bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hematologic Outcomes and Erythropoiesis-Stimulating Therapy Costs in Epoetin Alfa (EPO)- and Darbepoetin Alfa (DARB)-Treated Cancer Patients: Results of the Dosing and Outcomes Study of Erythropoiesis-Stimulating Therapies (D.O.S.E. Registry).
Authors: Chen Er , Peake Cyrus , Buscaino Erminia , Forlenza Jamie , Bookhart Brahim , McKenzie Scott 
Published: October 2019

Abstract
Background: National Comprehensive Cancer Network (NCCN) anemia treatment guidelines recommend maintenance of hemoglobin (Hb) levels between 11–12 g/dL. To investigate hematologic outcomes and costs of erythropoiesis-stimulating therapies (ESTs), data were analyzed from the D.O.S.E. Registry, an ongoing, prospective registry collecting data on real-world practice patterns and outcomes in cancer patients treated with ESTs.
Methods: Data come from U.S. hospital and community-based outpatient practices assessed from 1/04–6/06. Adult patients with a non-myeloid malignancy and receipt of at least 2 doses of either EPO or DARB were included. Outcomes assessed included mean treatment duration; mean cumulative dose; maintenance of Hb between 11–12g/dL; mean Hb level at Weeks 4, 8, 12, and 16; and proportion of patients receiving blood transfusions. EST costs were based on May 2006 wholesale acquisition costs.
Results: 861 patients (312 EPO, 549 DARB) from 45 sites were identified. Mean baseline characteristics were similar between the groups (entire cohort: age 62.4 years, 64.1% women, weight 75.9 kg, and Hb 10.4 g/dL) with the exception of a significantly higher proportion of patients receiving iron supplementation in the DARB-treated group (EPO 18%, DARB 29%, p<0.01). The most common malignancies were breast, lung and gastrointestinal. Both groups had similar mean treatment duration (approximately 8 weeks), number of Hb assessments (approximately 8) and proportion of patients requiring blood transfusion following the initial four weeks of treatment (EPO 9%, DARB 11%, p=0.32). The mean cumulative doses for EPO (373,827 Units) and DARB (1,185 mcg) were associated with EST drug costs of $4,550 for EPO and $5,267 for DARB, (p<0.001). Mean Hb level was ≥ 11 g/dL at all post-baseline time points in the EPO-treated group, however <11 g/dL in the DARB-treated group at Weeks 12 and 16. Mean Hb level was significantly higher in the EPO-treated group at Week 12 (EPO 11.3 g/dL, DARB 10.8 g/dL, p=0.03).
Conclusions: In this prospective observational study, EPO-treated patients achieved and maintained NCCN target Hb levels at all timepoints. These findings also showed EST cost to be 16% higher in the DARB-treated group than in the EPO-treated group.
Hematology-Related Direct-to-Consumer Advertising: A Content Analysis and Verification of Claims from Print Media.
Authors: Abel Gregory A. , Sorel Marie-Adele , Neufeld Ellis J. , Weeks Jane C. 
Published: October 2019

Abstract
Background: Patient-directed marketing of hematology medications is an increasingly prevalent and controversial practice. Content analysis of hematology-related direct-to-consumer advertising (DTCA), with attention to how benefit and risk/side effect information is presented as well as assessment of the appeals and claims made, is essential to understanding its potential effect on patient outcomes.
Methods: We reviewed all DTCA for hematological medications appearing in 2005 in the largest circulation patient-focused bleeding-disorder and cancer magazines (Hemaware and CURE), as well as a sample of popular magazines. We assessed the Flesch reading ease score (FRES) for the benefit and risk/side effect text presented in each advertisement. Ranging from 0 to 100, a FRES of 65 or higher is considered understandable for the average person. We also assessed the proportion of text dedicated to, and the largest type size of, benefit and risk/side effect information, as well as the nature and content of the advertisements’ appeals. We then attempted to link the advertisements’ main efficacy or safety appeal to the hematological literature based upon references available from a Medline search for the claim and the drug name.
Results: Of 134 total ads reviewed, 20 unique advertisements were analyzed (the remainder were repeats). Overall, the ratio of number of words devoted to benefit text versus risk/side effect text was 1.33. The mean FRES for benefit information was 39.0, while the mean FRES for risks/side effects was 23.7, a difference of 15.3 [95% CI: 6.4, 24.2]. The mean largest benefit type size was 6.1 mm, while the mean largest risk/side effect type size was 2.3 mm, a difference of 3.8 mm [95% CI: 1.7, 5.6]. 65% of ads made appeals to social-psychological enhancements (eg: regaining a normal life). 88% of the ads made appeals to efficacy, and 53% to safety; we were able to verify all of these except one through Medline.
Conclusion: Hematology print DTCA is difficult to read. When compared to risks/side effects, benefits often comprise more text, appear in larger typeface, and are presented in language that is somewhat more readable. Appeals to efficacy and safety are common, and, for the most part, easy to verify with Medline. Although the ultimate effects of hematology DTCA for patients and providers remain to be elucidated, awareness of its characteristics is a vital first step toward better informing its regulation.
Economic Burden of Hematologic Adverse Events in Cancer Patients Undergoing Chemotherapy: A Systematic Review.
Authors: Stephens Jennifer M. , Liou Sarah Y. , Tran Kimbach T. , Botteman Marc F. 
Published: October 2019

Abstract
OBJECTIVES: Hematologic adverse events such as neutropenia, thrombocytopenia, and anemia are commonly experienced by cancer patients receiving chemotherapy. These cytopenias are associated with increased morbidity and mortality, high healthcare costs, and decreases in quality of life. The objective of this study was to review the economic burden of these hematologic adverse events associated with chemotherapy in cancer patients.
METHODS: A systematic search of the English-language medical literature published between 1990 and 2006 was conducted. Online conference proceedings and a review of article bibliographies were included in the review. Articles selected included prospective or retrospective studies specifically designed to examine burden of illness, direct medical costs, indirect costs, or cost drivers associated with neutropenia, thrombocytopenia, and anemia in adult cancer patients treated with chemotherapy. All original costs were reported, with adjusted figures (to 2006 US dollars) presented in parentheses using the medical care component of the consumer price index from the US Bureau of Labor Statistics.
RESULTS: Of 160 studies initially identified, 64 met selection criteria and were reviewed in detail. The cost of neutropenia ranged from $1,893 (2006 US $2,632) per episode in the outpatient setting to $38,583 ($54,807) for a febrile neutropenia hospitalization. The cost of treating thrombocytopenia ranged from $1,037 ($1,395) to $7,550 ($9,336) per cycle or episode. Costs attributable to treating anemia ranged from $18,418 ($22,775) to $69,478 ($93,454) per year. Key cost drivers include hospitalization, drugs (e.g., granulocyte colony-stimulating factors and antibiotics), and diagnostic tests for neutropenia; hospitalization, major bleeding episodes, and platelet transfusions for thrombocytopenia; and inpatient and outpatient services, erythropoietic agents, and red blood cell transfusions for anemia. Another finding was that the costs of hematologic adverse events for patients with hematologic malignancies were up to twice that of patients with solid tumors.
CONCLUSIONS: Chemotherapy-related cytopenias result in a substantial economic burden on patients, payers, caregivers, and society in general. This burden is particularly high for patients with hematologic malignancies due to the underlying malignancy. Furthermore, AEs affect the ability to deliver planned treatments, resulting in potentially suboptimal clinical outcomes. An evaluation of both clinical outcomes of chemotherapy and economic consequences as a result of chemotherapy-induced toxicities is recommended in determining optimal treatments for patients with cancer.
Incidence, Risk Factors and Outcomes of Bronchiolitis Obliterans after Allogeneic Stem Cell Transplantation.
Authors: Nakaseko Chiaki , Ozawa Shinnichi , Nishimura Miki , Sakai Miwa , Ohshima Kumi , Kanda Yoshinobu , Takahashi Satoshi , Shimizu Takayuki , Okamoto Shinichiro , Yokota Akira , Yoshiba Fumiaki , Fujimaki Katsumichi , Kanamori Heiwa , Sakai Rika , Matsushima Takafumi , Sakura Tohru , Sakamaki Hisashi 
Published: October 2019

Abstract
Background: Bronchiolitis obliterans (BO) after allogeneic stem cell transplantation (allo-SCT) is a late-onset, life-threatening respiratory complication which significantly reduces patients’ quality of life. Despite different therapeutic protocols, BO mortality remains high and most patients die of respiratory failure or infections. In recent practice, the source of stem cells and the conditioning regimen for allo-SCT have become more varied, but their influence on the incidence of BO is not established. Here, we retrospectively analyzed incidence of and risk factors for BO in allo-SCT protocols.
Patients and methods: Between Jan 1994 and June 2005, 2692 patients underwent allo-SCT in 14 facilities of the Kanto Study Group for Cell Therapy (KSGCT) in Japan, and 2154 surviving at least 100 days after transplantation were evaluated in this study. Clinical diagnosis of BO was made by pulmonary function tests (PFT) revealing a forced expiratory volume for 1 second (FEV1) less than 70% and FEV1/forced vital capacity less than 80% of the predicted value, along with typical changes on high-resolution computed tomography.
Results: BO developed in 57 patients with a cumulative incidence at 5 years post transplant of 2.6%. The Kaplan Meier estimate of median time interval from transplant to diagnosis of BO was 335 days (83–907). The cumulative incidence of BO at 5 years was 1.62% (12/691) in bone marrow transplants from related donors (R-BMT), 3.83% (16/424) in peripheral blood stem cell transplantation from related donors (R-PBSCT), 2.91% (24/808) in BMT from unrelated donors (UR-BMT), and 2.65% (5/199) in unrelated cord blood transplantation (CBT). The incidence of BO after R-PBSCT was significantly higher than after any other type of allo-SCT (p=0.02). At BO diagnosis, the mean value of FEV1% decreased to 52.1% from 82.2% pre-transplant. 94% of patients had already developed chronic GVHD before the onset of BO. Risk factors for BO by univariate analysis were R-PBSCT (p=0.019) and preceding chronic GVHD (p=0.000). Twenty eight patients died after developing BO, 21 of respiratory failure. Only one patient died of relapse of primary disease. Overall 5 yr-survival of patients with BO from the time of diagnosis was 46.5%, significantly less than for those without (76.2% from day 335, p=0.000) by semi-landmark analysis.
Conclusions: The incidence of BO in CBT recipients was higher than R-BMT recipients and not significantly different with UR-BMT recipients. R-PBSCT recipients who have already developed chronic GVHD have a higher risk for developing BO and need extensive care and repeated PFT examinations.
Gene Expression Profiling of the Clinical Significant CD57+CD8+ Cytotoxic T Cell Expansions in Patients with Waldenstrom’s Macroglobulinemia.
Authors: Sze Daniel , Yamagishi Tetsuo , Kaplan Warren , Brown Ross D. , Ho Phoebe Joy , Gibson John , Joshua Douglas E. 
Published: October 2019

Abstract
Previous studies have suggested that expanded T-cell clones are found in the blood of 59% of patients with multiple myeloma. These expanded T-cell clones are associated with prolonged overall survival and thus it has been suggested that they may have anti-tumor activity. We have previously reported similar T-cell clones exist in the peripheral blood of patients with Waldenstrom’s Macroglobulinemia (WM) by using flow cytometry to determine the T cell receptor (TCR) Vβ repertoire. Expanded T-cell clones were detected in 9 of 15 (60%) patient samples. Of the nine patients with TCR Vβ clones, four patients had multiple clones. The TCR Vβ clones were not identical, representing a variety of families across the TCR Vβ repertoire.
We have previously found that while the TCRVβ+CD8+CD57 negative subset represents polyclonal populations, the CD57 positive subset represents either monoclonal or biclonal populations. By comparing the genetic profiling of these two subsets from a statistically significant gene list, two genes have been found to be highly upregulated in the CD57 negative polyclonal subset. These two genes are i.) SESN3, a member in the Sorting Nexin (SNX) protein family which is implicated in regulating membrane traffic capable of interaction with phosphatidylinositol-3-phosphate (10.4 fold, p=0.0241); ii.) Epstein-Barr virus induced gene 2 (lymphocyte-specific G protein-coupled receptor) EBI2 (7.4 fold, p=0.0207): This finding is in contrast to previous report that EBI2 is expressed in B-lymphocyte cell lines and in lymphoid tissues but not in T-lymphocyte cell lines or peripheral blood T lymphocytes.
For the CD57 positive clonal T cell expansions, consistent with our previous reports, CD28 expression was found to be down regulated by 2.6 fold. There are two genes found to be highly upregulated. They are i.) Granzyme B (4.3 fold, p=0.0337) also called Cytotoxic T-lymphocyte proteinase 2. This enzyme is necessary for target cell lysis in cell-mediated immune responses through caspase-dependent apoptosis; ii.) Granzyme H, also called Cytotoxic T-lymphocyte proteinase and probably necessary for target cell lysis in cell-mediated immune responses.
In summary, we have shown that CD57 positive clonal T cell populations exist in some patients with WM. Importantly, microarray results have indicated some genes and proteins that may related to better patients survival as previously demonstrated in patients with Multiple Myeloma.
Hematopoietic Stroma Confers Resistance to Immune Control by TRAIL in Multiple Myeloma through Induction of FLIP.
Authors: Perez Lia , Parquet Nancy , Shain Ken , Nimmanapalli Ramadevi , Alsina Melissa , Anasetti Claudio , Dalton William S. 
Published: October 2019

Abstract
TNF-related apoptosis inducing ligand/Apo-2L (TRAIL), a member of the TNF superfamily of death ligands, is preferentially cytotoxic against neoplastic cells, while sparing normal tissue. TRAIL has been implicated in tumor immune-surveillance and mediates murine allogeneic graft-versus-tumor responses. The bone marrow microenvironment provides tumor protection from chemotherapy and Fas-death receptor mediated apoptosis through a process known as environmental mediated death resistance (EM-DR). We tested whether the tumor microenvironment inhibits TRAIL-mediated killing of myeloma cells, as this process may contribute to multiple myeloma escape from immune-surveillance. Three drug-sensitive myeloma cell lines (RPMI-8226, U266 and MM1s) exhibit apoptosis resistance to recombinant human (rh) TRAIL while adhered to HS5 stromal cells that expresses green-fluorescence-protein (HS5-GFP). Apoptosis resistance to TRAIL was time- and dose- dependent. Evaluation of TRAIL apoptosis in a transwell (TW) assay, with HS5-GFP cells on the bottom and RPMI-8226 cells in the upper well (TW+HS5) revealed that HS5-GFP stromal cells blocked TRAIL-induced apotosis through soluble factors. We then assessed the modifications in the TRAIL signaling pathway induced by TW+HS5 and responsible for the observed phenotype. RPMI-8226 treated in TW+HS5 exhibited attenuated pro-caspase-8, pro-caspase-3, PARP, and BID cleavage, with diminished mitochondrial membrane potential changes, but without alterations on TRAIL receptors and other Bcl-2 family members. We found increased levels of Fas-associated death domain like IL-1 converting enzyme-like inhibitory protein (FLIP), a regulatory factor that competes with caspase-8 inhibiting apoptosis. Subcellular fractionation of RPMI-8226 cells showed that FLIPL is maintained in or associated with organelle membranes and is released to the cytosol when exposed to soluble factor (TW+HS5) suggesting that that soluble factor signaling may influence FLIPL localization and availability. Furthermore, FLIP reduction by FLIP-RNA interference increases TRAIL sensitivity of RPMI-8226 treated in TW+HS5. Bortezomib is a proteosome inhibitor that inhibits NF-KB and reduces FLIP levels. To this end, pretreatment of RPMI-8226 cells with bortezomib for 20 hours followed by TRAIL for 4 hours overcame TRAIL EM-DR through inhibition of FLIP, thus providing rationale for testing this drug combination in a clinical trial. In addition, rh-IL-6 induced FLIP levels in RPMI-8226 cells conferring resistance to TRAIL mediated apoptosis. Our results suggest that IL-6 and other soluble factors produced by marrow stromal cells promote myeloma cell survival by upregulating FLIP, thereby mitigating the influence of the microenvironment on TRAIL-induced apoptosis. We conclude that the cytotoxic effect of TRAIL may be enhanced by FLIP inhibitors.
IL-6, IGF-1 and IL-21 Act in Synergy with HGF in Myeloma Cells by Inducing the HGF-Receptor c-Met.
Authors: Hov Håkon , Fagerli Unn-Merethe , Tian Erming , Waage Anders , Borset Magne , Sundan Anders 
Published: October 2019

Abstract
HGF is known to be a prognostic factor in multiple myeloma, however the proliferative effect of HGF alone has been moderate. We investigated the effects of the myeloma growth factors IL-6, IGF-1 and IL-21 in combination with HGF in the myeloma cell lines IH-1, INA-6 and OH-2. In proliferation experiments the cells were grown in serum free media with 3 different HGF-concentrations together with various concentrations of IL-6, IGF-1 or IL-21. HGF alone had low effect. However, 200 ng/ml HGF in combination with IL-6 doubled the effect of IL-6 and tripled the effect of IGF-1 in INA-6. Similar results were obtained in OH-2 combining IL-6, IGF-1 and IL-21 with HGF and in IH-1 combining IL-6 with HGF. A combination of IL-6 and IGF-1 in INA-6 gave no synergistic effects, so the synergism seemed to be a specific effect for HGF in combination with the other cytokines.The myeloma cell line ANBL-6 harbours an autocrine growth promoting HGF-loop. We inhibited this autocrine HGF loop with a specific c-Met receptor tyrosine kinase inhibitor PHA-665752 in the presence of IL-6 and IGF-1. IL-6 and IGF-1 potentiated the decrease in proliferation caused by PHA-665752. These results demonstrate synergistic effects between the three cytokines (IL6, IGF-1, IL-21) and HGF. We also combined PHA-665752 and IL-6 in INA-6 cells, and 200 nM of the c-Met inhibitor halved the effect of IL-6. We have not seen any unspecific effects of PHA-665752 at 200 nM. This result raises the very interesting possibility that some of the effects of IL-6 can be due to c-Met signalling. At the protein level the cell lines responding to IL-6, IGF-1 or IL-21 also increased the level of c-Met expression in response to the individual cytokines. In OH-2 there was also an increase in the HGF transcript after IL-6, IGF-1 and IL-21 stimulation, as investigated by RT-PCR, indicating another mechanism for synergy between the HGF-c-Met pathway and the other cytokines in this cell line. In conclusion our results demonstrates the induction of c-Met by IL-6, IGF-1 and IL-21, and proliferative synergy between these cytokines and HGF in myeloma cell lines. Inhibition of c-Met with a specific tyrosine kinase inhibitor decreased the proliferative effect of IL-6. Together these results indicate that inhibition of c-Met signalling would target several pathways and could therefore be a promising treatment strategy in multiple myeloma.
BIRB796 Inhibits p38 MAPK/Hsp27 Pathway and Enhances Cytotoxicity Triggered by Bortezomib, Hsp90 Inhibitor, and Dexamethasone in Multiple Myeloma.
Authors: Yasui Hiroshi , Hideshima Teru , Ikeda Hiroshi , Jin Janice , Ocio Enrique M. , Kiziltepe Tanyel , Okawa Yutaka , Vallet Sonia , Chhetri Shweta , Ishitsuka Kenji , Tai Yu-Tzu , Podar Klaus , Chauhan Dharminder , Pargellis Chris , Moss Neil , Raje Noopur , Anderson Kenneth C. 
Published: October 2019

Abstract
We have previously shown that heat shock protein (Hsp) 27 or its upstream molecule p38 mitogen-activated protein kinase (MAPK) confers resistance to bortezomib and dexamethasone (Dex) in multiple myeloma (MM). In this study, we evaluate the anti-tumor activity of combination treatment with novel p38 MAPK inhibitor BIRB796 and other therapeutics agents in MM. Although BIRB796 alone triggers a marginal growth inhibitory effect in MM cells, it blocked baseline and bortezomib-triggered upregulated phosphorylation of p38 MAPK and Hsp27, associated with enhanced cytotoxicity in combination with bortezomib. BIRB796 augmented bortezomib- triggered cleavage of caspase-8, caspase-9, and poly(ADP)-ribose polymerase (PARP). We next examined the combination of BIRB796 with Hsp90 inhibitor 17-AAG. Surprisingly, 17-AAG up-regulates protein expression and phosphorylation of Hsp27; conversely, BIRB796 inhibits this phosphorylation and enhances 17-AAG-induced cytotoxicity. Importantly, BIRB796 enhances cytotoxicity induced by 17-AAG plus bortezomib. BIRB796 also augments cytotoxicity of Dex in MM cells, associated with inhibition of Hsp27 phosphorylation. In bone marrow stromal cells (BMSCs), BIRB796 inhibited phosphorylation of p38 MAPK and secretion of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) triggered by either tumor necrosis factor-α or tumor growth factor-β 1. BIRB796 also inhibits IL-6 secretion in BMSCs triggered by adherence to MM cells, thereby inhibiting MM cell proliferation. These studies therefore suggest that BIRB796 overcomes drug-resistance in the BM microenvironment, providing the framework for clinical trials of a p38 MAPK inhibitor alone, and in combination with bortezomib, Hep90 inhibitor, or Dex, to improve patient outcome in MM.