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1.  Health-related QoL of Bone Marrow versus PBSC Donors: A Pre-specified Subgroup Analysis from a Phase III RCT—BMTCTN protocol 0201 
Hematopoietic stem cells can be procured from unrelated donors via either the bone marrow (BM) aspiration or peripheral blood stem cell (PBSC) collection methods. There is no evidence from prospective randomized trials in the unrelated donor setting about the relative health-related quality-of-life (HRQoL) benefits/costs to donors. The goals of this prospective longitudinal investigation were to describe and compare the donation-related HRQoL experiences of 332 BM and PBSC donors.
Donors were interviewed at pre-donation, 48 hours after donation, weekly until fully recovered and at 6 and 12 months post-donation.
Pre-donation, BM donors had lower confusion, fewer concerns, and were more prepared for donation. Shortly post-donation BM donors reported more physical side effects. BM donors also reported more donation-related impact on their social activities. However, BM donors reported somewhat better psychological status and were more likely to indicate that the donation made their lives more meaningful. There were virtually no longer-term differences in the experiences of the two donor groups including no recovery time difference beginning 3 weeks after donation.
Although BM donors may experience the process as more physically stressful and more psychologically beneficial in the short-term, the longer-term HRQoL consequences of BM and PBSC donors are similar.
doi:10.1016/j.bbmt.2013.10.024
PMCID: PMC3978600  PMID: 24184336
2.  Differences in the phenotype, cytokine gene expression profiles and in vivo alloreactivity of T cells mobilized with plerixafor compared to G-CSF1 
Plerixafor (Mozobil®) is a CXCR4 antagonist that rapidly mobilizes CD34+ cells into circulation. Recently, plerixafor has been used as a single agent to mobilize peripheral blood stem cells (PBSC) for allogeneic hematopoietic cell transplantation. Although G-CSF mobilization is known to alter the phenotype and cytokine polarization of transplanted T-cells, the effects of plerixafor mobilization on T-cells have not been well characterized. In this study, we show that alterations in the T-cell phenotype and cytokine gene expression profiles characteristic of G-CSF mobilization do not occur following mobilization with plerixafor. Compared to non-mobilized T-cells, plerixafor-mobilized T-cells had similar phenotype, mixed lymphocyte reactivity, FoxP3 gene expression levels in CD4+ T-cells, and did not undergo a change in expression levels of 84 genes associated with Th1/Th2/Th3 pathways. In contrast to plerixafor, G-CSF mobilization decreased CD62L expression on both CD4 and CD8+ T-cells and altered expression levels of 16 cytokine-associated genes in CD3+ T-cells. To assess the clinical relevance of these findings, we explored a murine model of GVHD in which transplant recipients received plerixafor or G-CSF mobilized allograft from MHC-matched, minor histocompatibility mismatched donors; recipients of plerixafor mobilized PBSC had a significantly higher incidence of skin GVHD compared to mice receiving G-CSF mobilized transplants (100% vs. 50% respectively, p=0.02). These preclinical data show plerixafor, in contrast to G-CSF, does not alter the phenotype and cytokine polarization of T-cells, which raises the possibility that T-cell mediated immune sequelae of allogeneic transplantation in humans may differ when donor allografts are mobilized with plerixafor compared to G-CSF.
doi:10.4049/jimmunol.1301148
PMCID: PMC3892143  PMID: 24244025
Stem Cells; Th1/Th2 Cells; Transplantation
3.  Ascertainment of Iron Deficiency and Depletion in Blood Donors through Screening Questions for Pica and Restless Legs Syndrome 
Transfusion  2013;53(8):1637-1644.
Background
Pica and restless legs syndrome (RLS) are associated with iron depletion and deficiency. The presence of pica and RLS was prospectively assessed in blood donors.
Methods
During a 39-month period, 1236 donors deferred for fingerstick hemoglobin <12.5 g/dL and 400 non-deferred “control” donors underwent health screening and laboratory testing (CBC, ferritin, iron, transferrin). Pica and RLS were assessed by direct questioning. Deferred donors and iron-deficient control donors were given ferrous sulfate 325 mg daily for 60 days. Reassessments were performed and additional iron tablets dispensed at subsequent visits.
Results
Pica was reported in 11% of donors with iron depletion/deficiency, compared with 4% of iron-replete donors (p<0.0001). Pagophagia (ice pica) was most common and often of extraordinary intensity. Female sex, younger age, and lower MCV and transferrin saturation values were strongly associated with pica. Donors with pica given iron reported a marked reduction in the desire to consume the non-nutritive substance by day 5–8 of therapy, with disappearance of symptoms by day 10–14. RLS was reported in 16% of subjects with iron depletion/deficiency compared with 11% of iron-replete donors (p=0.012). Iron replacement generally resulted in improvement of RLS symptoms, however, at least 4–6 weeks of iron therapy was necessary.
Conclusion
The presence of pica is associated with a high probability of iron depletion/deficiency in blood donors; however, RLS lacks a strong correlation in this population. Screening questions for pagophagia may be useful in the ascertainment of iron deficiency in donors and may identify those who would benefit from oral iron.
doi:10.1111/trf.12061
PMCID: PMC3691288  PMID: 23305102
5.  Measurement of the absolute immature platelet number reflects marrow production and is not impacted by platelet transfusion 
Transfusion  2012;53(6):1201-1204.
BACKGROUND
The ability to distinguish increased platelet destruction from platelet hypo-production is important in the care of patients with bone marrow failure syndromes and patients receiving high dose chemotherapy. The measurement of immature circulating platelets based on RNA content using an automated counter is now feasible. This study evaluated the impact of recent platelet transfusion on measurement of immature platelet parameters.
STUDY DESIGN AND METHODS
The immature platelet fraction (IPF) and absolute immature platelet number (AIPN) were measured using the Sysmex XE-5000 analyzer prior to and following platelet transfusion in 9 transfusion-dependent patients with marrow failure secondary to aplastic anemia, myelodysplasia or transplantation conditioning. IPF and AIPN were also measured serially over 5 days of storage in 3 plateletpheresis components collected from normal donors.
RESULTS
Platelet transfusion did not significantly change the mean AIPN in transfused patients. In contrast, IPF decreased significantly from 6.6 ±4.6% at day -1 to 2.3 ±1.4% at day 0 before returning to 4.3 ±2.3% at day +1. In the platelet component, AIPN and IPF% increased significantly over 5 days of storage, most likely due to an artifact of the staining and detection process for stored platelets, no longer detected in vivo once the platelets were transfused.
CONCLUSION
Platelet transfusion decreases the IPF due to the resultant increase in circulating platelet count. However, platelet transfusion does not change the circulating absolute immature platelet number (AIPN), validating this assay as a reflection of ongoing platelet production by the bone marrow in various clinical settings, regardless of proximity to platelet transfusion.
doi:10.1111/j.1537-2995.2012.03918.x
PMCID: PMC3543490  PMID: 23043309
6.  Capillary versus Venous Hemoglobin Determination in the Assessment of Healthy Blood Donors 
Vox sanguinis  2013;104(4):317-323.
Background and Objectives
To determine the accuracy of fingerstick hemoglobin assessment in blood donors, the performance of a portable hemoglobinometer (HemoCue Hb 201+) was prospectively compared with that of an automated hematology analyzer (Cell-Dyn 4000). Hemoglobin values obtained by the latter were used as the “true” result.
Material and Methods
Capillary fingerstick samples were assayed by HemoCue in 150 donors. Fingerstick samples from two sites, one on each hand, were obtained from a subset of 50 subjects. Concurrent venous samples were tested using both HemoCue and Cell-Dyn devices.
Results
Capillary hemoglobin values (HemoCue) were significantly greater than venous hemoglobin values (HemoCue), which in turn were significantly greater than venous hemoglobin values by Cell-Dyn (mean ± SD: 14.05 ± 1.51, 13.89 ± 1.31, 13.62 ± 1.23, respectively; p<0.01 for all comparisons among groups). Nine donors (6%) passed hemoglobin screening criteria (≥12.5 g/dL) by capillary HemoCue, but were deferred by Cell-Dyn values (false-pass). Five donors (3%) were deferred by capillary sampling, but passed by Cell-Dyn (false-fail). Substantial variability in repeated fingerstick HemoCue results was seen (mean hemoglobin 13.72 vs. 13.70 g/dL, absolute mean difference between paired samples 0.76 g/dL). Hand dominance was not a factor.
Conclusions
Capillary samples assessed via a portable device yielded higher hemoglobin values than venous samples assessed on an automated analyzer. False-pass and false-fail rates were low and acceptable in the donor screening setting, with “true” values not differing by a clinically significant degree from threshold values used to assess acceptability for blood donation.
doi:10.1111/vox.12006
PMCID: PMC3633672  PMID: 23294266
capillary hemoglobin determination; venous hemoglobin determination; hemoglobin screening of blood donors; blood donor deferrals; handedness
7.  Peripheral-Blood Stem Cells versus Bone Marrow from Unrelated Donors 
The New England journal of medicine  2012;367(16):10.1056/NEJMoa1203517.
BACKGROUND
Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia.
METHODS
We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37).
RESULTS
The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P = 0.29), with an absolute difference of 5 percentage points (95% CI, −3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P = 0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P = 0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse.
CONCLUSIONS
We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute–National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.)
doi:10.1056/NEJMoa1203517
PMCID: PMC3816375  PMID: 23075175
8.  Iron Replacement Therapy in the Routine Management of Blood Donors 
Transfusion  2011;52(7):1566-1575.
Background
Iron depletion/deficiency in blood donors frequently results in deferrals for low hemoglobin, yet blood centers remain reluctant to dispense iron replacement therapy to donors.
Study Design and Methods
During a 39-month period, 1236 blood donors deferred for hemoglobin <12.5 g/dL and 400 non-deferred control donors underwent health history screening and laboratory testing (CBC, iron studies). Iron depletion and deficiency were defined as ferritin of 9–19 mcg/L and <9 mcg/L in females and 18–29 mcg/L and <18 mcg/L in males. Deferred donors and iron-deficient control donors were given a 60-pack of ferrous sulfate 325 mg tablets, and instructed to take one tablet daily. Another 60-pack was dispensed at all subsequent visits.
Results
In the low hemoglobin group, 30% and 23% of females and 8% and 53% of males had iron depletion or deficiency, respectively, compared with 29% and 10% of females and 18% and 21% of males in the control group. Iron depleted/deficient donors taking iron showed normalization of iron-related laboratory parameters, even as they continued to donate. Compliance with oral iron was 68%. Adverse gastrointestinal effects occurred in 21% of donors. The study identified 13 donors with serious medical conditions, including eight with GI bleeding. No donors had malignancies or hemochromatosis.
Conclusion
Iron depletion or deficiency was found in 53% of female and 61% of male low hemoglobin donors, and in 39% of female and male control donors. Routine administration of iron replacement therapy is safe, effective, and prevents the development of iron depletion/deficiency in blood donors.
doi:10.1111/j.1537-2995.2011.03488.x
PMCID: PMC3690467  PMID: 22211316
9.  Changes in Exercise Capacity of Cardiac Asymptomatic Hereditary Hemochromatosis Subjects over 5-Year Follow up 
Objective
A long-term effect of hereditary hemochromatosis (HH) on aerobic exercise capacity (AEC) has not been well described.
Design
Forty-three HH and 21 volunteer control (VC) subjects who were asymptomatic underwent cardiopulmonary exercise testing using the Bruce protocol. AEC was assessed with minute ventilation (VE), oxygen uptake (VO2), and carbon dioxide production (VCO2) at baseline (BL) at a 5-year follow up (5Y) assessment. A paired t-test was used for analyses of normality data; otherwise, a Wilcoxon singed rank sum test was used.
Results
Thirty-three HH subjects and 18 VC subjects returned for a repeat CPX at 5Y (80% overall return rate). At 5Y, AEC was not different between the two groups. As compared with BL measurements, exercise time, peak VO2, and the VE/VCO2 slope did not differ statistically at 5Y between both groups. Iron depletion by phlebotomy for 5 years did not significantly affect AEC in newly diagnosed HH subjects at baseline (n=14) and cardiac arrhythmias during exercise tended to decrease after 5 years of therapy in this group.
Conclusions
The AEC of asymptomatic HH subjects treated with conventional therapy is not statistically affected by the disease over a 5-year period.
doi:10.1097/PHM.0b013e3182465f5f
PMCID: PMC3331951  PMID: 22311055
Hereditary Hemochromatosis; Exercise Capacity; Cardiopulmonary Exercise Test; Prospective Study
10.  Incidence of Cardiac Arrhythmias in Asymptomatic Hereditary Hemochromatosis Subjects with C282Y Homozygosity 
The American Journal of Cardiology  2011;109(6):856-860.
It is not well known whether systemic iron overload per se in hereditary hemochromatosis (HH) is associated with cardiac arrhythmias before other signs and symptoms of cardiovascular disease occur. In this study, we examined the incidence of cardiac arrhythmias in cardiac asymptomatic HH subjects (NYHA functional class I), and compared it to that in age/gender-matched normal volunteers. The 42 HH subjects and 19 normal volunteer control subjects recruited through the NHLBI-sponsored "Heart Study of Hemochromatosis" completed 48-hour Holter electrocardiography ambulatory monitoring at the baseline evaluation. The HH subjects were classified as newly diagnosed (Group A) and chronically treated subjects (Group B). All HH subjects had C282Y homozygosity, and the normal volunteers lacked any HFE gene mutations which are known to cause HH. Although statistically insignificant, the incidence of ventricular and supraventricular ectopy tended to be higher in the combined HH groups than the controls. Supraventricular ectopy was more frequently noted in Group B as compared to the controls (ectopy rate per hour; 11.1±29.9 vs. 1.5±3.5, P < 0.05 by Kurskal Wallis test). No examples of heart block, other than first degree atrioventricular node block, were seen in any of the subjects. The incidence of cardiac arrhythmias was not significantly reduced after 6 months of intensive iron removal therapy in Group A subjects. No life threatening arrhythmias were observed in our HH subjects. In conclusion, our data suggest that the incidence of cardiac arrhythmias is, at most, marginally increased in asymptomatic HH subjects. A larger clinical study is warranted to further clarify our observation.
doi:10.1016/j.amjcard.2011.11.011
PMCID: PMC3294140  PMID: 22196777
Arrhythmias; Hereditary Hemochromatosis; Holter electrocardiogram
11.  Effects of Granulocyte Colony Stimulating Factor on Monosomy 7 Aneuploidy in Healthy Hematopoietic Stem Cell and Granulocyte Donors 
Transfusion  2011;52(3):537-541.
Background
Reports of monosomy 7 in patients receiving granulocyte colony stimulating factor (G-CSF) have raised concerns that this cytokine may promote genomic instability. However, there are no studies addressing whether repeated administration of G-CSF produces monosomy 7 aneuploidy in healthy donors.
Study Design and Methods
We examined chromosomes 7 and 8 by fluorescent in situ hybridization (FISH) in CD34+ cells from 35 healthy hematopoietic stem cell transplant (HSCT) donors after G-CSF administration for 5 days, and by spectral karyotyping analysis (SKY) in four individuals to assess chromosomal integrity. We also studied 38 granulocyte donors who received up to 42 doses of G-CSF and dexamethasone (Dex) using FISH for chromosomes 7 and 8.
Results
We found no abnormalities in chromosomes 7 and 8 in G-CSF mobilized CD34+ cells when assessed by FISH or SKY, nor did we detect aneuploidy in G-CSF/Dex treated donors.
Conclusion
G-CSF does not promote clinically detectable monosomy 7 or trisomy 8 aneuploidy in HSCT or granulocyte donors. These findings should be reassuring to healthy HSCT and granulocyte donors.
doi:10.1111/j.1537-2995.2011.03313.x
PMCID: PMC3235244  PMID: 21883270
12.  Ten-year follow-up of unrelated volunteer granulocyte donors who have received multiple cycles of granulocyte–colony-stimulating factor and dexamethasone 
Transfusion  2009;49(3):513-518.
BACKGROUND
The combination of granulocyte–colony-stimulating factor (G-CSF) and dexamethasone is an effective granulocyte mobilization regimen. The short-term side effects of G-CSF are well studied, but the potential long-term effects of repeated G-CSF stimulation in unrelated volunteer granulocyte donors have not been reported.
STUDY DESIGN AND METHODS
Donors who had received G-CSF three or more times for granulocytapheresis between 1994 and 2002 were identified and attempts were made to contact them if they were no longer active donors. They were matched with control platelet (PLT) donors for sex, age, and approximate number of cytapheresis donations. A health history was obtained and complete blood counts (CBCs) and C-reactive protein (CRP) determined where feasible.
RESULTS
Ninety-two granulocyte donors were identified, and 83 of them were contacted. They contributed to 1120 granulocyte concentrates, or a mean of 13.5 granulocytapheresis procedures per donor (and a mean of 87.5 plateletpheresis procedures per donor). There was no difference in CBCs between the granulocyte donors and the control PLT donors. There was no difference in CRP between the two groups, and no difference in pre- and post–G-CSF CRP in a subset of 22 granulocyte donors. Predefined health events included malignancies, coronary artery disease, and thrombosis. At a median 10-year follow-up, there were seven such events in the granulocyte donors and five in the PLT donors.
CONCLUSION
Although the number of granulocyte donors studied is small and continued surveillance of healthy individuals after G-CSF is prudent, our data suggest that G-CSF/dexamethasone stimulation appears to be safe.
doi:10.1111/j.1537-2995.2008.01983.x
PMCID: PMC3424604  PMID: 19243544
13.  The determinants of granulocyte yield in 1198 granulocyte concentrates collected from unrelated volunteer donors mobilized with dexamethasone and granulocyte–colony-stimulating factor: a 13-year experience 
Transfusion  2008;49(3):421-426.
BACKGROUND
The combination of granulocyte–colony-stimulating factor (G-CSF [filgrastim]) and dexamethasone (G-CSF/dex) is an effective granulocyte mobilization regimen, but the variables that affect donor neutrophil response and granulocyte collection yield are not well characterized.
STUDY DESIGN AND METHODS
A computerized database containing records of 1198 granulocyte collections from 137 unrelated volunteer apheresis donors during a 13-year period was retrospectively analyzed. Donors were categorized by age, sex, and cumulative number of granulocyte donations. Complete blood counts at baseline and after G-CSF/dex stimulation were recorded. The outcome variables include the pre-procedure absolute neutrophil count (preANC), which reflects G-CSF/dex stimulation, and the granulocyte product yield per liter processed (BagGranYield/L).
RESULTS
Higher baseline ANC and platelet (PLT) counts were significantly associated with higher preANC while a larger number of prior granulocytapheresis procedures was associated with lower preANC. Total filgrastim dose (used in weight-based dosing) did not significantly impact preANC or the granulocyte yield; weight-based dosing at 5 μg per kg and a uniform 480-μg dose produced equivalent preANC. PreANC and weight were the key determinants of granulocyte yield (BagGranYield/L).
CONCLUSION
Apheresis donors with higher baseline PLT counts and ANCs have higher ANCs after G-CSF/dex stimulation; donor age, weight, and sex do not have a significant impact. A uniform G-CSF dose of 480 μg is as effective as weight-based dosing at 5 μg per kg. Donor ANC monitoring should be considered after serial granulocytapheresis procedures.
doi:10.1111/j.1537-2995.2008.01997.x
PMCID: PMC3421027  PMID: 19040597
14.  Evaluation of low red blood cell mean corpuscular volume in an apheresis donor population 
Transfusion  2009;49(9):1971-1976.
BACKGROUND
Apheresis donors are routinely evaluated with a complete blood count (CBC). Low red blood cell mean corpuscular volume (MCV) values (<80 fL) in the presence of an acceptable hemoglobin (Hb; ≥12.5 g/dL) could be due to iron deficiency or hemoglobinopathy. The etiology of a low MCV in a healthy apheresis donor population was assessed.
METHODS
Predonation samples for CBC were obtained from 1162 consecutive apheresis donors. Donors with a MCV of less than 80 fL were evaluated by CBC, iron studies (ferritin, serum iron, transferrin, percentage of transferrin saturation), and hemoglobin (Hb) electrophoresis. Iron deficiency was defined as a ferritin value below the reference range. Beta chain Hb variants were determined by Hb electrophoresis. Alpha thalassemia trait was presumed if the red blood cell (RBC) count was elevated, no variant Hbs were detected, and the iron studies were within normal ranges.
RESULTS
In a 19-month period, 33 of 1162 apheresis donors had low MCV values. Iron deficiency was present in 64%; 49% had isolated iron deficiency and 15% had iron deficiency plus hemoglobinopathy. Hemoglobinopathy without concomitant iron deficiency was found in the remaining 36%.
CONCLUSION
Iron deficiency is present in the majority of apheresis donors with repeatedly low MCV values and Hb levels of 12.5 g/dL or more. Hemoglobinopathy is also commonly present but may not be easily recognized in the setting of iron deficiency. The MCV is a useful screening tool to detect iron deficiency and hemoglobinopathy. Low MCV values should be investigated to determine if iron replacement therapy is indicated.
doi:10.1111/j.1537-2995.2009.02207.x
PMCID: PMC3421029  PMID: 19453988
15.  Gravity sedimentation of granulocytapheresis concentrates with hydroxyethyl starch efficiently removes red blood cells and retains neutrophils 
Transfusion  2010;50(6):1203-1209.
BACKGROUND
Transfusion of granulocytapheresis concentrates can be limited by the volume of incompatible donor red blood cells (RBCs) in the component. Efficient reduction of RBCs in granulocyte units would result in safe transfusion of RBC-incompatible units.
STUDY DESIGN AND METHODS
Granulocyte concentrates were collected by continuous-flow apheresis from granulocyte–colony-stimulating factor (G-CSF) and dexamethasone-stimulated volunteer donors, with 6% hydroxyethyl starch (HES) added continuously during apheresis as a RBC sedimenting agent to enhance granulocyte collection efficiency. After collection, the component was placed in a plasma extractor for 4 hours. A sharp line of demarcation between the starch-sedimented RBCs and the granulocyte-rich supernatant developed, and the supernatant was transferred to a sterilely docked transfer pack. RBC reduction and white blood cell recovery were determined.
RESULTS
Gravity sedimentation was performed on 165 granulocyte concentrates. Mean sedimentation time was 267 minutes (range, 150–440 min). RBC depletion was 92% (range, 71%–99%) with mean residual RBC content of 3.2 ± 1.4 mL. Twelve percent of components contained less than 2 mL of RBCs. Mean granulocyte and platelet (PLT) recoveries were 80 and 81%, respectively. There were no transfusion reactions or signs of hemolysis after transfusion of 66 RBC-incompatible granulocyte concentrates (RBC volume, 1.6–8.2 mL). The remaining concentrates were used for topical or intrapleural applications.
CONCLUSIONS
RBCs were significantly reduced and granulocytes and PLTs effectively retained in G-CSF/ steroid–mobilized granulocyte components collected with HES and processed by gravity sedimentation. This procedure allows safe transfusion of RBC-incompatible sedimented granulocyte units and may be used to expand the pool of available granulocyte donors for specific recipients.
doi:10.1111/j.1537-2995.2009.02576.x
PMCID: PMC3421031  PMID: 20113453
17.  Does Oxidative Stress Modulate Left Ventricular Diastolic Function in Asymptomatic Subjects with Hereditary Hemochromatosis? 
Echocardiography (Mount Kisco, N.y.)  2009;26(10):1153-1158.
Little is known about the early mechanisms mediating left ventricular (LV) diastolic dysfunction in patients with hereditary hemochromatosis (HH). However, the increased oxidative stress related to iron overload may be involved in this process, and strain rate (SR), a sensitive echocardiography derived measure of diastolic function, may detect such changes. Thus, we evaluated the relationship between left ventricular diastolic function measured with tissue Doppler SR and oxidative stress in asymptomatic HH subjects and control normal subjects. Ninety-four consecutive visits of 43 HH subjects, age 30 to 74 (50 ± 10, mean ± SD) and 37 consecutive visits of 21 normal volunteers age 30 to 63 (48 ± 8) were evaluated over a three-year period. SR was obtained from the basal septum in apical 4 chamber views. All patients had confirmed C282Y homozygosity, a documented history iron overload and were New York Heart Association functional class I. Normal volunteers lacked HFE gene mutations causing HH. In the HH subjects, the SR demonstrated moderate, but significant correlations with biomarkers of oxidative stress; however, no correlations were noted in normal subjects. The biomarkers of iron overload per se did not show significant correlations with the SR. Although our study was limited by the relatively small subject number, these results suggest that a possible role of oxidative stress to affect LV diastolic function in asymptomatic HH subjects and SR imaging may be a sensitive measure to detect that effect.
doi:10.1111/j.1540-8175.2009.00956.x
PMCID: PMC3397801  PMID: 19725855
hereditary hemochromatosis; left ventricular diastolic function; oxidativestress; strain rate; iron overload; cohort study
18.  Accelerated Lymphocyte Reconstitution and Long-Term Recovery Following Transplantation of Lentiviral Transduced Rhesus CD34+ Cells Mobilized by G-CSF and Plerixafor 
Experimental hematology  2011;39(7):795-805.
Objective
Granulocyte colony-stimulating factor (G-CSF) in combination with plerixafor produces significant mobilization of CD34+ cells in rhesus macaques. We sought to evaluate whether these CD34+ cells can stably reconstitute blood cells with lentiviral gene marking.
Methods
We performed hematopoietic stem cell (HSC) transplantation using G-CSF and plerixafor-mobilized rhesus CD34+ cells transduced with a lentiviral vector, and these data were compared to those of G-CSF and stem cell factor (SCF) mobilization.
Results
G-CSF and plerixafor mobilization resulted in CD34+ cell yields that were 2-fold higher than yields with G-CSF and SCF. CD123 (IL-3 receptor) expression was greater in G-CSF and plerixafor-mobilized CD34+ cells when compared to G-CSF alone. Animals transplanted with G-CSF and plerixafor-mobilized cells showed engraftment of all lineages, similar to animals who received G-CSF and SCF-mobilized grafts. Lymphocyte engraftment was accelerated in animals receiving the G-CSF and plerixafor-mobilized CD34+ cells. One animal in the G-CSF and plerixafor group developed cold agglutinin associated skin rash during the first 3 months of rapid lymphocyte recovery. One year after transplantation, all animals had 2–10% transgene expression in all blood cell lineages.
Conclusion
G-CSF and plerixafor-mobilized CD34+ cells accelerate lymphocyte engraftment and contain HSC capable of reconstituting multi-lineage blood cells. These findings indicate important differences to consider in plerixafor based HSC mobilization protocols in rhesus macaques.
doi:10.1016/j.exphem.2011.04.002
PMCID: PMC3143244  PMID: 21549175
hematopoietic stem cell transplantation; hematopoietic stem cell mobilization; lentivirus vector
19.  Prevalence of Posterior Subcapsular Cataracts in Volunteer Cytapheresis Donors 
Transfusion  2010;51(5):921-928.
Background
Granulocyte donors routinely receive dexamethasone orally before donation. Steroids may increase the risk of posterior subcapsular cataract (PSC) formation.
Study design and methods
We recruited 100 granulocyte donors (≥4 granulocyte donations; any number of platelet donations) and 100 age-sex-matched platelet donors (0–3 granulocyte donations, any number of platelet donations) to examine the risk of PSC. PSC was assessed by a masked ophthalmologist and reading center lens photograph gradings, or medical record documentation of PSC as the reason for cataract extraction.
Results
Fourteen eyes of ten granulocyte donors and five eyes of four platelet donors had PSC (odds ratio (OR) = 2.82; 95% confidence interval [CI}, 0.83–9.61; p=0.10). Risk of PSC increased with number of granulocyte donations: compared to 0–3 donations (4.0%), risk for 4–9, 10–19, and ≥ 20 donations was 8.6% (OR=2.25; 95% CI, 0.31–13.99; p=0.30); 9.5% (OR=2.53; 95% CI, 0.44–14.20; p=0.21); and 13.0% (OR=3.60; 95% CI, 0.48–22.81; p=0.11), respectively(p=0.06 for trend).
Conclusion
We did not demonstrate a statistically significant increased risk of PSC associated with granulocyte donation. However, although this makes a large risk unlikely, we cannot rule out a small to moderate risk and there is biologic plausibility that the steroid administration associated with granulocyte donation could be associated with PSC formation. Transfusion medicine professionals should advise granulocyte apheresis donors to maintain an appropriate frequency of eye examinations.
doi:10.1111/j.1537-2995.2010.02948.x
PMCID: PMC3089717  PMID: 21091958
granulocyte donation; apheresis; cataract; steroid; dexamethasone; posterior subcapsular cataract; blood donation
20.  Expression of growth differentiation factor 15 is not elevated in individuals with iron deficiency secondary to volunteer blood donation 
Transfusion  2010;50(7):1532-1535.
BACKGROUND
Low serum hepcidin levels provide a physiologic response to iron demand in patients with iron deficiency (ID). Based on a discovery of suppressed hepcidin expression by a cytokine named growth differentiation factor 15 (GDF15), it was hypothesized that GDF15 may suppress hepcidin expression in humans with ID due to blood loss.
STUDY DESIGN AND METHODS
To test this hypothesis, GDF15 and hepcidin levels were measured in peripheral blood from subjects with iron-deficient erythropoiesis before and after iron supplementation.
RESULTS
Iron variables and hepcidin levels were significantly suppressed in iron-deficient blood donors compared to healthy volunteers. However, ID was not associated with elevated serum levels of GDF15. Instead, iron-deficient subjects’ GDF15 levels were slightly lower than those measured in the control group of subjects (307 ± 90 and 386 ± 104 pg/mL, respectively). Additionally, GDF15 levels were not significantly altered by iron repletion.
CONCLUSIONS
ID due to blood loss is not associated with a significant change in serum levels of GDF15.
doi:10.1111/j.1537-2995.2010.02601.x
PMCID: PMC3282986  PMID: 20210929
21.  Screening plateletpheresis donors for HLA antibodies on two high throughput platformsand correlation with recipient outcome 
Transfusion  2010;51(3):504-510.
Background
To determine the prevalence and impact of transfusing plasma containing leukocyte antibodies, we compared two high-throughput HLA antibody screening assays, and prospectively examined the medical records of all platelet recipients to detect subtle manifestations of TRALI and other transfusion reactions.
Methods
Serum samples from 136 plateletpheresis donors were tested for HLA Class I and II antibodies using microbead (Labscreen PRA) and microchip (Dynachip) assays. Electronic medical records of all recipients were reviewed for vital signs and nursing documentation before and after transfusion.
Results
In the microchip assay with a cutoff value of 0.25, 2.9% of samples were positive for Class I, and 8.9% for Class II antibodies; with a cutoff value of 0.1, the results were 14.9% and 21.6% respectively. In the microbead assay (NBG ratio 1.5), 15% were positive for Class I, and 21% for Class II antibodies. The prevalence of HLA antibodies was 17% in donors without pregnancy or transfusion history, and 47% in donors with such history. The platelets were transfused in 265 episodes to 67 patients. There were no reported reactions; however, symptoms or vital sign changes were noted in 7 transfusion episodes. The incidence of reactions was 2.7% (2/75) for antibody-positive units and 2.6% (5/190) for antibody-negative units.
Conclusions
Microbead and microchip assays yielded similar results. The prevalence of HLA antibodies was greater in donors with a history of pregnancy or transfusion, but no increase in the incidence of transfusion reactions was noted in recipients of components from donors with HLA antibodies.
doi:10.1111/j.1537-2995.2010.02874.x
PMCID: PMC3008757  PMID: 20849407
HLA antibodies; neutrophil-specific antibodies; apheresis platelets; transfusion reactions; transfusion related acute lung injury
23.  Adoptive Cell Therapy for Patients With Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative Regimens 
Journal of Clinical Oncology  2008;26(32):5233-5239.
Purpose
The two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens.
Patients and Methods
We performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied.
Results
Although nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells.
Conclusion
Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies.
doi:10.1200/JCO.2008.16.5449
PMCID: PMC2652090  PMID: 18809613
24.  A Pilot Study of Consolidative Immunotherapy in Patients with High-Risk Pediatric Sarcomas 
Purpose
Patients with metastatic or recurrent Ewing’s sarcoma (ESFT) and alveolar rhabdomyosarcoma (AR) have <25% 5-yr. survival in most studies. This study administered a novel immunotherapy regimen aimed at consolidating remission in these patients.
Experimental Design
52 patients with translocation positive, recurrent or metastatic ESFT or AR underwent pre-chemotherapy cell harvest via apheresis for potential receipt of immunotherapy. Following completion of standard multimodal therapy, 30 patients ultimately initiated immunotherapy and were sequentially assigned to three cohorts. All cohorts received autologous T cells, influenza vaccinations and dendritic cells (DCs) pulsed with peptides derived from tumor specific translocation breakpoints and E7, a peptide known to bind HLA-A2. Cohort 1 received moderate dose rhIL-2, cohort 2 received low dose rhIL-2 and cohort 3 did not receive rhIL-2.
Results
All immunotherapy recipients generated influenza specific immune responses, whereas immune responses to the translocation breakpoint peptides occurred in 39%, and only 25% of HLA-A2+ patients developed E7 specific responses. Toxicity was minimal. Intention-to-treat analysis revealed a 31% 5-year OS for all patients apheresed (median potential follow-up 7.3 yrs) with a 43% 5-year OS for patients initiating immunotherapy.
Conclusions
Consolidative immunotherapy is a scientifically based and clinically practical approach for integrating immunotherapy into a multimodal regimen for chemoresponsive cancer. Patients receiving immunotherapy experienced minimal toxicity and favorable survival. The robust influenza immune responses observed suggest that post-chemotherapy immune incompetence will not fundamentally limit this approach. Future studies will seek to increase efficacy by using more immunogenic antigens and more potent DCs.
doi:10.1158/1078-0432.CCR-07-4065
PMCID: PMC2497450  PMID: 18676758
Ewing’s sarcoma family of tumors; rhabdomyosarcoma; dendritic cell vaccine; immunotherapy; rhIL-2
25.  Analysis of a High-Throughput HLA Antibody Screening Assay for Use with Platelet Donors 
Transfusion  2008;48(6):1174-1179.
Background
Passive infusion of HLA antibodies has been implicated in transfusion reactions. A rapid, inexpensive method of screening blood donors for HLA antibodies might reduce the incidence of reactions. A high-throughput microbead-flow analyzer HLA antibody detection technique was compared with an ELISA method.
Materials and Method
96 apheresis platelet donors were tested for antibodies to Class I and II HLA antigens using mixed antigen microbead-flow analyzer and ELISA assays. For both assays, samples reactive in the mixed antigen assay were tested with a panel reactive antibody (PRA) assay. Samples reactive in both the mixed antigen and PRA assays were considered positive.
Results
In the mixed antigen microbead assay 46 (48%) samples were reactive to Class I antigens and 20 (21%) to Class II. Further testing in the microbead PRA assay revealed that 34 (35%) had antibodies to Class I antigens, 18 (19%) to Class II, and 42 (44%) to either Class I or II. Class I antibodies were present in 56% of females and 36% of males. In the mixed antigen ELISA assay 4 samples were reactive with Class I antigens; 4 with Class II antigens, and 5 with Class I or Class II. All 5 reactive samples were also reactive in the ELISA PRA assay and were from females.
Conclusion
The microbead assay was more sensitive than the ELISA assay and detected antibodies in a large proportion of donors. Samples reactive in the mixed antigen microbead assay should be confirmed by a second assay before concluding that antibodies are present.
doi:10.1111/j.1537-2995.2008.01684.x
PMCID: PMC2666543  PMID: 18422853

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