bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment of Essential Thrombocythemia with Anagrelide: A Novel Antiangiogenic Agent?.
Authors: Cacciola E. , Cipolla A. , Di Francesco E. , Giustolisi R. , Cacciola R. R. 
Published: October 2019

Abstract
Essential thrombocythemia is a myeloproliferative disorder complicated by thrombotic phenomena as a result of the platelet-clotting hyperactivation linked to increased angiogenesis. It is reported that vascular endothelial growth factor (VEGF) generates thrombin and promotes platelet activation and that activated megakaryocytes and platelets release VEGF. Anagrelide (ANA) is a newer cytoreductive agent which decreases megakaryocyte mass and inhibits the platelet activation. Therefore, we studied platelet factor 4 (PF4), as indicator of platelet activation, VEGF and prothrombin fragment 1+2 (F1+2) and d-dimer (DD), as indicators of thrombin generation, in 22 patients (12 males and 10 females, mean age 50 years) affected by ET diagnosed according to PVSG criteria. Their mean duration of disease was 4.8 years. All patients were on either HU (6 patients) or IFN-α (4 patients) and ANA (12 patients). HU was used at doses ranging between 1 and 1.5g/day. The dosage of IFN-α was 3 MIU, 3 days/week. ANA was initially administered in dose of 0.5 mg/day, with increases of 0.5 mg/day every 7 days until the platelets decreased below 500×109/L and with a average maintenance dosage of 2.2 mg/day. All patients recieved antiplatelets either aspirin (ASA) (15 patients) or indobufen (IND) (6 patients) and dipirydamole (DYP) (1 patient). Platelets, PF4, VEGF, F1+2 and DD were measured before cytoreduction and to complete response defined as platelets≤ 500×109/L. Platelets were determined by automated analyser. PF4, VEGF and F1+2 were assayed by ELISA and DD by immunoturbimetric latex agglutination. Before treatment all patients had marked platelets (1060±356×109/L) and high PF4 and VEGFPLT (157±83 IU/ml vs 1.6±0.9 IU/ml and 1.2±1 pg/ml vs 0.3±0.2 pg/ml, respectively) (p<0.0001 and p= 0.002, respectively). F1+2 and DD were elevated 3.6±3.7nml/L and 205±83 μg/L, respectively) than controls (0.6±0.3nmol/L and 75±21 μg/L, respectively) (p<0.0001 and p<0.0001, respectively). After a median time of 4.5 months from cytoreduction all patients had platelets ≤ 500 × 109/L (430±70 × 109/L). PF4 and VEGFPLT remained high (121±72 IU/ml and 3.5±4.6 pg/ml, respectively) such as F1+2 and DD (3.5±3.8 nmol/L and 197±55 μg/L, respectively) in the HU- and IFN-α-treated patients. PF4 and VEGFPLT normalised (7.4±3 IU/ml and 0.9±0.5 pg/ml, respectively) in the ANA-treated patients such as F1+2 and DD (1.1±0.4 nmol/L and 98±62 μg/L, respectively). These measurements were repeated in another sample collected after 1 o 2 months and showed concordance for PF4, VEGFPLT, F1+2 and DD concentrations. A positive correlation we found between PF4 and F1+2 and DD (p=0.023 and p=0.019, respectively) and between VEGF and F1+2 (p=0.020, respectively). Interestingly, these data might suggest that ANA has antiangiogenic property and hence antiplatelet and anticoagulant effects.
Long Term Follow-Up of 198 IgM Monoclonal Gammopathy of Undetermined Significance (MGUS).
Authors: Annibali Ombretta , Petrucci Maria T. , Bartolozzi Francesco , Levi Anna , Del Bianco Patrizia , Gallucci Cristiano , Foa Robin , Mandelli Franco , Avvisati Giuseppe 
Published: October 2019

Abstract
MGUS is found in more than 1 % of people 50 years or older and in approximately 3% of those older than 70 years. Of these the great majority are of IgG or IgA type while IgM MGUS are less frequent.The aim of this study was to analyse the natural history of IgM MGUS and the risk of progression to lymphoproliferative disorders. From July 1973 to June 2004, we observed 323 monoclonal gammopathies of IgM type. At diagnosis, 198 (61%) were MGUS, 111 (34%) were Waldeström’s Macroglobulinemia (WM) of whom 11 were pretreated, 8 (2,4%) were non Hodgkin Lymphoma (NHL), 5 (1,5%) were IgM Myeloma and only 1 was a chronic lymphocytic leukaemia. Of 198 patients with IgM MGUS, 125 (63%) were men and 73 (37%) were women ( ratio 1.71).Median age at diagnosis was 65.7 (range 33–89 years). At diagnosis, all patients had an IgM concentration less than 2 gr/dl with a median of 1.7 g/dl. Median Hb, serum creatinine and albumin levels were: 13.2 gr/dl, (range 6.9–17.9), 1,04 mg/dl ( range 0.6– 2,5) and 3.9 gr/dl ( range 2.4–5). Hepatomegaly as well as splenomegaly were present in 24% and 14% of patients, respectively. The 198 patients were monitored for 8741 months/person (median 25 months, range 0–411). During The follow up a lymphoproliferative disorder developed in 17 (8.5%) patients. In particular 11 pts (5.5%) pts evolved to WM and 6 (3%) to NHL. Progression incidence to linfoproliferative disorders was 0.001 months/person. Cumulative incidence of progression to lymphoproliferative disease was 1.3 % at 1 years, 6.8 % at 5 years, 23.2% at 10 years and 45.4% at 15 years. In conclusion the patients with IgM MGUS are more likely to die of unrelated diseases than to have progression to a malignant lymphoproliferative disorder.
Chromosome Aberrations in 130 Patients with Multiple Myeloma Detected by Interphase FISH and Their Diagnostic and Prognostic Relevance.
Authors: Glasmacher Axel , Hahn Corinna , Juttner Andrea , Schubert Regine , Busert Barbara , Schwanitz Gesa , Schmidt-Wolf Ingo G.H. 
Published: October 2019

Abstract
Recent publications have shown that chromosomal abnormalities in patients with leukemias play an important role with respect to therapy and prognosis. In multiple myeloma (MM) the role of specific cytogenetic changes relevant for the prognosis is still to be defined. Recent data suggest that much more patients show chromosomal aberrations than previously suspected, but differentiation between main and side lines of karyotype evolution was problematic. In the present investigation, cytogenetic analysis was performed using interphase FISH in 130 patients with multiple myeloma. For hybridization, 9 repetitive (chromosomes 3, 7, 9, 11, 15, 17, 18, X, Y) and 7 single copy probes (2x5, 13, 17, 21, 2x22) were used. Aberrations were detected in 87% of the patients. Most cases showed 1–3 aberrations. There was a correlation between the number of aberrations per patient and the tumor stage. E.g. the percentage of patients with 7–12 aberrations increased from 16% in stage II to 28% in stage III. Gains and losses of chromosomes showed significant interchromosomal differences with gains being more frequent than losses. Chromosomes 3, 5, 7, 9, 21 and 22 showed predominantly gains. Losses were found in chromsomes 13, 17, X and Y. But monosomy of sex chromosomes (average age of 63.5 years) may be in part explained by the age of the patients. For chromosomes 15 and 18 a similar number of monosomies and trisomies was found which might be caused by mitotic nondisjunction. Deletions 13q14 (28%), gain of 11q13 and translocation of IgH locus 14q32 (79%) are specific aberrations detected in 39 patients analysed with specific DNA probes of the relevant loci. All three aberrations led to modified survival times of the patients. Summarizing our results in 130 patients with MM, we found that the number of numerical chromosomal aberrations as well as selected structural aberrations proved to be of diagnostic and prognostic relevance.
Association between Regimen Related Toxicity and Acute-Graft-Versus-Host Disease.
Authors: Copelan Edward A. 
Published: October 2019

Abstract
Tissue injury resulting from preparative therapy for transplantation is integral to the development of acute graft-versus-host disease (GVHD) according to current theory. If toxicity to normal tissues is a critical factor in the pathophysiology of GVHD, greater degrees of regimen related toxicities should be associated with a higher incidence and greater severity of GVHD. We analyzed 438 patients who underwent allogeneic transplantation from related (n=360) or unrelated (78) donors and who survived > 100 days following transplantation. Patients had received preparative regimens of BuCy (n=340) or BuCyVP16 (n=98). Median age was 36 (range 4–66). There were 263 males and 175 females. This cohort survived a median of 35 months (range 3 months to 20 years).
Sixty-eight of these patients had developed (Bearman) grade 3-4 regimen related toxicities. These patients had a 50% incidence of acute GVHD > grade II and a 26% incidence of developing GVHD ≤ grade II, compared to significantly lower incidences of 33% (P=.01) and 14% (P=.02) respectively in the group experiencing < grade 3 regimen related toxicity. Exclusion of patients whose GVHD prophylactic regimens were significantly altered because of toxicity did not significantly influence these results.
This data suggest that patients who develop severe regimen related toxicity are significantly more likely to develop severe acute GVHD, supporting a potential pathophysiologic role for tissue injury in the development of acute GVHD.
The Lymphocyte Recovery on Day +23 Correlates with Survival after Autologous Peripheral Blood Stem Cell Transplantation in Multiple Myeloma.
Authors: Kim Hawk , Kim Shin , Kim M. Wookun , Lee Jung-Shin , Suh Cheolwon 
Published: October 2019

Abstract
Absolute lymphocyte count (ALC) ≥1000 cells/mm3 on day +23 was an independent predictor of prolonged survival in patients with T/NK-cell lymphoma after autologous peripheral blood stem cell transplantation (APBSCT). To understand the prognostic value of lymphocyte recovery, we performed a retrospective study analyzing the result of 59 patients with multiple myeloma (MM) patients who underwent APBSCT. All patients were in complete or partial response after APBSCT. A median age at APBSCT was 51. Peripheral blood stem cells were mobilized and collected after cytoxan and G-CSF. The conditioning regimen was melphalan 200. ALC recovery day was defined as a first day of 3 consecutive days when ALC has been recovered more than 1000/mm3. A median value was used for the analysis of each noncategorical variable. A median follow-up time after APBSCT was 33.8 months and median recovery days of ALC ≥1000 cells/mm3 was 23 days. Prognostic factors at the time of APBSCT for transplant OS and PFS included beta-2 microglobulin, serum albumin, recovery days of neutrophil ≥500/mm3, infused mononuclear cell dose, infused CD+34 cell dose and recovery days of ALC ≥1000 cells/mm3. Univariate analysis revealed that significant variables at APBSCT for overall survival (OS) were beta-2 microglobulin, day of neutrophil engraftment and recovery days of ALC. Positive predictors at APBSCT for progression-free survival (PFS) were beta-2 microglobulin, day of neutrophil engraftment, serum albumin, infused mononuclear cell count, infused CD +34 cell count and recovery days of ALC. ALC ≥1000 cells/μL on day +23 was an independent predictive prognostic factors for better PFS (P = 0.003; Relative risk (RR) = 3.710; 95% Confidence interval (CI), 1.576–8.736) and showed tendency for prolonged OS (P = 0.065; RR=2.411; 95% CI, 0.946–6.142) (Table 1).In conclusion, ALC ≥1000 cells/mm3 recovery on day +23 was a good predictor for better survival in MM after APBSCT.
Table 1. Multivariate analysis for OS and PFS
Variables OS PFS RR 95% CI P RR 95% CI P ANC, absolute neutrophil count; MNC, Mononuclear cell; ALC, absolute lymphocyte count β2 microglobulin ≤ 3 vs > 3 mg/l 3.497 1.32–9.25 0.012 2.215 0.962–5.101 0.062 Serum albumin ≤ 3.7 vs > 3.7 g/dl 0.337 0.139–0.816 0.016 ANC≥ 500/mm³ recovery days≤ 11 vs > 11 2.677 1.044–6.864 0.040 1.360 0.616–3.001 0.447 Infused MNC dose≤ 3.4 vs > 3.4 ×10^8/kg 1.351 0.552–3.310 0.510 Infused CD+34 dose≤ 6 vs > 6 ×10^6/kg 0.609 0.209–1.779 0.365 ALC≥ 1000/mm³ recovery days≤ 23 vs > 23 2.411 0.946–6.142 0.065 3.710 1.576–8.736 0.003
Utilization Trends of Epoetin Alfa and Darbepoetin Alfa in Adult Patients with Cancer Receiving Chemotherapy in Community Practice Settings.
Authors: Coletti Ted , Howell Jamie B. , Todoroff Karen , Gregory Keith L. , Fastenau John M. 
Published: October 2019

Abstract
Background: Comparing dose utilization in actual practice in a defined patient population and setting for both epoetin alfa (EPO) and darbepoetin alfa (DARB) may improve understanding of the dose ratio at which these two agents are equally effective in those patients. The dose ratio is also important for providers and payers to gauge true comparative costs.
Objective: A cross-sectional study was conducted to understand utilization trends of EPO and DARB, estimate a dose ratio between these two agents, and compare weekly treatment costs in adult patients with non-myeloid malignancies receiving chemotherapy in community oncology practices.
Methods: Aggregated, de-identified data were obtained from a commercial drug ordering, inventory, and utilization database (OTN Lynx™ System) representing treatment patterns at the patient visit dosing level across approximately 800 community oncology practices nationwide. EPO and DARB medication records for adult patients with non-myeloid malignancies receiving chemotherapy during the period May 2003 through May 2004 were included. Monthly dosing trends for EPO and DARB were analyzed. Weekly treatment costs were estimated by applying 2004 Red Book-August Update average wholesale prices to mean weekly doses. Outcomes evaluated included: dosing frequency, mean weekly dose, dose ratio and weekly treatment costs.
Results: Data were contributed each month for an average of 6,379 EPO patients and 5,124 DARB patients. Frequency of administration for both agents remained constant. Most EPO patients received therapy weekly (QW) followed by every 2 week dosing (Q2W) while most DARB patients were dosed Q2W followed by QW dosing (EPO: QW 64%, Q2W 27%, other 9%; DARB: QW 19%, Q2W 61%, other 20%). Examination of the mean weekly doses (5/03 versus 5/04) showed an increase of 1.2% for EPO (35,735 to 36,169 Units) and 8.4% for DARB (122 to 132 mcgs) resulting in an overall decline in the EPO:DARB dose ratio (294:1 to 274:1). Weekly treatment costs showed a slight increase of $6.12 for EPO patients, but a notably greater increase of $50.76 for DARB patients.
Conclusions: The dose ratios over the 13-month study period were all less than the current ratio of 330:1 adopted by the Centers for Medicare and Medicaid Services for hospital outpatient reimbursement. Mean weekly dose and treatment costs remained relatively constant for EPO patients, but increased for DARB patients. These utilization data suggest treatment costs for EPO are consistently and markedly lower than those for DARB in community oncology patients.
Table 1
Month/Year 5/03 8/03 11/03 2/04 5/04 Mean dose per week EPO (Units) 35,735 36,034 36,738 36,143 36,169 Mean dose per week DARB (mcgs) 122 123 129 129 132 Dosing ratio EPO (Units): DARB (mcgs) 294 294 286 280 274 Weekly cost (USD) EPO $503.86 $508.08 $518.01 $509.62 $509.98 Weekly cost (USD) DARB $619.27 $624.35 $654.80 $654.80 $670.03
AMD107: Efficacy as a Selective Inhibitor of the Tyrosine Kinase Activity of BCR-ABL in Murine Leukemia Models.
Authors: Griffin James D. , Fabbro Doriano , Fendrich Gabriele , Huntly Brian , Jacob Sandra , Kung Andrew , Mestan Jurgen , Weisberg Ellen , Gilliland D. Gary , Manley Paul W. 
Published: October 2019

Abstract
Patient relapse due to the emergence of imatinib-resistance in advanced chronic myelogenous and Ph+ acute lymphocytic leukemias has prompted the search for improved Bcr-Abl kinase inhibitors. Up to 40% imatinib-resistant patients express mutant forms of the Bcr-Abl kinase that reduce binding of imatinib without significantly decreasing kinase activity. However, some mutants are only partially resistant, since higher concentrations of imatinib may still block kinase activity and have a beneficial clinical effect. More potent Bcr-Abl inhibitors or inhibitors with different contact points with the kinase domain are predicted to be useful for the treatment of imatinib-resistant disease. Rational drug design based upon the crystal structure of an Abl-imatinib complex, together with medicinal chemistry paradigms, resulted in the discovery of AMN107. AMN107 is a low molecular weight compound that selectively inhibits the c-Abl/Bcr-Abl, imatinib-resistant mutants of Bcr-Abl, PDGFR, and c-Kit tyrosine kinases, with IC50 values for the inibition of autophosphorylation (cell capture ELISA) of 23 nM (32D cells transfected with p210 Bcr-Abl), 83 nM (A31 cells) and 192 nM (GIST cells), respectively. Following oral administration to mice (20 mg/kg in NMP-PEG300 10:90 v/v), AMN107 was well absorbed, with a mean plasma level after 2 h in the range of 6.0-12.1 M, which corresponds to >100-fold that required to inhibit Bcr-Abl autophosphorylation in 32D.p210 cells. Following injection of 32D.p210-luciferase cells into Balb/c mice, serial imaging of the leukemic clone in live mice indicated that AMN107 could substantially reduce the accumulation of leukemic cells in the marrow, nodes, liver, and spleen, compared to a vehicle control. Further, administration of AMN107 (75 mg/kg/day p.o.) to BALB/c mice over an 18 day period, commencing 3 days after the injection of 32 D.p210 cells, resulted in the protection of 15/20 animals over 100 days observation, whereas 19/20 vehicle treated animals developed a lethal leukemic disease(all deaths occurred within 36 days of cell injection). The spleen sizes of the surviving animals in the treated group were in the normal range (0.142±0.043 g; n = 17), whereas those of the vehicle treated animals were 0.50±0.045 (n = 20). These results were confirmed in a bone marrow transplant assay, where AMN107 was found to prolong survival of mice transplanted with marrow cells infected with a p210Bcr/Abl retrovirus. AMN107 also prolonged survival of mice transplanted with a Bcr/Abl mutant (E255V) associated with imatinib resistance in patients, while imatinib treatment was unsuccessful. These in vivo studies, along with in vitro studies reported separately, indicate that AMN107 is a highly active inhibitor of Bcr/Abl that may have clinical utility in patients with Bcr/Abl+ leukemias.
VEGF Upregulates Mcl-1 Expression and Protects Multiple Myeloma Cells Against Starvation Induced-Apoptosis.
Authors: Le Gouill Steven , Podar Klaus , Amiot Martine , Hideshima Teru , Chauhan Dharminder , Ishitsuka Kenji , Kumar Shaji , Raje Noopur , Richardson Paul , Harousseau Jean-Luc , Anderson Kenneth 
Published: October 2019

Abstract
Vascular endothelial growth factor (VEGF) induces proliferation of MM cells and induces interleukin-6 (IL-6) secretion in a paracrine loop involving MM cells and bone marrow stromal cells. In turn, IL-6 triggers multiple myeloma (MM) cell proliferation and also protects against apoptosis by upregulating Myeloid-cell-leukemia 1 (Mcl-1), a critical survival protein in MM cells. The goal of our study was to investigate the role of Mcl-1 in VEGF induced-proliferation and protection against apoptosis. Using two murine embryonic fibroblast cell lines as a model (a Mcl-1 deleted cell line and its wild type: Mcl-1Δ/null and Mcl-1wt/wt MEFs, respectively), we here demonstrate that deletion of Mcl-1 reduces fetal bovine serum (FBS), VEGF, and IL-6 induced-proliferation. In addition, we demonstrate that the percentage of cells in S phase is lower in Mcl-1Δ/null compared to Mcl-1wt/wt MEFs (21% (+/−1) versus 30% (+/− 3), respectively). Taken together, these results demonstrate that Mcl-1 is required to mediate VEGF, Il-6 and FBS-induced-proliferation and cell cycle progression.
To highlight the key anti-apoptotic role of Mcl-1 in MM cells, humans MM1s cells were transfected with Mcl-1 siRNA. Specific inhibition of Mcl-1 was associated with decreased proliferation (42% and 61% decreases at 24 and 48 h, respectively) and induction of apoptosis (subG1 peak: 22% and 41% in Mcl-1 siRNA transfected cells versus 15% and 15 % in non-transfected cells at 24 and 48 h, respectively), confirming that Mcl-1 is critical for both proliferation and protection against apoptosis in MM cells. In 3 human MM cell lines (MM1s, U266 and MM1R) and MM patient cells we next showed that Mcl-1 protein expression, but not other bcl-2 family members, is upregulated by VEGF in a time and dose manner; and conversely that the pan-VEGF inhibitor GW654652, blocks VEGF induced-upregulation of Mcl-1. Furthermore using flow cytometry with a double staining (CD38-FITC and Apo 2.7-PE), we demonstrate that VEGF protects MM patient cells from FBS-starvation-induced-apoptosis: the percentage of apoptotic MM patient cells (CD38++ and Apo 2.7+) in non starved medium (RPMI 1640 supplemented with 10% FBS) was 15% versus 93% in starved medium (RPMI 1640 supplemented with FBS 2%), and 48% in starved medium supplemented with 25ng/ml VEGF. In conclusion, our study demonstrates that VEGF protects MM cells against apoptosis, and that VEGF-induced MM cell proliferation and survival is mediated via Mcl-1. these studies provide the preclinical framework for novel therapeutics targeting both Mcl-1 and/or VEGF to improve patient outcome in MM.
Formation of Pancreatic Duct Cells from Bone Marrow during Neonatal Development.
Authors: Wang Xiuli , Ge Shundi , McNamara George , Bhushan Anil , Crooks Gay M. 
Published: October 2019

Abstract
A debate has raged in recent years over whether cells within the bone marrow have the capacity to generate non-hematopoietic, specialized tissue in other organs. Previous reports have studied bone marrow transplantation in adult recipients; most models have found that tissue injury was necessary for organ engraftment of bone marrow and at best low levels of engraftment are seen. In the present study, we show complex ductal epithelial structures in the pancreas completely derived from bone marrow transplanted during the neonatal period in the absence of tissue injury. BRDU labeling showed that epithelial cells lining the ducts and islet cells were cycling at significantly higher levels in the neonatal than in the adult pancreas (P<0.0001). The contribution of transplanted bone marrow to neonatal pancreatic development was thus explored. To exclude the effect of injury on engraftment patterns, non-conditioned, immune deficient neonatal mice were used as bone marrow recipients. 5-10x106 bone marrow cells from male transgeneic GFP mice were injected into female neonatal Nod/Scid/b2Mnull mice 24 hours after birth through the superficial temporal vein. Two months after bone marrow transplantation, hematopoietic engraftment of donor cells was obtained in all transplanted mice, with 22.3 ±4.9% GFP+ cells observed in the peripheral blood (n=9 mice) and pancreas was analyzed with immunohistochemistry, FISH and confocal microscopy. Co-staining of GFP, with anti-cytokeratin (CK) Ab for epithelium, and FISH for the presence of donor Y chromosome indicated that up to 40% of ducts (mean 8.4%) contained epithelium derived from donor bone marrow. In approximately half of these donor derived ducts, there were clusters of large and small ducts, all expressing GFP as if whole branching structures were derived from donor bone marrow. In addition, 2.5% of islets contained cells that co-expressed GFP and Insulin. Donor derived duct and islet cells did not co-express hematopoietic markers excluding donor blood cell contamination. Unlike pancreatic damage models, no donor derived vascular endothelial cells were found in the study. In contrast, bone marrow transplanted into adult mice rarely generated ductal epithelium (0.7% ducts) or islet cells. These findings indicate that the neonatal period may provide a unique window during which mechanisms exist to recruit transplanted bone marrow to proliferating pancreatic tissue without tissue damage. The data also support that existence in bone marrow of pluripotent stem cells or epithelial precursors that can home to pancreas and differentiate into complex organ specific structures.