bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concordance with National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines (CPGs): A Quality of Care Tool for Newly Diagnosed Patients (pts) with Mantle Cell Lymphoma (MCL).
Authors: Rodriguez Maria Alma , Veer Anna Ter , Nademanee Auayporn , Niland Joyce , Lepisto Eva , Kho Michelle , LaCasce Ann , Weeks Jane Carrie , Czuczman Myron , Millenson Michael , Friedberg Jonathan , Zelenetz Andrew D. 
Published: October 2019

Abstract
Introduction: In 1999, the NCCN published its first NHL CPG and in 2000, established the NCCN NHL Outcomes Database Project to monitor patterns of care, CPG concordance and outcomes in participating institutions. We report here on clinical characteristics and CPG concordance among newly diagnosed (dx) pts with MCL in the database.
Methods: We prospectively collected demographic, staging, and treatment information on consecutive pts with MCL presenting at 5 geographically diverse NCCN institutions (Dana-Farber, Roswell Park, City of Hope, Fox Chase and MD Anderson). We assessed concordance with 2 CPG’s relevant to the concordance impacting the majority of pts: 1) bone marrow biopsy (BMBx) as part of the initial work-up and 2) use of an endorsed first line regimen among pts with stage III/IV disease. CPG concordance was assessed by comparing each pt’s care against the version on the NCCN guideline in effect at the time the pt was diagnosed.
Results: Between 7/2000 and 10/2005, we enrolled 132 MC evaluable pts. Median age was 58; 43% had high-intermediate or high risk disease according to the IPI at presentation; 123 (93%) pts presented with stage III/IV disease. The median follow-up was 22.6 months. Overall, 91% of pts underwent a staging BMBx as recommended by the guidelines. Concordance varied by institution, low 78% to high 98%. Among 123 pts with stage III/IV disease, first-line therapy was concordant with CPG recommendations in only 59%. Use of rituximab accounted for 92% of all non-concordance. When the guidelines were modified in 2003 to include rituximab as an option for first-line therapy of MCL, concordance rose from 31% (2000) to 100% (2003–5). Of concordant pts receiving combination chemotherapy, 33% received CHOP-based standard dose therapy and 62% received dose-intense therapy. NCCN guidelines consider all therapy administered as part of a clinical trial to be concordant; trial-directed treatment accounted for 42% of concordant care.
Conclusions: Our data suggest that the majority of MCL pts in these centers receive care that is concordant with current standards. In this subgroup of patients, participation in clinical trials occurred at an impressively high rate. However, not all pts undergo BMBx as a routine component of staging as recommended by NCCN guidelines suggesting that this is an area for potential quality improvement. This study also highlights that differences in management exist even within national comprehensive cancer centers. Because long-term follow-up is possible with this database, future studies will assess the initial treatment and guideline concordance on long-term outcomes in this unique group of pts.
Quality of Life and Satisfaction with Iron Chelation Therapy in Patients with Beta Thalassemia Major: Results from the ITHACA Study.
Authors: Mantovani Lorenzo Giovanni , Scalone Luciana , Ravera Simona , Rofail Diana , Cappellini Maria Domenica ,   the ITHACA Study Group
Published: October 2019

Abstract
Background Patients with beta Thalassemia Major (TM) require life-long blood transfusions, which often cause iron overload that may increase patients’ morbidity and mortality. Iron Chelation Treatment (ICT), aimed to reduce iron overload, is based on 8–12 hour infusions of Deferoxamine (DFO) for 5–7 days/week, and/or Deferiprone (L1) orally administered. Current ICT can be related to low satisfaction, low compliance, and potentially negative consequences on clinical effectiveness, patients’ wellbeing and on healthcare costs.
Aims: To investigate the Health-Related Quality-of-Life (HRQoL) of TM patients and their satisfaction with ICT.
Methods: The Italian-THAlassemia-Cost-&-Outcomes-Assessment (ITHACA) was a naturalistic multicentre study conducted to evaluate costs, HRQoL, compliance and treatment satisfaction in TM patients undergoing ICT for at least 3 years, enrolled at Italian Thalassemia Care Centers. HRQoL was measured in >14 years old patients with 2 generic instruments: EQ-5D; Short Form-36 (SF-36). To measure satisfaction >12 years old patients received a 28-item instrument consisting of 4 domains: ‘perceived effectiveness’, ‘acceptance’, ‘burden’, and ‘side effects’. Each domain scored from from 1 (very dissatisfied) to 5 (very satisfied). Results Based on 126 patients: median age 29.4 years (12.3–48.5), 49.6% male. At enrolment 48.0% were using DFO, 33.6% L1, 18.4% were treated with DFO+L1. 86.5% of patients had at least one TM-related complication, 13.5% changed treatment regimen at least once in a median of 11.6 months before enrolment. With EQ-5D profile patients reported moderate problems with ‘mobility’ (9.1%), ‘self care’ (0.8%), ‘usual activities’ (23.5%), moderate or severe ‘pain/discomfort’ (60.5%) and ‘anxiety/depression’ (39.5%). Mean EQ-5D-Visual Analogue Scale was 73.0 (30–100). The SF-36 Physical Component Summary mean(SD) score was 47.7(8.4), while the mean score estimated in the Italian general population comparable for age and sex is 53.3; the Mental Component Summary mean(SD) score in TM patients was 45.1(8.8), while the Italian general population mean score was 47.7. Mean satisfaction scores were 4.29 (perceived effectiveness), 3.37 (acceptance), 3.87 (burden), and 3.57 (side effects). Simple linear regression analysis showed that satisfaction with burden (r2=12.6%, p<0.0001), side effects (r2=12.3%, p<0.0001) and acceptance(r2=11.3%, p=0.0001), are positively associated with the adherence item ‘never thinking about stopping medication’ (p<0.0001 in both cases).
Conclusions: TM patients on ICT have impaired levels of physical and mental HRQoL. Therapies improving patients’ satisfaction and compliance to ICT may have positive consequences not only on clinical effectiveness but also on overall patients’ well-being.
Long-Term Follow-Up of Treatment for Acute Myeloid Leukemia with Allogeneic Hematopoetic Cell Transplantation Using BuCy2 as Preparation.
Authors: Pant Shubham , Crilley Pamela Ann , Dodds Anthony J. , Szer Jeffrey , Bolwell Brian J. , Elder Patrick , Styler Michael , Kalaycio Matt , Sobecks Ronald , Nivison-Smith Ian , Avalos Belinda R. , Copelan Edward A. 
Published: October 2019

Abstract
In 1991, we reported the results of 127 patients with Acute Myeloid Leukemia (AML) who underwent conditioning for allogeneic transplant with busulfan, 4 mg/kg on each of 4 days and cyclophosphamide 60 mg/kg on each of 2 days. In the current abstract, we report data on 295 patients, including the initial cohort, who underwent allogenic transplantation for AML from 1984 to 1995 at 7 participating institutions. Median age of patients is 33. One hundred forty nine men and 126 women underwent transplant. All patients received marrow from related HLA-identical donors. One hundred seven patients (36%) remain alive. One hundred forty one patients were transplanted in first remission (group I), 43 in second remission (group II) and 111 patients were in > 2nd remission or had refractory disease (group III). The median follow-up of patients in the initial study was 3 years and is 12 years in the current study. Seventy-five percent of patients surviving 3 years after transplantation are estimated survivors 12 years after transplant. Relapse (20), chronic GVHD (5) and infection (3) were the major causes of death in patients who died more than 3 years after transplantation. The estimated relapse rate for group I at 3 and 12 years is 18%(95% CI: 2–32%) and 29% (95% CI 11–47%) for group II is 40% (95% CI: 8–72%) and 52% (95% CI: 16–84%), and group III is 59% (95% CI: 37–81%) and 69% (95% CI: 45–93%) respectively. The estimated leukemia-free survival (LFS) for group I at 3 and 12 years is 60% (95% CI: 44–76%) and 47% (95% CI: 29–65%), for group II is 47% (95% CI: 17–77%) and 34% (95% CI: 4– 64%)and group III is 22% (95% CI: 6–38%) and 15% (95% CI: 1–29%) respectively. Remission stage was predictive of long-term LFS (P<0.001), with patients transplanted in first remission doing better than the rest. Older age was a risk factor for late failure (death or relapse beyond 3 years, P=0.05). Remission stage at transplant (p=0.44), chronic GVHD (P=0.08) and acute GVHD (P=0.12) were not significantly predictive of late failure. In conclusion a vast majority of patients alive and well at 3 years post transplant seem destined to be cured. A proportion of patients do fail beyond 3 years, but the remission stage of disease at transplant is not predictive of late failure.
Pediatric Hematopoietic Progenitor Cell Collection and Transplant: Does Pegfilgrastim Represent Progress?.
Authors: Merlin Etienne , Auvrignon Anne , Dubray Claude , Rapatel Chantal , Deméocq François , Kanold Justyna 
Published: October 2019

Abstract
The particular technical challenges of apheresis in children require the highest quality of stem cell mobilisation. To date, G-CSF remains the reference. The arrival of pegfilgrastim (pegf) theoretically allows the maintenance of an elevated and constant serum level of G-CSF after only one injection.
DESIGN: eleven children (2–16 yrs) undergoing chemotherapy for malignancy were consecutively included in a prospective pilot study. Mobilization consisted of one sc injection of 300 μg/kg pegf in haematological steady state. Apheresis was begun once the value of 20 CD34+/μl cells was reached in the blood, or at day 4 after pegf administration.
RESULTS: at first apheresis the mean CD34+ cell, mononuclear cell and polynuclear blood counts were respectively 98/μl (12–353), 7.26×109/l (1.0–9.5) and 39.3×109/l (4.6–57.3). The CD34+cell peak level was obtained on day 3 after injection (3–5). The first standard apheresis (less than 3 patient blood volumes) allowed the harvest of more than 5×106 CD34+ cells in 9/11 pts, the median CD34+ cell harvest being 13.5×106/kg (range 1.6–36). On day six after injection, the median ANC was 13.6×109/l. These results were compared to 3 historical prospective cohorts of children who received non-conjugated G-CSF at 10, 20 or 2×12 μg/kg/j, respectively. The four cohorts were not different for age, weight, diagnosis and rounds of chemotherapy. Mobilisation with pegf was more efficient than with G-CSF at 10 μg/kg/d (p<0.001); there were no significant differences between the other regimens.
Figure Figure
Tolerance: 8 pts had an elevation of LDH, 3 a hyperuricemia respectively up to 2 times and 1.5 times the upper limit. After reinfusion, polynuclear recovery (ANC>500/μl) was obtained after (median) 11.5 days (11–13); platelet recovery (>20 G/l) was reached on median day 17 (12–20).
CONCLUSION: the combination of predictable mobilisation kinetics similar to those of non-pegylated G-CSF, a better acceptance profile together with an efficiency which appears to be at least as good, seems to represent progress in stem cell mobilisation in children. However, sustained blood WBC levels indicating that hematopoiesis has not returned to steady state necessitates a slight delay (at least 7 days) in resuming the chemotherapy program.
Fucoidan down Regulates the Expression of CXCR4 In Vitro on Human Hematopoietic CD34+ Cells.
Authors: Irhimeh Mohammad R. , Nordon Robert E. , Ko Kap-Hyoun E. , Fitton Helen , Lowenthal Raymond M. 
Published: October 2019

Abstract
Sulfated glycans such as fucoidan have been shown to induce rapid hematopoietic progenitor stem cell (HPCs) mobilization in mice and primates. Our previous clinical study has demonstrated up-regulation of CXCR4 on peripheral CD34+ cells in volunteers who had received oral doses of 75% pure fucoidan. The aim of this study was to investigate the in vitro effects of fucoidan on a cytokine mediated CD34+ cell expansion system and to characterize the fucoidan effects on CD34+ proliferation and differentiation using a factorial design experiment and flow cytometry. Isolex selected CD34+ cells harvested from multiple myeloma patients were used in the study. There is institutional approval for the in vitro growth of CD34+ cells from mobilized peripheral blood.
Fractional (25−1 resolution V, 16 runs, 2 blocks, E=ABCD) and full (24, 16 runs, 2 blocks) factorial design experiments were used to investigate the effects of depyrogenated fucoidan (DP-GFS) and cytokines on the growth of CD34+ cells. The cells were grown in 24 well dishes (1 ml/well) at an inoculum density of 20,000 cells/ml in serum free media and cultured for 10 days in a cytokine cocktail including G-CSF, FL, SCF, TPO and SDF1 each at two levels 100 ng/ml or 1000 ng/ml. DP-GFS was used in the cultures at four different levels including 0, 10, 100 and 500 μg/ml. Cells were then harvested and analyzed using three color flow cytometry and a panel of antibodies that includes CD15, CD14, CD41a, CD38, CD34, and CXCR4.
The in vitro effect of DP-GFS on CXCR4 expression was opposite to that found in vivo using 75% fucoidan. At 100 ng/ml and at saturating levels of FL, SCF, TPO and G-CSF (1000 ng/ml), DP-GFS at 10 μg/ml was observed to reduce the number of CD34+ cells produced per input CD34+ cell (1.09±0.07 versus 0.84±0.05, n=16, p=0.002) and have a negative effect on the percentage of CD34+ cells that express CXCR4 (87.2±1.8 versus 77.4±2.3, n=16, p=0.001). There was no significant effect of DP-GFS on the total cellular output nor other cell subsets examined (CD41a+CD14−, CD15+, CD14+). Our in vitro results are more consistent with a recent clinical study that demonstrates down-regulation of CXCR4 receptors on CD34+ cells in G-CSF or GM-CSF mobilized blood (Dlubek et al, 2006). We hypothesize that fucoidan acts in vitro and in vivo via different mechanisms.
Angiogenesis in Multiple Myeloma (MM): Angiogenic Switch or Reflexion of Plasma Cell Number? A Gene Expression Based Survey in Primary Myeloma Cells and the Bone Marrow Microenvironment.
Authors: Hose Dirk , DeVos John , Heiß Christiane , Rossi Jean-Francois , Rösen-Wolff Angela , Benner Axel , Mahtouk Karène , Hundemer Michael , Reme Thierry X. , Hillengass Jens , Herde Katja , Mazitschek Uta , Moreaux Jérôme , Wenisch Sabine , Pantesco Véronique , Jauch Anna , Jourdan Eric , Goldschmidt Hartmut , Klein Bernard , Möhler Thomas 
Published: October 2019

Abstract
BACKGROUND. Angiogenesis is a hallmark of active multiple myeloma. However, two etiologic hypotheses have been proposed:
an angiogenic switch (i.e. differential or de novo expression of pro/antiangiogenic genes in MM), and, alternatively an effect of increased plasma cell number.
AIM of this study was to investigate the angiogenic signature of multiple myeloma cells (MMC), normal bone marrow plasma cells (BMPC), the bone marrow microenvironment (BMME) and cellular subfractions therein.
PATIENTS AND METHODS. 128 newly diagnosed MM-patients (65 training (TG) / 63 independent validation group (VG)) and 14 normal donors (ND) were included. Bone marrow aspirates were CD138-purified by activated magnetic cell sorting. Whole bone marrow (n=49) and FACSAria sorted subfractions thereof (n=5) were investigated. RNA was in-vitro transcribed and hybridised to Affymetrix HG U133 A+B GeneChip (TG) and HG U133 2.0 plus arrays (VG). Expression data were gcrma-normalised and the empirical Bayes algorithm used. p-Values were adjusted using the Benjamini-Hochberg method (Bioconductor). iFISH was performed on purified MM-cells using probesets for chromosomes 1q21, 9q34, 11q23, 11q13, 13q14, 15q22, 17p13, 19q13, 22q11 and the translocations t(4;14) and t(11;14). HGF expression was verified by real time RT-PCR and western blotting. Based on Medline review, we established a list of 89 pro- and 56 antiangiogenic genes and investigated their expression according to the stage of disease: BMPC vs. MGUS, SD stage I (asymptomatic myeloma) vs. SD stage II/III (symptomatic myeloma requiring therapy).
RESULTS.
BMPC express pro- (e.g. VEGFA) and antiangiogenic genes (e.g. TIMP2). Only one pro-angiogenic gene (hepatocyte growth factor, HGF) is significantly overexpressed in MMC compared to BMPC. HGF has previously been linked with myeloma progression and induction of angiogenesis. Six antiangiogenic genes (TIMP2, SERPINF1, COL18A1, PF4, THBS1, CXCL14) are downregulated in MMC compared with BMPC. Compared to healthy donors, the BMME of MM shows a significant downregulation of PLAU (urokinase, antiangiogenic) and upregulation of TNF(proangiogenic).
CONCLUSION. Upregulation of HGF-expression, downregulation of TIMP2, SERPINF1, COLA18A1, PF4, THBS1 and CXCL14 expression in MMC as well as downregulation of PLAU and upregulation of TNFα in the BMME seem to indicate an “angiogenic switch”. However, given the relatively low number of differentially expressed genes (7/145) and the expression of angiogenic genes by BMPC, an effect caused by an increasing number of plasma cells might be evenly important.
Akt Inhibitor Perifosine-Induced Cytotoxicity Is Associated with Significant Downregulation of Survivin in Human Multiple Myeloma (MM) Cells.
Authors: Hideshima Teru , Yasui Hiroshi , Catley Laurence , Raje Noopur , Chauhan Dharminder , Ishitsuka Kenji , Podar Klaus , Mitsiades Constantine , Tai Yu-Tzu , Vallet Sonia , Kizitepe Tanyel , Ocio Enrique , Ikeda Hiroshi , Okawa Yutaka , Hideshima Hiromasa , Munshi Nikhil C. , Richardson Paul G. , Anderson Kenneth C. 
Published: October 2019

Abstract
Perifosine (NSC 639966; Keryx Biopharmaceuticals, New York, NY) is a synthetic novel alkylphospholipid, a new class of anti-tumor agents which potently inhibits Akt (PKB) activity. Our previous studies have shown that Perifosine induces significant cytotoxicity in MM cells triggered by c-Jun NH2-terminal kinase (JNK) activation followed by caspase-8, caspase-9, and PARP cleavage even in the presence of cytokines (ie, IL-6 and IGF-1) or bone marrow stromal cell (BMSCs). Importantly, MEK inhibitor and bortezomib enhance Perifosine-induced cytotoxicity. It has also shown significant anti-tumor activity in a human MM cell xenograft mouse model (Hideshima et al. Blood2006, 107:4053–4062). In this study, we further delineated molecular mechanisms whereby Perifosine triggers cytotoxicity as a single agent and in combination with bortezomib in MM cells. In most MM cell lines, the IC50 for Perifosine-induced cytotoxicity is 5–10 μM range assessed by MTT assay at 24h; however, apoptosis assessed by APO2.7 staining, varied in each cell line. Moreover, neither the degree of JNK phosphorylation nor caspase-8/9/PARP cleavage correlated with Perifosine-induced cytotoxicity. Therefore we further examined expression level of anti-apoptotic proteins in MM cell lines and found that survivin, which has a crucial role in regulation of caspase-3 activity, was markedly downregulated by Perifosine treatment in a time- and dose-dependent fashion, without affecting expression of other anti-apoptotic proteins (ie, cIAP, XIAP, Bcl-2, Bcl-xL). Since survivin is a known downstream protein of β-catenin/TCF-4 cascade, we next hypothesized that Perifosine may inhibit β-catenin activity. As expected, Perifosine significantly downregulated both phosphorylation and protein expression of β-catenin, associated with downregulation of survivin and enhanced caspase-3 cleavage. Real-time PCR confirmed that gene expression of survivin was suppressed 35% and 55% after 3h and 6h Perifosine treatment, respectively. Since β-catenin is a substrate of proteasomes, we further examined whether bortezomib could augment survivin expression by blocking its degradation. Importantly, bortezomib significantly upregulated β-catenin and survivin, which was blocked in the presence of Perifosine. These results suggest that inhibition of bortezomib-induced survivin expression, at least in part, accounts for enhanced bortezomib-induced cytotoxicity by Perifosine. Based upon these preclinical studies, a rational combination trial of bortezomib with Perifosine to treat relapsed refractory MM is currently ongoing.
Inhibition of Kinesin Spindle Protein Induces Apoptosis and Overcomes Drug Resistance in Models of Multiple Myeloma.
Authors: Chen Qing , Pamarthi Vishwan , Kuhn Deborah J. , Voorhees Peter M. , Strader John S. , Orlowski Robert Z. 
Published: October 2019

Abstract
Introduction: Kinesin spindle protein is a mitotic kinesin that is expressed only in proliferating cells and plays a key role in spindle pole separation, formation of a bipolar mitotic spindle, and thus in satisfaction of the mitotic checkpoint. Ispinesib (SB-715992) is a potent and selective inhibitor of kinesin spindle protein with a Ki of 0.6 nM, has cytotoxic activity at less than 10 nM in a spectrum of tumor cell lines, and disrupts the assembly of functional bipolar mitotic spindles.
Methods: This study sought to examine whether spindle disruption by inhibition of kinesin spindle protein with ispinesib may have therapeutic potential in the treatment of multiple myeloma.
Results: Ispinesib reduced cell viability in both interleukin-6-independent (RPMI 8226 and U266) and interleukin-6-dependent (ANBL-6 and KAS-6/1) models of multiple myeloma in a time- and concentration-dependent fashion. The average IC50 for ispinesib against these cell lines was 3.0 nM, 1.7 nM, 1.8 nM, and 1.8 nM, respectively. Cell cycle analysis showed that ispinesib induced growth arrest of myeloma cells with 4N DNA content (in M phase) within 24-hours. Two days after treatment at a 1 nM concentration, cells were able to recover from M phase arrest and resume normal cycling but, after exposure to 10 nM, treated cells could not escape M phase arrest, and instead entered apoptosis as determined by an increased sub-G1 population. Ispinesib was able to overcome resistance to melphalan in that the IC50 in melphalan-resistant RPMI 8226/LR5 cells (1.6 ± 0.2 nM) was comparable to that in parental RPMI 8226 controls (3.0 ± 0.9 nM). Similarly, ispinesib was also able to overcome dexamethasone resistance and bortezomib resistance. In regard to the latter, KAS-6/VR5 bortezomib-resistant cells (IC50 of 12.5 nM for bortezomib) retained sensitivity to ispinesib (IC50 1.6 ± 0.2 nM). Combination therapy with ispinesib and bortezomib in these cells resulted in enhanced levels of specific apoptosis (24%) that were greater than the sum of either agents alone (7% for ispinesib and 1% for bortezomib), suggesting synergy. Importantly, ispinesib was also active against freshly isolated CD138+ patient-derived multiple myeloma cells, while relatively sparing CD138− cells.
Conclusions: Taken together, these studies demonstrate that kinesin spindle protein inhibition with ispinesib was able to induce growth arrest and apoptosis in myeloma cells, and overcome resistance to both conventional drugs and novel agents such as bortezomib. Moreover, the preferential activity against transformed plasma cells with sparing of normal bone marrow cells provides a strong rationale for translation of this agent into the clinic to combat relapsed/refractory multiple myeloma.