bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinetics of Thrombin Generation in Patients with Multiple Myeloma.
Authors: Petropoulou Anna D. , Gerotziafas Grigoris T. , Zervas Kostas , Mpanti A. , Samama Michel Meyer , Rendu Francine 
Published: October 2019

Abstract
Thalidomide has emerged as a promising treatment for multiple myeloma (MM). Thrombosis is the most serious complication of thalidomide therapy, essentially when it is combined with dexamethasone. The pathogenesis of thrombosis in MM patients (pts) treated with thalidomide is not clear and probably of multi factorial origin. We used the Thrombin Generation test (TGT) and measured the plasma levels of soluble thrombomodulin (sTM) to better clarify the MM-related and thalidomide-related thrombogenicity. TGT was performed in citrated frozen platelet poor plasma (PPP). Blood was obtained from 26 MM pts, Salmon and Durie stage II and III, 62.5 years old (42–77), 9 males and 17 females, 10 treated with thalidomide (100–200mg/d orally) and dexamethasone (40mg/d for 4 days) (TD group) and 16 receiving no treatment (MM group). 13 healthy volunteers formed the control group. Thrombin Generation (TG) was initiated by adding the PPP reagent (Thrombogram-Thrombinoscope®) and the triggering solution (CaCl2 and fluorogenic substrate). We analyzed the endogenous thrombin potential (ETP), the Cmax and the velocity index of TG. The plasma levels of sTM in PPP were measured by a specific ELISA (Diagnostica Stago, France). In the MM group we observed an increase of the ETP, though not significant compared to the controls. The Cmax was almost equal to the control group value, while the velocity index of TG was statistically lower in the MM group compared to controls. In the TD group, a statistically significant increase of ETP was observed as compared to the control group. The Cmax was higher, compared to controls, though not significantly, whereas the velocity index of TG was almost equal to the control group value. There was no significant difference in the TG parameters between MM and TD groups. sTM in the control group was 45±14ng/ml. Both groups of pts had significantly increased sTM plasma levels as compared to the control but the difference between the two groups did not reach significance. Results are shown in Table 1. In patients with MM coexists an increase of sTM, a marker of endothelial cell damage, together with an increased TG capacity. The addition of thalidomide treatment is associated with a slight but not significant increase of ETP and Cmax. The co-existence of endothelial cell damage with increased TG capacity could be associated to the increased thrombotic risk in MM patients treated with thalidomide. This hypothesis will be controlled in a prospective study.
Table 1: Thrombogram parameters and sTM plasma levels of studied pts. Control MM group TD group * Results significantly different between the MM and TD groups and the control group (p<0.05 vs the control group) ETP (nM×min) 1399±297 1651±478 1747±448* Cmax (nM) 366±54 342±52 402±99 Velocity Index (nM/min) 198±45 160±19* 184±65 STM (ng/ml) 45±14 84±42* 73±30*
Use of Palifermin for the Prevention of High-Dose Methotrexate-Induced Oral Mucositis.
Authors: Schmidt Eva , Thoennissen Nils H. , Rudat Annika , Bieker Ralf , Schliemann Christoph , Mesters Rolf M. , Zühlsdorf Michael , Müller-Tidow Carsten , Berdel Wolfgang E. 
Published: October 2019

Abstract
Oral mucositis is a frequent problem in high-dose methotrexate (HD-MTX) based chemotherapy, impairing the patient’s quality of life, leading to higher rates of infections and delaying subsequent chemotherapy. Numerous substances have been used to prevent or treat oral mucositis, but none of them has proven clinical benefit. Palifermin, a recombinant human keratinocyte growth factor, can lead to a prevention of oral mucositis by different effects. Clinical activity of palifermin has been proven in a controlled randomized study with patients undergoing high-dose therapy with autologous stem cell rescue. The purpose of this report is to describe the effect of palifermin in patients treated within the GMALL-B-ALL 2002 protocol containing HD-MTX who developed a severe mucositis in cycles A1 or B1. Ten patients who were treated within this protocol developed a severe WHO grade III–IV oral mucositis in cycles A1 or B1. Before and after the subsequent similar or identical cycles A2 or B2 palifermin was given to reduce the risk of mucositis. Thus, patients serve as their own control for efficacy of palifermin. All ten patients developed a grade III–IV mucositis in cycles A1 or B1 without palifermin, whereas only 2/10 developed a grade III–IV mucositis in corresponding cycles A2 or B2 with palifermin (Mann-Whitney-Wilcoxon-test p < 0.05). Five patients were treated with a lower palifermin dose than recommended. Also these patients did not develop a higher grade mucositis. Only 4/10 patients showed infections in the cycles with palifermin compared to 10/10 patients without palifermin. The duration of mucositits in patients who aquired a higher-grade (III, IV) mucositis despite treatment with palifermin could be reduced from 12.9 days (median) without to 10.4 days with palifermin. In conclusion, palifermin can significantly reduce the incidence and severeness of oral mucositis and may influence clinical sequelae such as infection and quality of life.
Rituximab-EPOCH, an Efective Front-Line Therapy for Mantle Cell Lymphoma.
Authors: Palacios Andres , Lopez Andres , Salar Antonio , Cervera Marta , Gironella Merche 
Published: October 2019

Abstract
Introduction: Mantle-cell lymphoma accounts for 3–10% of non-Hodgkin’s lymphomas, with a median survival not exceeding of 3–4 years and its remains incurable with conventional therapy. CHOP plus Rituximab can induce a molecular complete response in 36% of patients. More aggressive combinations, as Hyper CVAD achieved an overall response rate of 97% with 87 of complete response, data no further confirmed in other studies in which Hyper-CVAD together with Rituximab achieve an overall response rate of 62.5%, with 33% of complete responses (CR). Being toxicity high mainly in elderly patients. Infusional chemotherapy combinations have shown efficacy in mantle-cell lymphoma (as VAD). Based this premise and in the efficacy of infusional R-EPOCH in aggressive lymphomas (DLBCL and PMBCL) we have conducted a compassionate prospective study of non-adjusted infusional EPOCH-R in patients with mantle -cell lymphoma as first-line therapy.
Aim: To evaluate the clinical activity and toxicity of non-escalated infusional EPOCH-R as upfront therapy in patients newly diagnosed of mantle-cell lymphoma.
Patients and methods: Herein, 12 patients of an ongoing compassionate prospective study in newly diagnosed patients with mantle-cell lymphoma are reported. EPOCH-R consisted on Rituximab 375 mg/m2 day 1, vincristine 0.4 mg plus doxorubicine 40 mg/m2 plus etoposide 50 mg/m2 days 1 to 4 in four day continuous infusion, cyclophsphamide 750 mg/m2 day 5, and prednisone 60 mg/m2 for 5 days, repeated every 21 days if feasible for 6 cycles. The median age of 65 yrs (range, 49–76). 50% of patients were males. 91% of patients presented with an Ann Arbor stage III–IV, high LDH in 50% of cases, leukemic status in 66.6%, Bone Marrow involvement in 66.6% and ECOG <2 was present in 91% of the cases.
Results: The response rate to EPOCH-R was 100% with 91% complete response (11 out of 12 patients). Neutropenia grade III–IV was observed in 16% of cases and anemia grade III–IV in 16% of cases. One case of neutropenic fever and two cases of grade III diarrhoea.
Conclusions: These preliminary results suggest that EPOCH-R is an effective as other more aggressive combinations and probably with less toxicity profile. More experience and longer follow-up is warranted to confirm this initial appealing experience.
Effect of Hypoxia on the Expression of BRIT1 in K562 Cell Line: Implication for Resistance to Imatinib.
Authors: Giallongo Cesarina , Tibullo Daniele , La Cava Piera , Chiarenza Annalisa , Berretta Salvatore , Palumbo Giuseppe A. , Di Raimondo Francesco 
Published: October 2019

Abstract
BRIT1 (Microcephalin, MCPH1) is a chromatin binding protein that forms ionizing irradiation-induced nuclear foci (IRIF); it is a crucial DNA damage regulator in the ATM/ATR pathways. Here we have analyzed BRIT1 expression on K562 cell line after treatment with imatinib 0,1-1 μM, UV irradiation (12 μJ/cm2) and after exposure to an hypoxic condition (3% O2). K562 in standard culture conditions (21% O2) were used to establish BRIT1 basal expression. Total RNA from K562 cultures was prepared at 24 and 48 hs. 1 μg total RNA was reverse transcribed from each sample. TaqMan Gene expression assay (Applied Biosystems) in Real-Time PCR was employed to examine the expression of BRIT1. Cellular count was assayed by trypan blue. Treatment with IM (0,1 and 1 μM) and UV induced a 2–3 fold increased expression of BRIT1 at 24 h and a minor increase at 48 h. Cell mortality at 24 h was 30% for IM and 20% for UV while at 48 h cells started to grow again, possibly as a consequence of the DNA damage repair by BRIT1. Exposure of K562 cells to hypoxia increased BRIT1 expression about 5- and 6-folds at 24 and 48 h respectively. Cell mortality at 24 h was 30% while after 48 h it was 20%. We therefore concluded that BRIT1 expression increases in hypoxia more than after IM and UV exposure. Since we have found that K562 in hypoxic conditions are relatively resistant to imatinib, (K562 cell mortality after 24 h exposure to IM 1μM was 30% ± 0,3 in normoxia vs 9% ± 0,8 in hypoxia, P<0,005) we have hypothesized that BRIT1 could be involved in resistance to IM. Therefore, we exposed K562 to UV and, after 48 h we incubated the cells with imatinib 1 μM. Pre-exposure of K562 cells to UV reduced imatinib-induced mortality (9,7% ± 1,6 vs 21,3% ± 1,5 of control, p< 0,005) thus indicating that upregulation of BRIT1 (as we have observed especially in hypoxia) could contribute to resistance to imatinib in K562 cell line. Understanding of BRIT1 function may well contribute to novel therapeutic approaches for cancer.
CMV Colitis in a Patient Receiving Dasatinib.
Authors: Khan Mudussara A. , Walling Terri , Cumpston Aaron , Craig Michael 
Published: October 2019

Abstract
Introduction: CMV generally produces an asymptomatic or minimally symptomatic acute illness in immunocompetent patients. CMV reactivation commonly occurs in patients with CML after allogeneic transplant but has not been described in those who are treated with tyrosine kinase inhibitors. We report a case of a patient with CML in lymphoid blast phase treated with dasatinib to cytogenetic remission that presented with CMV Colitis.
Method: 73-year-old male diagnosed with CML in lymphoid blast crisis 2/2006 treated with chemotherapy and imatinib with good response. He relapsed in 2/2007 with leukostasis and underwent leukopharesis. His BCR/ABL mutation analysis was positive for F359V mutation conferring resistance to imatinib. He was started on dasatinib 70 mg twice daily and had a cytogenetic remission within four months. He presented five months after starting therapy with four weeks of recurrent fevers, chills, malnutrition and diarrhea.
Results: CBC and differential revealed only mild thrombocytopenia, Absolute CD4 count of 209; absolute CD8 count of 1495. CMV DNA PCR Quantification of 1500 copies/ml. CT chest abdomen and pelvis showed right sided pleural effusion but no pneumonitis. Flex sigmoidoscopy showed inflamed edematous mucosa with submucosal hemorrhages scattered throughout colon and rectum. Pathology showed chronic colitis, focal viral cytopathic changes consistent with CMV presence. Presence of CMV was confirmed by immunoperoxidase stain for CMV. Treatment was started with IV ganciclovir then switched to oral valganciclovir with good response and resolution of CMV infection.
Conclusion: CMV colitis is a well-known complication in immunocompromised hosts after HCT. We are reporting a case of CMV colitis in a patient with CML and had hematologic and cytogenetic remission on a novel tyrosine kinase inhibitor - dasatinib. CMV reactivation may occur in patients who are receiving dasatinib. Furthur evaluation is necessary to determine the incidence of this complication.
Expression of Genes Regulating Iron Metabolism in Hepatocyte Cell-Line HepG2 Induced by Sera from MDS Patients.
Authors: Breda Laura , Ghoti Hussam , Rivella Stefano , Rechavi Gideon , Cabantchik Ioav , Rachmilewitz Eliezer A. 
Published: October 2019

Abstract
Liver expression of hepcidin, a key factor in the regulation of iron absorption and recycling, responds commensurately to plasma iron levels. However, in thalassemic humans and mouse models, despite the overt iron overload found, there is a low expression of liver hepcidin and low levels in urine. We have recently shown that hepcidin expression induced by plasma factors in hemochromatosis is overriden in thalassemic patients (Weiser-Stern et al, Brit. J. Haemat.135:129,2006). As low urinary hepcidin levels were also found in patients with Myelodysplastic Syndrome (MDS), mainly in those with refractory anemia (RA) with or without ring sideroblasts (RARS) and iron overload, we set out to examine whether plasma factor(s) in MDS might also affect the expression of liver genes of iron metabolism.
Patients and methods. Serum samples were collected from 19 MDS patients, average age: 75.7 y, Hb 6.5–12.0 gm/dl; type and #: RA 11, RARS 5 and 3 RA with excess of blasts (RAEB). The international prognostic score (IPSS) was low in 13/19 and intermediate 1 (Int 1) in 6/19. Only 7/19 patients received less that 5 blood units, while 12/19 received 20–140 units and in 11/19 serum ferritin was >1000 ng/ml. The serum samples were incubated with human hepatoma HepG2 cells, which were harvested and their RNA isolated and analyzed by quantitative RT-PCR for: hepcidin (Hamp), the lipocalin Ngal, HFE, transferrin receptors (TfR) 1 and 2, and DMT1-IRE(−). Values were normalized against those obtained from 3 healthy individuals.
Results and discussion. An apparently normal expression of all the above genes was found in 13/19 patients (group I), whereas in the remaning 6/19 (group II) there was: A. a significant increase in expression relative to normal controls (1.0±0.20) of Ngal (4.64±2.15) p<0.01, TfR1 (5.24±0.59) p<0.01, HFE (1.76±0.12) p<0.05 and DMT1-IRE(−) (1.64±0.24) p<0.05; B. a significant decrease in TfR2 (0.19±0.11) p <0.01 and C. an increased Hamp expression in only 3/6 (7.2±5.0) p<0.05 patients and normal expression in 2/6 (1.03±0.3). No clear correlation could be established between expression of the above mentioned genes and iron overload parameters (serum iron and/or ferritin) or the number of transfusions. This study shows a heterogeneous behavior of MDS sera in eliciting gene expression and highlights that increased Hamp expression of HepG2 cells in response to plasma factors is found only in a small fraction of this class of iron overloaded patients. Thus as in thalassemia (1), most of the MDS sera with ferritin levels >1000 ng/ml failed to induce Hamp, suggesting that also in MDS patients there might be circulating factors overriding the serum iron effect on Hamp expression. It remains to be established whether the putative factors modulating expression of key genes of liver iron metabolism in MDS are of the same origin or biochemical character as in thalassemia.
Decreased Megakaryocytepoiesis and No Excess of Platelet Destruction in Myelodysplastic Syndrome Patients.
Authors: Murai Kazunori , Oyake Tatsuo , Kowata Shugo , Ishiguro Mamiko , Ito Shigeki , Ishida Yoji 
Published: October 2019

Abstract
Myelodysplastic syndrome (MDS) is a malignant disorder of hematopoietic progenitor cells and characterize by peripheral blood cytopenias with normo- to hyper-cellular bone marrow (BM) and morphologically dysplastic changes. Thrombocytopenia is observed in approximately 50% of MDS. The underlying pathophysiology is not fully understood. We analyzed the megakaryocytopoiesis and thrombocytopoiesis state by several parameters, including % reticulated platelet (%RP), which indicated platelet production state, glycoalicine index (GCI), which indicated platelet destruction state, and serum thromopoietin (TPO) levels in 47 refractory anemia in myelodysplastic syndrome (MDS-RCMD) patients with platelet counts less than 100 x 109/L. Furthermore, apoptosis frequency of megakaryocyte progenitors was analyzed in several patients. In all patients, dysmegakaryocytopoiesis findings such as hypolobulated micromegakaryocyte, non-lobulated nuclei in all sizes, and multiple, widely-separated nuclei were observed. The megakaryocytes in BM was normal to decreased in number in 32 patients (70%). Plasma TPO levels were significantly higher (718.7±746.0 pg/ml, n=50) in MDS-RCMD, while they were less than 205.0 pg/ml in normal volunteers (68.3 ±65.3 pg/ml, n=32)(p< 0.01). The %RPs in MDS-RCMD and normal controls were similar (MDS-RCMD 1.7±0.9% vs control 1.2±0.6%), indicating that increased thrombocytopoiesis was not observed in MDS-RCMD, regardless of high TPO levels. GCI was similar to normal controls (MDS-RCMD, 1.5±1.3% vs controls, 1.6±0.3%), indicating no excess of platelet destruction. There was no correlation between %RP and GCI. These data strongly suggested that platelet life span be not shortend in MDS-RCMD. We have reported that excessive apoptosis of CD34(+) cells was observed in MDS patients in the previous ASH meetings. The three-color flow cytometric analysis of bone marrow mononuclear cells using PE labeled Annexin V, PerCP labeled anti-CD34 antibody and FITC labeled anti-CD41 antibody were carried out in 17 MDS-RCMD patients. Much higher frequency of apoptosis was observed in double positive cells for CD34 and CD41 (48.1%:13.4∼78.4%, median: range) in MDS-RCMD, compared to that in normal controls (7.7%: 4.4∼17.2%, median: range) (P<0.05). The frequency of apoptosis was not increased significantly in CD34(−)CD41(+) cells in MDS-RCMD patients (median: 6.9% ; 1.3∼21.5%), n=12), compared to those in normal controls (3.3%: 1.5∼8.1%, n=10). These data strongly suggested that the main cause of thrombocytopenia in MDS-RCMD should be apoptosis in megakaryocytes progenitors, followed by the decreased megakaryocytopoiesis.
Enhanced HDAC (Histone Deacetylase) Enzyme Activities in Blood CD 34 + Cells in Patients with Myeloid Metaplasia Myelofibrosis (MMM).
Authors: Wang Jen-Chin , Chen Chi , Dumlao Theresa , Chang Thong , Xiao Yng-Li , Sominsky Inna , Burton Jack 
Published: October 2019

Abstract
We previously reported that histone deacetylase (HDAC) activity is elevated, but is not correlated to the JAK-2 mutation status, in patients with myelofibrosis myeloid metaplasia (MMM) (Blood 107:319b 2005). Now we have studied more patients: totally, 17 with MMM, 19 with other myeloproliferative disorders (MPD), and 16 normal volunteers as controls. Significantly elevated HDAC levels again was shown in patients with MMM compared with other MPD patients and normal volunteer controls (p<0.05). Sixteen patients with MMM were also studied for correlation between JAK-2 mutation status and HDAC levels; no significant correlation was found. We then studied which members of HDACs were elevated in patients with MMM. cDNA was prepared from total RNA obtained from blood CD 34+ cells; then QRT-PCR was performed using pre-made mixtures of primer and FAMTAMRA-labeled probes from ABI (www.appliedbiosystems.com). Primers and probe to GAPDH were used as internal controls. Cycle threshold (Ct) values were obtained graphically for target genes and internal control GAPDH gene products. Amplification efficiencies were calculated by plotting Ct s from serial diluted cDNAs for target genes and GAPDH and all with slopes below 0.1. Δ Ct values were obtained by subtracting GAPDH Ct from target gene Ct. Relative mRNA levels were determined by subtraction of normal control Δ Ct values from MMM Δ Ct values to give ΔΔ Ct values, which were converted to 2− ΔΔ Ct (Relative Quantitation of Gene Expression). The results showed elevated HDAC1 (2.80), HDAC2 (18.45), HDAC3 (2.10), HDAC 6 (2.03) HDAC 9 (2.71), SIRT3 (70.20), and SIRT6 (39.40) and depressed HDAC4 (0.01), HDAC5 (0.001), HDAC8 (0.001), SIRT2 (0.23), SIRT5 (0.005), and SIRT7 (0.88). () indicates relative mRNA values of MMM to controls. These results suggest that HDAC activities are elevated in patients with MMM and are elevated in many members of HDAC. This study may lay the basis for using HDAC inhibitors in clinical trials treating patients with MMM.
Genome-Wide DNA Profiling Identifies a Stable Profile Although with Aberrations Targeting the Fibroblast Growth Factor Pathway in Hairy Cell Leukemia.
Authors: Forconi Francesco , Poretti Giulia , Kwee Ivo , Sozzi Elisa , Rossi Davide , Capello Daniela , Rinaldi Andrea , Zucca Emanuele , Lauria Francesco , Gaidano Gianluca , Bertoni Francesco 
Published: October 2019

Abstract
Hairy cell leukemia (HCL) is a rare B-cell neoplasm with largely unravelled features of lymphomagenesis. Molecular mechanisms of disease are largely unknown and genomic aberrations have infrequently been investigated in HCL. In order to elucidate the genetic mechanisms of HCL pathogenesis, we analyzed copy number changes and loss of heterozigosity (LOH) by genome wide DNA profiling with the Affymetrix Human Mapping 250k Nsp arrays in 16 HCL. All investigated cases expressed multiple pre- (IgM+/−D) and post-switch (IgG+/−A) isotypes. Tumor IGHV gene transcript homology to germline ranged from 88.4 to 98.6%, with 4/16 HCL having >98% homology. Four of 16 patients were refractory or had progressive disease after first line purine-analogue-based treatments. CD103+ve hairy cells were >60% in all test samples. Genome wide DNA profiling demonstrated gross non recurrent copy number deletions in only 4/16 cases (25%), affecting 14q24-q32, 3q23, 3q27.3-q29, 8p12-pter 10q21-q23, 10q25-q26, 17p11-pter, 17q11-q21, 17q22–23, Xp21.2-p22.11, Xq13.3, Xq21.1-q21.33, Xq22.2–q28, the whole chromosomes 21 and X. Five of 16 patients (31%) presented LOH. Most interestingly, the 5 patients showed LOH regions, with a region of overlap in two patients at 6q25.1, without any copy number changes, indicative of uniparental disomy. Genes involved in bone marrow fibrosis, multiple isotype expression and response to treatment were specifically investigated. Interestingly, among genes critical for fibrosis, FGF12, a member of the fibroblast growth factors family, was specifically targeted by a complex chromosomal rearrangement at 3q27.3-q29, and reverse transcript-polymerase chain reaction confirmed FGF12 transcript expression. Among genes associated with poor response, p53 deletion was documented in a non-responder HCL. Conversely, no abnormalities at 14q32 locus (duplications or gains) were observed at IgH 14q32 region in these multiple IgH isotype expressing HCL. Overall, our analysis showed a highly stable genome with lack of gross recurrent abnormalities, which is an additional unique feature of HCL among B-cell neoplasms. However, our genomic analyses were able to identify specific chromosomal rearrangements targeting genes involved in fibrosis. Lack of gains of 14q32 locus was consistent with our hypothesis that multiple IgH isotypes are generated at RNA level in multiple IgH expressing HCL. The present analysis provides the basis for further molecular and epigenetic investigations.