Marrow transplantation from unrelated donors for patients with severe aplastic anemia who have failed immunosuppressive therapy

AbstractAllogeneic marrow transplantation offers curative therapy for patients with aplastic anemia. We analyzed retrospective results in 141 patients with severe aplastic anemia who received transplants between 1988 and 1995 from an unrelated volunteer donor identified through the National Marrow Donor Program (NMDP). All patients had failed one or more courses of immunosuppressive therapy. Of the patients, 121 (86%) received a radiation-containing conditioning regimen, and 20 (14%) were given chemotherapy only. Based on serologic human leukocyte antigen (HLA) typing (class I and II), 105 patients (74%) received HLA-matched marrow, and 36 (26%) received marrow mismatched for at least one HLA-A, -B, or -DR antigen. Allele-level (molecular) typing for HLA-DRB1 was available in 108 donor-recipient pairs; 77 patients received DRB -matched and 31 DRB1-mismatched transplants. All but 13% of patients were given a cyclosporine-containing regimen for graft-vs.-host disease (GVHD) prophylaxis, and 45 patients (32%) received marrow that was T cell-depleted. Among 131 evaluable patients, 116 (89%) achieved sustained engraftment and 15 (11%) did not. Among patients with engraftment, acute GVHD of grades II-IV developed in 60 patients (52%) and extensive chronic GVHD in 24 patients at risk (31%). Currently, 51 patients (36%) are surviving at 11-94 months (median 36) after transplantation. All but five have Karnofsky scores > or =80. Patients who received a serologically matched transplant fared somewhat better than did patients given a serologically mismatched transplant p = 0.03). Patients with donors matched by both serology and allele-level DRB1 typing had significantly better survival than DRB1-mismatched patients with 56 vs. 15% surviving at 3 years p = 0.001). Outcome in patients transplanted within 3 years of diagnosis was superior to that among patients transplanted with greater delay. Major causes of death were graft failure, GVHD, and infections. These data suggest that unrelated marrow transplantation offers successful therapy for a proportion of patients who have failed immunosuppressive therapy.Biol Blood Marrow Transplant 1999;5(4):243-52

Psoralen and ultraviolet A irradiation (PUVA) as therapy for steroid-resistant cutaneous acute graft-versus-host disease

AbstractPsoralen plus ultraviolet A irradiation (PUVA) has immunomodulatory effects and is used to treat a variety of immune-mediated dermatologic diseases. We administered PUVA to 103 patients for treatment of steroid-resistant acute graft-versus-host disease (GVHD) of the skin. Twenty-nine patients had related donors (12 HLA-mismatched) and 74 had unrelated donors (23 HLA-mismatched). The median onset of GVHD was day 13 after transplantation, and the median onset of PUVA treatment was day 46. PUVA was administered as secondary therapy for 86 patients and tertiary therapy or greater for 17 patients. The median number of treatments was 16, and the mean cumulative exposure was 41 J/cm2. PUVA was generally well tolerated with 8 patients discontinuing therapy because of toxicity. At the start of PUVA treatment, 48 patients had rash affecting >50% of their body surface area (BSA), and 91 had rash involving >25% BSA. Of 65 patients who were evaluated after 6 weeks of PUVA treatment, 11 still had rash involving >50% BSA, 24 had rash involving >25% BSA, and 24 had no rash. The mean daily dose of prednisone at the start of PUVA therapy was 1.6 mg/kg compared to 0.7 mg/kg after 6 weeks of therapy. Fifty-nine patients (57%) did not require additional therapy for skin GVHD after starting PUVA. Ninety-two percent of patients developed chronic GVHD. Fifty-three patients (51%) remain alive at 129-1883 days after transplantation. These results suggest that PUVA can be an effective therapy for steroid-resistant acute GVHD of the skin.Biol Blood Marrow Transplant 2002;8(4):206-12

Marrow transplants from unrelated donors for patients with aplastic anemia: Minimum effective dose of total body irradiation

AbstractPatients with aplastic anemia who do not have suitably HLA-matched, related donors generally receive immunosuppressive treatment as first-line therapy and are considered for transplantation from an unrelated donor only if they fail to respond to immunosuppressive treatment. In this setting, rates of transplantation-related morbidity and mortality have been high. We conducted a prospective study to determine the minimal dose of total body irradiation (TBI) sufficient to achieve sustained engraftment when it is used in combination with 3 cycles of 30 mg/kg of antithymocyte globulin (ATG) and 4 cycles of 50 mg/kg of cyclophosphamide (CY). We also wanted to determine the tolerability and toxicity of the regimen. The starting dosage of TBI was 3 x 200 cGy given over 2 days following CY/ATG. The TBI dose was to be escalated in increments of 200 cGy if graft failure occurred in the absence of prohibitive toxicity, and de-escalated for toxicity in the absence of graft failure. Twenty-one female and 29 male patients aged 1.3 to 46.5 years (median age, 14.4 years) underwent transplantation at 14 medical centers. The time interval from diagnosis to transplantation was 2.8 to 264 months (median, 14.5 months). All patients had been transfused multiple times and all had received 1 to 11 courses (median, 4 courses) of immunosuppressive treatment and other modalities of treatment. In 38 cases, the donors were HLA-A, -B and -DR phenotypically matched with the patients, and, in 12 cases, the donor phenotype differed from that of the recipient by 1 HLA antigen. Recipients of mismatched transplants were considered separately for TBI dose modification, and this study is still ongoing. Seven patients did not tolerate ATG and were prepared with 6 x 200 cGy of TBI plus 120 mg/kg of CY. Of the HLA-matched recipients prepared with CY/ATG/TBI, all 20 who received 3 x 200 or 2 x 200 cGy of TBI achieved engraftment, and 10 are alive. Of the 13 patients who received 1 x 200 cGy of TBI, 1 failed to engraft, and 8 are alive. Each of 10 patients who received an HLA-nonidentical transplant achieved engraftment, and 3 of 6 who were given 3 x 200 cGy of TBI, and 4 of 4 who were given 2 x 200 cGy are alive. Pulmonary toxicity occurred in 8 of 30 patients who were given 3 x 200 or 2 x 200 cGy of TBI concurrently with ATG and CY at 200 mg/kg, and in 2 of 13 patients who received 1 x 200 cGy of TBI, a pattern that suggests a decrease in toxicity with TBI dose de-escalation. Overall, the highest probability of survival (73%) was observed among patients who underwent transplantation within 1 year of diagnosis, compared with patients who underwent transplantation after a longer period of disease. In addition, younger patients (aged < or = 20 years) were more likely to survive than older patients (aged > 20 years). Thus, for patients with an HLA-matched, unrelated donor, a TBI dose of 200 cGy (in combination with CY/ATG) was sufficient to allow for engraftment without inducing prohibitive toxicity. As in previous studies, patient age and pretransplantation disease duration remain important prognostic factors.Biol Blood Marrow Transplant 2001;7(4):208-15

Conditioning with Treosulfan and Fludarabine followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

In this prospective study 60 patients of median age 46 (range: 5-60 years), with acute myelogenous leukemia (AML; n = 44), acute lymphoblastic leukemia (ALL; n = 3), or myelodysplastic syndrome (MDS; n = 13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine (Flu) combination. Most patients were considered at high risk for relapse or nonrelapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m2/day (n = 5) or 14 g/m2/day (n = 55) on days −6 to −4, and Flu (30 mg/m2/day) on days −6 to −2, followed by infusion of marrow (n = 7) or peripheral blood stem cells (n = 53) from HLA-identical siblings (n = 30) or unrelated donors (n = 30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival (RFS) for all patients was 58% and 88% for patients without high-risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/Flu regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/Flu to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients

Do people with risky behaviours participate in biomedical cohort studies?

BACKGROUND: Analysis was undertaken on data from randomly selected participants of a bio-medical cohort study to assess representativeness. The research hypotheses was that there was no difference in participation and non-participations in terms of health-related indicators (smoking, alcohol use, body mass index, physical activity, blood pressure and cholesterol readings and overall health status) and selected socio-demographics (age, sex, area of residence, education level, marital status and work status). METHODS: Randomly selected adults were recruited into a bio-medical representative cohort study based in the north western suburbs of the capital of South Australia – Adealide. Comparison data was obtained from cross-sectional surveys of randomly selected adults in the same age range and in the same region. The cohort participants were 4060 randomly selected adults (18+ years). RESULTS: There were no major differences between study participants and the comparison population in terms of current smoking status, body mass index, physical activity, overall health status and proportions with current high blood pressure and cholesterol readings. Significantly more people who reported a medium to very high alcohol risk participated in the study. There were some demographic differences with study participants more likely to be in the middle level of household income and education level. CONCLUSION: People with risky behaviours participated in this health study in the same proportions as people without these risk factors

In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Comment in Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016] In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016] US oncologists call for government regulation to curb drug price rises. [BMJ. 2015

Accelerometer-based physical activity in a large observational cohort - study protocol and design of the activity and function of the elderly in Ulm (ActiFE Ulm) study

<p>Abstract</p> <p>Background</p> <p>A large number of studies have demonstrated a positive effect of increased physical activity (PA) on various health outcomes. In all large geriatric studies, however, PA has only been assessed by interview-based instruments which are all subject to substantial bias. This may represent one reason why associations of PA with geriatric syndromes such as falls show controversial results. The general aim of the Active-Ulm study was to determine the association of accelerometer-based physical activity with different health-related parameters, and to study the influence of this standardized objective measure of physical activity on health- and disability-related parameters in a longitudinal setting.</p> <p>Methods</p> <p>We have set up an observational cohort study in 1500 community dwelling older persons (65 to 90 years) stratified by age and sex. Addresses have been obtained from the local residents registration offices. The study is carried out jointly with the IMCA - Respiratory Health Survey in the Elderly implemented in the context of the European project IMCA II. The study has a cross-sectional part (1) which focuses on PA and disability and two longitudinal parts (2) and (3). The primary information for part (2) is a prospective 1 year falls calendar including assessment of medication change. Part (3) will be performed about 36 months following baseline. Primary variables of interest include disability, PA, falls and cognitive function. Baseline recruitment has started in March 2009 and will be finished in April 2010.</p> <p>All participants are visited three times within one week, either at home or in the study center. Assessments included interviews on quality of life, diagnosed diseases, common risk factors as well as novel cognitive tests and established tests of physical functioning. PA is measured using an accelerometer-based sensor device, carried continuously over a one week period and accompanied by a prospective activity diary.</p> <p>Discussion</p> <p>The assessment of PA using a high standard accelerometer-based device is feasible in a large population-based study. The results obtained from cross-sectional and longitudinal analyses will shed light on important associations between PA and various outcomes and may provide information for specific interventions in older people.</p

How Many Varieties of Capitalism? Comparing the Comparative Institutional Analyses of Capitalist Diversity

This essay reviews the development of approaches within the comparative capitalisms (CC) literature and points to three theoretical innovations which, taken together, define and distinguish these approaches as a group. First, national economies are characterized by distinct institutional configurations that generate a particular systemic 'logic' of economic action. Second, the CC literature suggests a theory of comparative institutional advantage in which different institutional arrangements have distinct strengths and weaknesses for different kinds of economic activity. Third, the literature has been interpreted to imply a theory of institutional path dependence. Behind these unifying characteristics of the literature, however, lie a variety of analytical frameworks and typologies of capitalism. This paper reviews and compares these different frameworks by highlighting the fundamental distinctions among them and drawing out their respective contributions and limitations in explaining economic performance and institutional dynamics. The paper concludes that the way forward for this literature lies in developing a more dynamic view of individual institutions, the linkages between domains, and the role of politics and power.In diesem Discussion Paper werden Ansätze der Comparative-Capitalism-Diskussion vorgestellt. Sie haben drei theoretische Innovationen gemein. Erstens: Nationale Ökonomien werden durch institutionelle Konfigurationen geprägt, die auf jeweils eigene "systemische Logiken" wirtschaftlichen Handelns hinwirken. Zweitens: Die Comparative-Capitalism-Literatur beinhaltet eine Theorie der komparativen institutionellen Vorteile, der zufolge institutionellen Konfigurationen spezifische Wettbewerbsvorteile zugeordnet werden können. Zudem, drittens, beinhaltet die Comparative-Capitalism-Literatur auch eine implizite Theorie der Pfadabhängigkeit. Trotz dieser Gemeinsamkeiten unterscheiden sich die Ansätze hinsichtlich analytischer Zugriffe und Vorschläge zur Typologisierung nationaler Kapitalismen. Beim Vergleich dieser Ansätze werden besonders deren Stärken und Schwächen bei der Analyse wirtschaftlicher Performanz und institutioneller Entwicklungsdynamiken hervorgehoben. Der Aufsatz kommt zu dem Schluss, dass die Comparative-Capitalism-Literatur in dreierlei Hinsicht der Weiterentwicklung bedarf: hinsichtlich einer dynamischeren Modellierung von Institutionen, einem besseren Verständnis der Interaktion institutioneller Domänen und der Berücksichtigung von Macht und Politik in der Analyse von Produktionsregimen

Gender differences in marital status moderation of genetic and environmental influences on subjective health

From the IGEMS Consortium, data were available from 26,579 individuals aged 23 to 102 years on 3 subjective health items: self-rated health (SRH), health compared to others (COMP), and impact of health on activities (ACT). Marital status was a marker of environmental resources that may moderate genetic and environmental influences on subjective health. Results differed for the 3 subjective health items, indicating that they do not tap the same construct. Although there was little impact of marital status on variance components for women, marital status was a significant modifier of variance in all 3 subjective health measures for men. For both SRH and ACT, single men demonstrated greater shared and nonshared environmental variance than married men. For the COMP variable, genetic variance was greater for single men vs. married men. Results suggest gender differences in the role of marriage as a source of resources that are associated with subjective health