bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of High-Dose Cyclophosphamide and Growth Factor with Growth Factor Alone for Mobilization of Stem Cells for Transplantation in Patients with Multiple Myeloma.
Authors: Gertz Morie Abraham , Kumar Shaji , Lacy Martha , Dispenzieri Angela , Hayman Suzanne , Buadi Francis , Dingli David , Gastineau Dennis , Winters Jeffery , Litzow Mark 
Published: April 2020

Abstract
Introduction: We retrospectively analyzed outcomes of 716 patients with multiple myeloma who were mobilized using cyclophosphamide and growth factor (n=370) or growth factor alone (n=346) before stem cell transplantation.
Table. Patient Characteristics (N=716)
Variable Cyclophosphamide (n=370) Growth Factor Only (n=346) P Value Abbreviation: IQR, interquartile range. *Or equivalent dosage. Men, No. of patients (%) 224 (61) 202 (58) .50 Age, median (IQR), y 58 (52–64) 60 (53–65) .11 b-2 Microglobulin, median (IQR), mcg/mL 2.7 (1.9–4.0) 2.3 (1.9–3.2) .01 Creatinine, median (IQR), mg/dL 1.1 (0.9–1.3) 1.0 (0.8–1.2) .002 Apheresis, median (IQR) collections, No. 2 (1–3) 4 (3–6) .001 Marrow plasma cells, % 17 (5–34) 5 (1–13) .001 CD34+cells, median (IQR), cells/kg Total collected 10.3x106(7.2x106–14.6x106) 9.9x106(7.6x106–11.9x106) .01 Infused 5.6x106(4.5x106–7.6x106) 4.2x106(3.8x106–5.0x106) &lt;.001 Duration of hospitalization, median (IQR), d 4 (0–10) 4 (0–9) .92 Nonstaphylococcal bacteremia, No. of patients (%) 48 (13) 25 (7) .01 Melphalan dosage, No. of patients (%) .04 200 mg/m2* 337 (91) 298 (86) 140 mg/m2* 33 (9) 48 (14) Exposure before mobilization, No. of patients (%) Melphalan 45 (12) 44 (13) .50 Lenalidomide 14(4) 63(18) .01
Results: Patients receiving cyclophosphamide had higher stem cell yields than the growth factor only group (median number of apheresis sessions needed to achieve stem cell collection goals, 2 vs 4 sessions, respectively [P=.001]). However, patients treated with cyclophosphamide required more time for engraftment of platelets and neutrophils (P&lt;.001 for both).
For patients receiving cyclophosphamide, 75% achieved engraftment (defined as a platelet count of 50x109/L) by day 39, whereas 75% of patients not receiving cyclophosphamide achieved engraftment by day 18. Similar results were observed for neutrophil engraftment. These differences did not affect the duration of hospitalization, but patients treated with cyclophosphamide had a higher incidence of posttransplant nonstaphylococcal bacteremia. For cyclophosphamide-mobilized patients, considerably faster platelet engraftment (5 fewer days) resulted if stem cell reinfusion occurred more than 30 days after the first apheresis session.
Conclusion: Our data suggested that cyclophosphamide damaged the microenvironment and slowed engraftment. By lengthening the period between the completion of apheresis and stem cell reinfusion, the microenvironment may recover and result in faster engraftment. We suggest that the cyclophosphamide used for mobilization may affect the marrow microenvironment. Cyclophosphamide improves yields but increases bacteremia rates after transplantation. Cyclophosphamide increases time required to collect stem cells and slows engraftment.
Figure Figure
The Effect of Physical Conditions on the Transportation of Peripheral Blood Progenitor (PBPC) Products.
Authors: Jansen Jan , Nolan Pamela L , Reeves Margaret I , Akard Luke Paul , Thompson James M. , Dugan Michael J , Hanks Susan G 
Published: April 2020

Abstract
The viability of transported PBPC products has not been studied extensively. Commonly, PBPC products are transported at a concentration of &gt;200 x109/l in containers with −20oC ice packs. Continuous temperature monitoring has shown that the temperatures of these products stays at &lt;10oC for less than 24 hours and reaches room temperature by 48 hours. Samples of freshly collected PBPC from 12 allogeneic donors were studied for various viability parameters during storage for up to 96 hours. The effects of storage time, concentration of cells, temperature, and storage in gas-permeable bags were studied. Trypan-blue exclusion and double fluorescence for 7-AAD and CD34 were used for viability assessment. Over a wide range of temperatures and storage times, the viable CD34+ assay was more sensitive to damage than trypan-blue exclusion (mean Δ 10.7%, p&lt;0.0001 in paired t-test). The viable CD34+ assay was routinely used in parallel with CFU-GM cultures. No difference in survival of viable CD34+ cells or CFU-GM was found whether cells were incubated for 48hr in test-tubes or in gas-permeable bags. When cells at 200 x 109/l were incubated for 48hr at room temperature, the mean viability decreased to 19% and 6% of starting values of viable CD34+ cells and CFU-GM, respectively. Serial dilution to 25 x 109/l improved the survival to 81% and 51% respectively. Similarly, incubation at lower temperatures led to better survival of CD34+ cells and CFU-GM: 67% and 18% at 17oC, 80% and 50% at 13oC, and 95% and 86% at 4oC. At 200 x109/l and 22oC the survivals of CD34+ cells and CFU-GM were 74% and 21% at 24hr, 19% and 7% at 48hr, 7% and 6% at 72hr, and 3% and 13% at 96hr. The effects of concentration, temperature and duration of storage were all significant (p&lt;0.05). Transportation at 4oC leads to the best survival of CD34+ cells and CFU-GM, in particular at a low concentration. If transportation at a slightly higher temperature is necessary, dilution of the PBPC product will enhance the survival of CD34+ cells and CFU-GM. Proliferative assays such as CFU-GM appear the most sensitive parameters of PBPC survival, and should be included in the validation process of PBPC transportation.
Interaction with Human Stromal Cells Enhances CXCR4 Expression and Engraftment of Cord Blood Lin-CD34-Cells Via Wnt Signaling.
Authors: Kobune Masayoshi , Murase Kazuyuki , Iyama Satoshi , Sato Tsutomu , Kikuchi Shohei , Kawano Yutaka , Takada Kohichi , Miyanishi Koji , Takimoto Rishu , Kato Junji 
Published: April 2020

Abstract
Ex vivo manipulation of hematopoietic stem/progenitor cells has been performed in preclinical and clinical settings for expansion of hematopoietic stem cells (HSCs) and enhancement of HSC engraftment. Because the absolute HSC dose in a cord blood (CB) unit is a limiting factor for its use as a graft for adult transplant recipients. Transplantation of hematopoietic stem cells (HSCs) is usually accomplished through intravenous injection, a complex process that requires recognition of bone marrow vasculature and migration to a supportive microenvironment. Hence, some populations of HSCs, including cord blood (CB) Lin-CD34-stem cells, do not engraft well in bone marrow (BM) of NOD/SCID mice. In this study, we examined the effect of human stromal interactions on the properties of CB Lin-CD34-cells. CD34 and CXCR4 expression on fresh CB Lin-CD34-cells and CB Lin-CD34-cells co-cultured with human stromal cells were analyzed. Homing activity and engraftment of these cells were assessed using NOD/SCID mice. Co-culture with human stromal cells induced expression of CD34 and CXCR4 on CB Lin-CD34-cells. Furthermore, these cells acquired homing activity and engrafted in the BM of primary and secondary recipients of NOD/SCID mice after intravenous injection. In an attempt to identify the stromal CXCR4-inducing factor, we conducted comparative experiments using stroma-free, contact culture or non-contact culture. As a result, CXCR4 expression on CB Lin-CD34-cells was induced even in the non-contact culture condition but not stroma-free condition, suggesting that this CXCR4-inducing factor is soluble. Because the function of hematopoietic stem/progenitor cells was modulated by several hematopoietic growth factors, angiogenic factors and morphogens, we next screened for soluble CXCR4 inducing factors using blocking antibodies for hedgehog protein, VEGF receptor (anti-KDR) and angiopoietin-1 receptor (anti-Tie2), BMP inhibitor (noggin), pan Wnt inhibitor (sFRP-1), Wnt/β-catenin signaling inhibitor (DKK1) and Wnt/RhoA signaling inhibitor. We found that DKK1 significantly reduced the expression of CXCR4. This indicated that CXCR4 could be regulated by the Wnt signaling pathway. Subsequently, we analyzed the expression of Wnt family members in human stromal cells by RT-PCR. High expression of Wnt1, Wnt2B, Wnt5A and Wnt11 were observed in human stromal cells. Thus, these Wnts may contribute to the induction of CXCR4 expression on CB Lin-CD34-CXCR4-cells. These findings may be useful for understanding the role of stromal cells in homing and engraftment of HSCs and may provide a new strategy to utilize CB and human stromal cells for HSC transplantation.
Retroviral Gene Therapy for X-Linked Chronic Granulomatous Disease: Results from Phase I/II Trial.
Authors: Kim Joong Gon , Ahn Hyo Seop , Kang Hyoung Jin , Kim Sujeong , Hong Youngtae , Joo Chang-Wan , Yoon Nam-Kyung , Kim Sunyoung 
Published: April 2020

Abstract
X-linked chronic granulomatous disease (X-CGD) is an inherited immunodeficiency disease caused by a defect in the gp91phox gene encoding one of the subunits of the NADPH oxidase complex. NADPH oxidase plays an important role in eradicating the pathogen engulfed by the phagocytes. Therefore, CGD patients suffer from recurring life-threatening infection by bacteria or fungi, and die before 30 in most cases. In an effort to treat this life-threatening disease, we initiated a phase I/II gene therapy trial in 2007. Two X-CGD patients were enrolled in the trial. The retroviral vector used for gene delivery was the MLV-based MT vector containing gp91 phox cDNA (Yu et al., Gene Ther2000; 7: 797, Hong et al., J Gene Med2004; 6: 724). Viral vectors have been produced from PG13 packaging cells in compliance with GMP. The clinical protocol was approved by the Korean FDA. G-CSF mobilized peripheral blood CD34+ cells were obtained from patients, and transduced in retronectin-coated gas-permeable bags containing SCGM media supplemented with SCF, FLT3L, TPO, and IL-3. The transduction efficiency was 10.5% for patient #1 and 28.5% for patient #2 when assessed by gp91 FACS analysis. Before receiving transduced cells, patients were treated with a conditioning regimen consisting of busulfan (3.2 mg/kg/day for 2 days) and fludarabine (40 mg/m2/day for 3 days). No adverse effects were observed from the use of busulfan and fludarabine. The percentage of superoxide-producing cells, as determined by DHR assay, was 6.4% and 14.5% at day 17, and decreased to less than 0.1% (after 1 year) and 0.4% (after 7 months). Thus far, abnormal cell expansion has not been observed.
Evaluating the Safety and Efficacy of Anti-HIV Transgenic Cells in a Humanized Mouse Model (NOD/SCIDγc−/−) for HIV Stem Cell Gene Therapy.
Authors: Anderson Joseph S. , Walker Jon , Wirthlin Louisa , Javien John , Nolta Jan A. , Bauer Gerhard 
Published: April 2020

Abstract
In vivo mouse models for safety and efficacy studies of anti-HIV gene therapeutics have been lacking in their ability to evaluate normal systemic hematopoiesis with the development of a functional immune system. These deficiencies in modeling these normal and essential physiologies can now be generated in the recently developed NOD/SCIDγc−/− mouse model. Human CD34+ progenitor cells after intrahepatic injection will undergo multi-organ engraftment generating a functional thymus along with the production of T cells, B cells, and macrophages. Upon injection with various strains of HIV-1, engrafted mice display a disseminated infection due to viral replication in human T cells and macrophages. Infected mice acquire characteristics of increased viremia over time with human CD4+ T cell depletion. Anti-HIV immune responses can also be generated in mice with high viremia. Here we demonstrate the successful engraftment of NOD/SCIDγc−/− mice after injection with human CD34+ progenitor cells isolated from umbilical cord blood. Human cell engraftment was observed in both primary and secondary lymphoid organs including the bone marrow (B cells and macrophages), thymus (T cells), spleen (T cells and B cells), lymph nodes (T cells and B cells), and peripheral blood (T cells and B cells). Human CD34+ cells were found in the liver concluding either organ retention from the initial injection or circulation in the peripheral blood. After displaying a high level of engraftment (&gt;50%), we are now able to proceed with evaluating a number of anti- HIV gene therapeutic constructs for pre-clinical testing. These lentiviral vector constructs include a CCR5 shRNA which has been previously shown to knock down complete expression of CCR5, a human/rhesus macaque chimeric isoform of TRIM5α capable of potently inhibiting HIV-1 infection at the pre-integration step, and combination constructs containing multiple anti-HIV genes. The NOD/SCIDγc−/− mouse model will allow us to evaluate both the safety of these various anti-HIV lentiviral constructs in generating normal functioning transgenic immune system cells and also the efficacy of these anti- HIV genes in inhibiting HIV-1 infection in vivo. With the ability to facilitate multilineage human cell engraftment with the susceptibility for HIV infection, this in vivo model allows for the evaluation of anti-HIV gene therapeutic constructs in a stem cell-based setting. Lentiviral vector transgenic cells can now be tested for their capacity for normal immune system reconstitution.
Systemic Therapy Utilization Patterns among US Dermatologists and Oncologists Treating Cutaneous T-Cell Lymphoma
Authors: Pinter-Brown Lauren , Wisniewski Tami , Katic Bozena , Chandwani Sheenu , Chen Ya-Ting 
Published: April 2020

Abstract
Background: Several systemic therapies are available for patients with cutaneous T-cell lymphoma (CTCL). However, little is known about physicians’ familiarity with and utilization of these therapies. To address this issue, we conducted a web-based survey among physicians treating CTCL with systemic therapies in the United States.
Methods: We surveyed a geographically representative panel of dermatologists and oncologists in September 2007. Physicians had to have treated at least one CTCL patient systemically over the past two years and been practicing medicine for &gt;2 years. Individual systemic therapies were grouped according to NCCN guidelines as Category A (ECP, bexarotene, denileukin diftitox, interferon, vorinostat, and methotrexate) or Category B therapies (gemcitabine, CHOP, and doxorubicin). Chi-square or Fisher’s exact tests assessed statistical differences between specialties.
Results: A total of 250 physicians participated; 128 dermatologists and 122 oncologists. Mean age was 47.5 (std =9.9) years and 20.0% were female. Significantly more (p &lt; 0.0001) dermatologists than oncologists reported being not or somewhat familiar with denileukin diftitox (49.2% vs. 14.8%), gemcitabine (71.1% vs.7.4%), doxorubicin (57.8% vs. 5.7%), CHOP (33.6% vs. 1.6%) and vorinostat (67.2% vs. 36.9%). Overall, use of Category A therapies decreased in later stage disease while use of Category B therapies increased. Dermatologists chose Category A therapies and referred patients more frequently, whereas oncologists chose Category B therapies and referred less frequently.
Conclusions: Familiarity with and utilization of systemic therapies for CTCL differ by physician specialty. Educational efforts aimed at highlighting advances in CTCL treatment and newly implemented treatment guidelines may help optimize patient care.
Economic Analysis of Alemtuzumab in Fludarabine-Refractory and Relapsed Chronic Lymphocytic Leukemia in Canada
Authors: Isogai Pierre K , Cheung Matthew , Mittmann Nicole 
Published: April 2020

Abstract
Background: Alemtuzumab (ALEM), a humanized antibody that recognizes the CD52 antigen, is indicated for the treatment of B-cell chronic lymphocytic leukemia (CLL) in patients who have been treated with alkylating agent and who had failed fludarabine therapy. The objective of this economic analysis was to determine the incremental cost-effectiveness of ALEM in patients with fludarabine-refractory and relapsed CLL from the perspective of a publicly funded health care system in Canada. ALEM was compared to accepted treatments for this patient population.
Methods: A two-year time horizon was used. Effectiveness and adverse event information was obtained from an extensive literature review process. Resource utilization was based on guidelines, literature and expert opinion. Costs were obtained from provincial sources and presented in 2008 Canadian dollars. Only direct medical costs were considered. A number of comparators were used to represent standard treatment: salvage therapy, which included a variety of literature-based treatment options for fludarabine-refractory patients, fludarabine+cyclophosphamide (FC), flud arabine+cyclophosphamide+rituximab (FCR), and best supportive care (BSC). BSC included the palliative costs for caring for individuals previously treated with FC.
Results: Mean survival for ALEM was 20.89 months (1.74 years), salvage therapy 16.32 months (1.36 years), FC 17.44 months (1.45 years), FCR 20.06 months (1.67 years). The incremental cost-effectiveness ratio (ICER) for the base case-ALEM vs. salvage therapy was Canadian $52,021/life year gained (LYG); ALEM vs. FC $68,165/LYG; ALEM vs. FCR $20,886/LYG. For ALEM vs. BSC, there was increased survival and cost savings with ALEM. Base case ICERs were sensitive to four variables: treatment duration of FC; treatment duration of FCR; treatment duration of ALEM; and additional survival due to rituximab for FCR patients compared to FC. Sensitivity analyses of the remaining variables showed minimal change to the base case ICERs. These variables were: ALEM administration (proportion of intravenous to subcutaneous); cytomegalovirus (CMV) complication rate for ALEM; discount rate; neutropenia and thrombocytopenia rates for ALEM; and neutropenia and thrombocytopenia rates for FCR.
Conclusion: The results show that ALEM has a favourable ICER and provided good economic value for patients with fludarabine-refractory and relapsed CLL when compared to salvage therapy, FC and FCR. ALEM was found to be dominant over BSC.
Patient Nonadherence and Treatment Response to Imatinib in Patients with Chronic Myeloid Leukemia: Results from the ADAGIO Study
Authors: Noens Lucien , van Lierde Marie-Anne , De Bock Robrecht , Verhoef Gregor , Zachee Pierre , Berneman Zwi , Martiat Philippe , Mineur Philippe , Van Eygen Koen , MacDonald Karen , De Geest Sabina , Albrecht Tara , Letvak Laurie , Abraham Ivo 
Published: April 2020

Abstract
BACKGROUND. Imatinib therapy for chronic myeloid leukemia (CML) is a long-term treatment potentially compromised by patient nonadherence.
OBJECTIVE. To examine whether patients (pts) at different levels of treatment response differ in adherence to imatinib treatment.
DESIGN & PATIENTS. The ADAGIO study1 is a prospective, 90-day (90d) observational, open-label, multicenter study of pts with chronic myeloid leukemia (CML) and treated with imatinib. 169 evaluable pts who had been on imatinib for a minimum 30 days at enrollment were studied. A sub-analysis included pts with optimal vs. suboptimal response (all patients) and complete vs. incomplete cytogenetic response (CgR; all patients and those treated with imatinib ≥12 months).
MEASUREMENTS. Adherence: imatinib pill count over 90d expressed as % of prescribed imatinib taken. Suboptimal response (SR): incomplete hematologic response at 3 months, and/or less than partial CgR at 6 months, and/or less than major molecular response and, in case of loss of major molecular response, other limitations or chromosomal abnormalities at 18 months (all else: optimal response [OR]). CgR: complete (0% Ph+ metaphases) or incomplete (≥1 Ph+ metaphases).
RESULTS. Pill count percentages ranged from 29%–202% of prescribed dose (M=90.9±20.1). Pts with SR (n=14) had significantly higher %s of imatinib not taken (23.2±23.8) than did those with OR (n=124; 7.3±19.3, P=0.005). Among pts treated with imatinib ≥12 months, those with complete CgR (n=98) had significantly lower mean percentages of imatinib not taken (9.0±18.6) than those with incomplete CgR (n=9; 26.0±24.4, P=0.012). Among all patients regardless of length of treatment, those with complete CgR (n=109) also had significantly lower mean percentages of drug not taken (9.1±18.1) than those with incomplete CgR (n=19; 23.9±19.2, P=0.004).
CONCLUSIONS. Proportions of CML patients with poor treatment response are low (10.1%, 8.4%, and 14.8% resp. for parameters above), underscoring the high efficacy of imatinib in CML. Pts with poor response tended to have higher % of imatinib not taken over 90d, an index of overall adherence behavior. Clinicians should be aware of the association between adherence and imatinib response and should query patients about their adherence behavior. Nonadherence should be ruled out prior to classifying a patient as imatinib-resistant. Enhanced adherence is likely to optimize the effectiveness of imatinib treatment in CML.
Intravital Imaging of Young and Aged Stem Cells in the Marrow of Long Bones: Visualizing Mammalian Stem Cell Behavior in Real-Time in Vivo
Authors: Köhler Anja , Schmithorst Vince , Filippi Marie-Dominique , Ryan Marnie A. , Daria Deidre , Gunzer Matthias , Geiger Hartmut 
Published: April 2020

Abstract
Hematopoiesis, the process in which blood cells are generated from hematopoietic stem and progenitor cells (HSPCs) is primarily confined to the bone cavities. The interactions of hematopoietic cells with stroma cells forming niches inside the bone cavities are central to hematopoiesis, as these regulate cell proliferation, self-renewal and differentiation. Hematopoietic cell/stroma interactions have thus been, in analogy to the immunological synapse, named stem/progenitor cell synapses. So far, visualization of the behavior of somatic stem and progenitor cells in an undisturbed in vivo environment has not been reported for the mammalian system and consequently, the cellular dynamics of stem, progenitor and differentiated cells in vivo are only poorly defined. We developed and performed intravital time-lapse 2-photon microscopy in the marrow of the long bones (tibia) of mice to study the behavior and dynamics of differentiated hematopoietic cells as well as HPCs and HSCs in close vicinity to the endosteum in vivo over time. We demonstrate that HPCs as well as HSCs reside in close vicinity to the endosteum, further supporting the notion of an endosteal stem cell niche, and that they are, in contrast to differentiated macrophages and dendritic cells, solitary and immobile. Both HPCs and HSCs occupy distinct positions relative to the endosteum and show cell protrusion movement consistent with an active stem/progenitor cell synapse. Lastly, we report that aged HSCs show increased protrusion movement and localize more distantly to the endosteum compared to young HSCs. In addition, aged HSCs present with reduced adhesion to stroma as well as reduced polarity upon adhesion in vitro, implying a connection between altered stem cell dynamics in vivo and stem cell aging. The intravital imaging technology developed might establish a basis for further delineating additional important questions in stem cell biology like cellular mechanisms of hematopoietic stem cell self-renewal and differentiation in the context of the stroma/niche in vivo.