expression. Our results show an activation of caspase-3 in the mobilized peripheral blood CD34+ cells, which appears to be independent of apoptosis induction. The role of this activation and possible control by HSPs warrants further analysis to establish its relationship with mobilization mechanisms.