Superior physical and mental health of healthy volunteers before and five years after mobilized stem cell donation.

BACKGROUND: Safety, tolerability and efficacy of granulocyte colony-stimulating factor (G-CSF) for mobilization of hematopoietic stem and progenitor cells (HSPCs) from healthy donors have been conclusively demonstrated. This explicitly includes, albeit for smaller cohorts and shorter observation periods, biosimilar G-CSFs. HSPC donation is non-remunerated, its sole reward being "warm glow", hence harm to donors must be avoided with maximal certitude. To ascertain, therefore, long-term physical and mental health effects of HSPC donation, a cohort of G-CSF mobilized donors was followed longitudinally. METHODS: We enrolled 245 healthy volunteers in this bi-centric long-term surveillance study. 244 healthy volunteers began mobilization with twice-daily Sandoz biosimilar filgrastim and 242 underwent apheresis after G-CSF mobilization. Physical and mental health were followed up over a period of 5-years using the validated SF-12 health questionnaire. RESULTS: Baseline physical and mental health of HSPC donors was markedly better than in a healthy reference population matched for ethnicity, sex and age. Physical, but not mental health was sharply diminished at the time of apheresis, likely due to side effects of biosimilar G-CSF, however had returned to pre-apheresis values by the next follow-up appointment after 6 months. Physical and mental health slightly deteriorated over time with kinetics reflecting the known effects of aging. Hence, superior physical and mental health compared to the general healthy non-donor population was maintained over time. CONCLUSIONS: HSPC donors are of better overall physical and mental health than the average healthy non-donor. Superior well-being is maintained over time, supporting the favorable risk-benefit assessment of volunteer HSPC donation. Trial registration National Clinical Trial NCT01766934.

Deferrals of volunteer stem cell donors referred for evaluation for matched-unrelated stem cell donation.

To minimize donor risk and maintain public support, volunteer donor stem cell donation, whether by mobilized leukapheresis or marrow aspiration, requires careful donor eligibility assessment. Many contraindications to stem cell donation exist, yet analyses of donor deferral rates are not available. In a 36-month series encompassing 2493 potential stem cell donors, we analyzed frequencies and reasons for deferrals. All were presumed eligible by their registries because of previously submitted structured health questionnaire and formal telephone interviews. After assessment by our center's physicians, 3.3% of donors proved ineligible, but 5.6% more were eligible for only one of the collection methods. Higher deferral rates were associated with female sex, increasing age and mobilized stem cell donation vs marrow. Exclusion criteria were identified with approximately similar frequency by medical history, physical examination and laboratory testing. Reasons for deferrals almost exclusively served to protect donor safety; the rare recipient-directed safety concerns could be, and often were, overridden in agreement with the transplant center. As formal analyses have shown, with careful assessment, stem cell donation is acceptably safe, but the plethora of deferral reasons mandate that only physicians with specific experience should evaluate stem cell donors, that is, this task should not be delegated to paramedical personnel.

Safety and efficacy of healthy volunteer stem cell mobilization with filgrastim G-CSF and mobilized stem cell apheresis: results of a prospective longitudinal 5-year follow-up study.

BACKGROUND AND OBJECTIVES: G-CSF-mobilized peripheral blood stem cells have long replaced marrow as the major source for allogeneic transplants. Conclusive evidence questioning the long-term safety of G-CSF for donors has not been provided, but the cumulative number of followed donors remains insufficient to rule out rare adverse events. A long-term active follow-up study of G-CSF-mobilized healthy volunteer donors was therefore performed. PATIENTS AND METHODS: Two hundred and three successive donors were evaluated pre-apheresis, subjected to G-CSF-mobilization/apheresis, and actively followed for 5 years by the same physicians and laboratories. Follow-up laboratory work included standard biochemical/haematological tests and T-cell phenotyping. RESULTS: Donor epidemiology was typical for reported stem cell donor cohorts. Acute adverse effects of G-CSF and apheresis were mild and transient, consistent with the previous reports. Mean circulating CD34(+) cells after nine doses of G-CSF were 124 per µl. Other biochemical/haematological parameters were also altered, consistent with G-CSF treatment. Spleen enlargement was modest. At first follow-up, all clinical and laboratory parameters had normalized. Leucocyte/lymphocyte counts and CD4/CD8 ratios were the same as during premobilization work-up and remained unchanged throughout. A single severe but likely unrelated adverse event, a case of papillary thyroid carcinoma, was reported. CONCLUSION: The studies add an observation time of almost 500 donor years to the growing body of evidence of the long-term safety of G-CSF for allogeneic donor stem cell mobilization.

Resolution of single spin flips of a single proton.

The spin magnetic moment of a single proton in a cryogenic Penning trap was coupled to the particle's axial motion with a superimposed magnetic bottle. Jumps in the oscillation frequency indicate spin flips and were identified using a Bayesian analysis.

Mobilized allogeneic peripheral stem/progenitor cell apheresis with Spectra Optia v.5·0, a novel, automatic interface-controlled apheresis system: results from the first feasibility trial.

BACKGROUND AND OBJECTIVES: G-CSF mobilized peripheral blood stem/progenitor cells are frequently used for allogeneic transplantation. Available manual apheresis systems generate stem cell products of consistently high quality. Short-comings include need for continuous interface monitoring/adjustment, interface instability in donors with inconsistent blood flow, high collection variability, high platelet loss, and failure to electronically document apheresis parameters. MATERIAL AND METHODS: A fundamentally different, novel apheresis system, Spectra Optia v.5·0, featuring optical sensors, which provide real-time automatic interface and product collect line control, and newly developed tubing sets, was designed to address these short-comings. In a prospective validation study, 30 healthy volunteer stem cell donors were subjected to apheresis with Spectra Optia to test feasibility and effectiveness. Results were compared to 608 historic first-day allogeneic aphereses with COBE Spectra MNC. RESULTS: Usability and function of automatic interface control of Spectra Optia were good. Most collection parameters, including collection efficiency and product size, were similar. Cells were viable and provided timely engraftment. Platelet loss with Spectra Optia was 25% less than with COBE Spectra MNC. Products contained fewer erythrocytes, but more granulocytes. CONCLUSION: The automatic apheresis system Spectra Optia is functional and user-friendly. Thus Spectra Optia aphereses are associated with similar, and equally variable, collection efficiencies as COBE Spectra MNC.

Evaluation of diagnostic methods for the detection of cytomegalovirus in recipients of allogeneic stem cell transplants.

BACKGROUND: Although several diagnostic methods are available for the surveillance of patients at risk of human cytomegalovirus (CMV) infection and disease, little data is available on their comparative performances in the diagnostic setting. OBJECTIVES: To compare different assays for CMV detection, especially assays based on (quantitative) DNA and mRNA detection. STUDY DESIGN: Eight allogeneic bone marrow and stem cell transplant recipients at high risk for developing CMV disease (donor CMV-negative, recipient positive) were regularly tested for 7-20 weeks post-transplant by spin-amplification rapid culture from urine (viruria), antigenemia (pp65 assay), pp67 mRNA in whole blood (NASBA), and CMV DNA both qualitatively (in-house PCR, whole blood) and quantitatively (in-house PCR, plasma; Cobas Amplicor CMV Monitor Test, plasma and whole blood; Hybrid Capture, whole blood). RESULTS: Four patients (50%) suffered CMV reactivation during follow-up. Out of 104 sample dates, 41 (39.4%) yielded a positive CMV result in at least one assay. Out of the 28 samples tested by all assays, the highest percentage of positive results was obtained with the in-house quantitative PCR (60.7%), followed by the Hybrid Capture system (39.3%), the Cobas Amplicor CMV Monitor Test, plasma version (35.7%), the Cobas Amplicor CMV Monitor Test, whole blood version (32.1%), in-house qualitative PCR (28.6%), and the mRNA assay (21.4%). Viruria was positive in one sample and pp65 antigenemia was found in two samples. CONCLUSIONS: Despite a considerable incidence of CMV reactivations, pre-emptive anti-CMV chemotherapy prevented the development of CMV disease with the exception of one case. The molecular assays had superior sensitivity to conventional ones. The antigenemia assay proved unsuitable for the surveillance of hematological transplant patients. However, none of the tests recognized all timepoints with CMV reactivation. Further comparative studies are needed to determine their respective diagnostic values.

[Reversibility of changes in left and right ventricular geometry and hemodynamics in pulmonary hypertension. Echocardiographic characteristics before and after pulmonary thromboendarterectomy]. / Reversibilität von Veränderungen der links- und rechtsventrikulären Geometrie und Hämodynamik bei pulmonaler Hypertonie. Echokardiographische Charakterisierung bei Patienten vor und nach pulmonaler Thrombendarteriektomie.

Pulmonary thromboendarterectomy (PTE) leads to an acute decrease of right ventricular (RV) afterload in patients with chronic thromboembolic pulmonary hypertension. We investigated the changes in right and left ventricular (LV) geometry and hemodynamics by means of transthoracic echocardiography. The prospective study was performed in 14 patients (8 female, 6 male; age 55 +/- 20 years) before and 18 +/- 12 days after PTE. Total pulmonary vascular resistance and systolic pulmonary artery pressure were significantly decreased (PVR: preoperative 986 +/- 318, postoperative 323 +/- 280 dyn x s/cm5, p < 0.05; PAP preoperative 71 +/- 40, postoperative 41 +/- 40 mm Hg + right atrial pressure, p < 0.05). End diastolic and end systolic RV area decreased from 33 +/- 12 to 23 +/- 8 cm2, respectively, from 26 +/- 10 to 16 +/- 6 cm2, p < 0.05. There was an increase in systolic RV fractional area change from 20 +/- 12 to 30 +/- 16%, p < 0.05. RV systolic pressure rise remained unchanged (516 +/- 166 vs. 556 +/- 128 mm Hg/sec). LV ejection fraction remained within normal ranges (64 +/- 16 vs. 62 +/- 12%). Echocardiographically determined cardiac index increased from 2.8 +/- 0.74 to 4.1 +/- 1.74 l/min/m2. A decrease in LV excentricity indices (end diastolic: 1.9 +/- 1 vs. 1.1 +/- 0.3, end systolic: 1.7 +/- 0.6 vs. 1.1 +/- 0.4, p < 0.05) proved a normalization of preoperatively altered septum motion. LV diastolic filling returned to normal limits: (E/A ratio: 0.62 +/- 0.34 vs. 1.3 +/- 0.8; p < 0.05); Peak E velocity: 0.51 +/- 0.34 vs. 0.88 +/- 0.28 m/sec, p < 0.05; Peak A velocity: 0.81 +/- 0.36 vs. 0.72 +/- 0.42 m/sec, ns; E deceleration velocity: 299 +/- 328 vs. 582 +/- 294 cm/sec2, p < 0.05; Isovolumic relaxation time: 134 +/- 40 vs. 83 +/- 38 m/sec, p < 0.05). We could show a marked decrease in RV afterload shortly after PTE with a profound recovery of right ventricular systolic function--even in case of severe pulmonary hypertension. A decrease in paradoxic motion of the interventricular septum and normalization of LV diastolic filling pattern resulted in a significant increase of cardiac index.

[Tilt-table study in vasovagal syncope. The diagnostic gain from isoprenaline administration]. / Die Kipptischuntersuchung bei vasovagaler Synkope. Diagnostischer Zugewinn durch Isoprenalin-Gabe.

OBJECTIVE: The cause of syncope remains unclear in half of the cases, even after extensive neurological and cardiological examination. A study was, therefore, undertaken to determine the number of patients with the suspected diagnosis of vasovagal syncope that were confirmed by the tilting table test and how often it required the additional administration of isoprenaline to do so. PATIENTS AND METHODS: A tilting table test was performed on 75 patients (49 men, 26 women; mean age 41 [17-80] years) with syncopes of uncertain cause, previous examinations having failed to discover any neurological or cardiological cause. The test was done with a head-up angle of 60 degrees for 30 min. ECG and arterial blood pressure by indwelling catheter were recorded continuously. If the test was negative, isoprenaline was given intravenously at a rate of 5 micrograms/min during a five-minute period in the horizontal position, followed by 10 minutes at 60 degrees head-up position. RESULTS: Vasovagal syncope or presyncope was induced in 49 of the 75 patients during the tilting table test, a sensitivity of 65%. But 45% of the tests were positive only with the administration of isoprenaline, i.e. an increase in sensitivity to 81.5%. In 96% of the patients with a positive test there was conformity of symptoms between the induced and the spontaneously occurring syncopes. CONCLUSION: The tilting table test is a valuable means of investigating cases of syncope. More than half of the cases of syncope of uncertain cause can be correctly diagnosed classified in this way. The additional use of isoprenaline infusion greatly increases the sensitivity of the method.

[Single right coronary artery with absence of the left coronary ostium]. / Singuläre rechte Kranzarterie bei fehlendem linkskoronarem Ostium.

We report the rare congenital anomaly of a singular right coronary artery in absence of the left coronary ostium. In a 31-years-old man, coronary arterial angiography demonstrated a right coronary artery which, arising from the right Sinus Valsalvae, first described the normal right coronary arterial course but in the apical region continued to follow, in reverse direction, the normal course of the left anterior descending artery. The proximal diameter of the vessel measured 5.2 mm. Thallium scintigraphy showed no ischemia of the anterior wall. The risk of developing circumscribed atherosclerosis due to anatomical reasons seems not to be increased, as no additional bifurcation nor kinking was to be found.

[Right ventricular thrombi in primary antiphospholipid syndrome]. / Rechtsventrikuläre Thromben bei primärem Antiphospholipid-Syndrom.

Over a period of several months a 33-year-old man had recurrent pulmonary emboli. No thromboses could be demonstrated in the peripheral venous system. Transoesophageal echocardiography showed two spherical space-occupying structures in the right ventricle which were removed operatively under the suspected diagnosis of multilobular myxomas. However, their histological examination revealed pure thrombi that had grown by apposition. This unusual findings of right-ventricular thrombi could not be explained pre- and intraoperatively by any local thrombi-favouring changes in the right heart. Tests of clotting mechanisms demonstrated lupus anticoagulant (kaolin-clotting-time mixture test: LA index 21.7 [normal: < 15]), as well as an increased IgG cardiolipin antibody concentration of 19.3 U/l). As no underlying disease was discovered, the diagnosis was by definition primary antiphospholipid syndrome. No further thrombo-embolism has occurred during continuing oral anticoagulation with phenprocoumon.