ALBERT

Beschreibung: Evidence from a well-designed randomized controlled trial (RCT) is generally considered to be the gold standard that can inform clinical practice and guide decision-making. However, several deficiencies in the reporting of RCTs have frequently been identified, including incomplete, selective, and biased or inconsistent reporting. Such suboptimal reporting may lead to irreproducible results, substantial waste of resources, impaired study validity, erosion of public trust in science, and a high risk of research misconduct. In this article, we present an overview of the reporting of RCTs in the biomedical literature with a focus on the three most common reporting problems: (i) lack of adherence to reporting guidelines, (ii) inconsistencies between trial protocols or registrations and full reports, and (iii) inconsistencies between abstracts and their corresponding full reports. Unsatisfactory levels of adherence to guidelines and frequent inconsistencies between protocols or registrations and full reports, and between abstracts and full reports, were consistently found in various biomedical research fields. A variety of factors were found to be associated with these reporting challenges. Improved reporting can build public trust and credibility of science, save resources, and enhance the ethical integrity of research. Therefore, joint efforts from the various sectors of the biomedical community (researchers, journal editors and reviewers, educators, healthcare providers, and other research consumers) are needed to reduce and reverse the current suboptimal state of RCT reporting in the literature.

Beschreibung: Introduction Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). Many endocrine receptors, such as insulin receptors, are tyrosine kinase receptors. Hence, TKIs may have effects that impact endocrine function. However, it is not clear to what extent glycemic outcomes are affected by TKI use in this patient population, including children (

Beschreibung: While children with brain tumors are surviving at record rates, survivors are at risk of cardiovascular disease and type 2 diabetes mellitus; these conditions may be driven by excess body fat. Adiponectin in an adipokine that is inversely associated with the fat mass, and has been linked to cardiometabolic risk stratification in the general population. However, adiponectin’s profile and determinants in SCBT have not been established. We tested the hypothesis that high molecular weight (HMW) adiponectin levels, the more biologically active form of adiponectin, were associated with adiposity in SCBT similarly to non-cancer controls. Seventy-four SCBT (n = 32 female) and 126 controls (n = 59 female) who were 5–17 years old were included. Partial correlations and multivariable regression analyses assessed the relationship between HMW adiponectin and adiposity. HMW adiponectin was inversely associated with total and central adiposity (FM%: β − 0.21, 95% CI − 0.15, − 0.08; p value 

Beschreibung: Background: Individuals with non-O blood group are shown to have increased risk of thromboembolism (TE). The exact pathogenesis of the prothrombotic effect of non-O blood group, is however not known. Because individuals with O-blood group have low levels of von Willebrand factor (vWF) compared to those with non-O blood group, vWF has been contemplated as a pathogenetic mechanism in ABO blood group-related prothrombotic risk. However, the available data regarding the role of vWF in the thrombotic risk of non-O blood group are inconclusive. Children with acute lymphoblastic leukemia (ALL) are at increased risk of TE. Several factors such as older age, leukemia phenotype and asparaginase have been shown to impact the risk of TE in children with ALL. We have recently shown that non-O blood group and circulating blasts were significant risk factors for TE in children with ALL. We have also shown that at diagnosis of ALL patients with circulating blasts have significantly higher levels of vWF compared to those without circulating blasts.  Within the context of a larger study aimed to define risk factors for symptomatic TE (sTE) in children with de novo ALL, we undertook a sub-study to evaluate the relationship of ABO blood groups and vWF level at diagnosis of ALL, and to evaluate the impact of circulating blasts on the vWF levels in children with O and non-O blood groups. We hypothesized that compared to patients with O-blood group, those with non-O blood group will have significantly higher levels of vWF and that circulating blasts will have additive effect on the vWF levels in patients with non-O blood group.  Methods : The multicenter, prospective, analytical cohort study included consenting patients (1-≤18 yrs. of age) with de novo ALL enrolled on the Dana-Farber Cancer Institute 05-001 therapeutic trial. Details of patient demography including ABO blood group, ALL diagnosis, therapy and symptomatic TE (sTE) were collected. Samples collected prior to starting ALL-therapy were analyzed centrally for prothrombotic defects (PD) including [protein C, S, antithrombin, Factor VIII:C, vWF, anticardiolipin antibodies and gene polymorphisms of methylene tetrahydrofolate reductase C677T, prothrombin G20210A, Factor V Leiden]. Age-adjusted standardized laboratory data defined PD. Regression analyses evaluated relationship between risk factors and sTE. Thrombosis-free survival was estimated using Kaplan-Meier method.  Results : Of 131 enrolled patients [mean age (range) 6.4 (1-17) yrs.; 70 boys], 21 (16%) developed sTE. ABO blood group information was available for 127 patients; 51 patients had blood group O and 76 non-O (57 with blood group A, 15 with B, and 4 with AB). There was no impact of PD including vWF on the risk of sTE. Older age compared to age ≤ 5 yr. [Odds Ratio (OR) 1.9, p=0.029] and non-O blood-group (OR 4.27, p=0.028) compared to O group were identified as independent predictors for development of sTE. Patients with peripheral blasts had higher odds of developing sTE (OR 7.79; p=0.059).The sTE-free survival was affected by older age (Hazard ratio (HR) 1.1, p 0.03), ALL risk type (HR 3.0, p 0.025) and blood group (O blood group vs non-O blood group, HR 0.23, p 0.03). Table 1 compares the vWF levels in patients with O and non-O blood group and those with and without circulating blasts. Overall, there was no difference in the vWF level at ALL diagnosis between patients with O vs. Non-O blood group. Patients with circulating blasts had higher levels of vWF at ALL diagnosis compared to those without circulating blasts; this comparison was statistically significant for non-O blood group. However, there was no interaction between ABO blood group and circulating blasts on vWF levels (p=0.723)  Conclusion : There was no effect of blood group type on the vWF level at diagnosis of ALL. Patients with circulating blasts had significantly higher levels of vWF at ALL diagnosis and the vWF levels were significantly higher in patients with non-O blood group and circulating blasts. Although it is likely that the relationship between blood group and vWF may be affected by effect of circulating blasts on vWF, we showed no interaction between ABO blood groups and circulating blasts on the vWF levels at diagnosis of ALL in children. Small sample size is a limitation of current study. Further studies with larger sample size are needed to elaborate the relationship between vWF, ABO blood groups, and circulating blasts. Disclosures No relevant conflicts of interest to declare.

Beschreibung: Background: Children with acute lymphoblastic leukemia (ALL) are known to have thrombin activation at diagnosis. However, the pathophysiology of thrombin generation and the impact of therapy on thrombin activation are so far unknown. Steroids are shown to induce prothrombotic state by increasing prothrombotic factors and reducing fibrinolytic potential. The investigational window on DFCI 05-01 protocol offered an unique opportunity to study the haemostatic effects of prednisone, independent of previous or concurrent therapy, in children with newly diagnosed ALL. Aims: In children with newly diagnosed ALL, To evaluate the effects of methyleprednisone monotherapy (PMT) (32 mg/m2/day IV for 3 days) on the parameters of thrombin generation [prothrombin fragments 1.2 (F1.2), thrombin-antithrombin complex (TAT), and D-Dimer], fibrinolytic potential [plasminogen, tissue plasminogen activator (tPA), alpha-2 antiplasmin, alpha-2 macroglobulin, plasminogen activator inhibitor-1 (PAI-1), ratio of tPA/PAI-1], and coagulation factors [FVIII:C, von Willebrand factor (vWF) and fibrinogen] To study the effect age at diagnosis (〈 10 Vs ³ 10 years), gender, risk categorization of ALL [standard (SR) Vs high risk (HR)], presence or absence of circulating blasts, presenting white cell and platelet count on the above hemostatic factors pre and post steroid therapy Methods: Children (〉 1 to £ 18 years of age) enrolled on DFCI ALL 05-01 protocol, without prior steroid therapy or presence of clot, were eligible for study. Overnight fasting blood samples was collected prior to and after PMT, and analyzed for hemostatic factors. The change in the level of each of the hemostatic parameters following PMT was expressed as percent increase or decrease from the baseline. The effect of steroids was tested using “paired t test”. To assess the effects of patient and disease variable student’s t-test was used. Results: Of 30 patients (13 females) enrolled, 8 (27%) had HR ALL. The mean age was 6.33 years (SD 4.35); 24 patients were 〈 10 years. At baseline the levels of F1.2 (mean 1.54 nmol/L; SD 0.90), TAT (mean 10.90 microgram/L; SD 14.93) and D-dimers (2,766.03ng/mL; SD 2385.82) were increased indicating endogenous thrombin activation. Patients with circulating blasts (n=17) had significantly higher mean levels of vWF [1.89 (0.61) vs. 1.14 (0.48) p=0.001], TAT [15.39 (18.62) vs. 5.02 (3.29) p=0.038] and D-dimer [3640 (2499) vs. 1623 (1711) p=0.019] compared to those without circulating blasts. For children with circulating blasts at diagnosis, following steroid therapy the blast count decreased significantly from 24.2% to 3.5% (P

Beschreibung: Introduction: The efficacy of factor VIII and IX concentrates administered to prevent bleeding episodes in patients with hemophilia A and B is correlated with the plasma levels measured over time after the infusion. The inter-patient variability of pharmacokinetic (PK) parameters is large, and it is difficult to assess individual PK profiles due to the need for multiple time points. This is often not feasible, particularly for pediatric patients. Population PK modeling potentially provides a practical solution to this problem. The successful modelling of PK parameters at the population level requires knowledge of disposal characteristics and relevant covariates. We performed a systematic review of the available evidence in order to identify available PK data for factor VIII and IX concentrates to facilitate the implementation of a population PK approach. Methods: We conducted a literature search in MEDLINE and EMBASE from January 1997 to May 2014, using the keywords "hemophilia" and "pharmacokinetic". We included only articles that published original PK data for factor VIII and IX concentrates in humans and published in English. Two authors independently screened the studies and extracted the relevant data. Results: We retrieved 237 unique articles published between 1998 and 2013. We excluded 185 articles that did not meet our research criteria. We included 52 articles, with a total of 1365 patients included in PK analyses. 26 articles reported PK data on factor VIII concentrates, 18 articles report PK data on factor IX concentrates, and one article reported on both factor VIII and IX concentrates. Seven articles reported pharmacokinetic data on both factor VIII and Von Willebrand factor concentrates. We extracted the following data: number of patients, type and severity of hemophilia, patient age, factor concentrate infused, dose infused, sampling data points, half-life, clearance, recovery and the model used for pharmacokinetics, and inclusion of patients undergoing surgery or with inhibitors. The main results are summarized in table 1. Conclusions: This review provides the first systematic appraisal of the methods and results of published papers in the field. The data gathered confirms the intra-patient variability of factor concentrate PK and provides useful information on which to build population based PK models. *3 FIX articles and 2 FVIII articles did not report lab test; one article reported PK data for both FIX and FVIII †11 articles reported FVIII PK data for both one-stage clotting and chromogenic assays ǂPapers reporting on long-acting FVIII and FIX were included in the review, but not summarized in the table. For this reason, not all 1365 patients are accounted for in the table §Estimate of the range of the means found in the papers Disclosures Xi: Baxter: Research Funding. Navarro-Ruan:Baxter: Research Funding. Mammen:Baxter: Research Funding. Collins:Baxter: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL: Consultancy, Honoraria, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Neufeld:Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: data safety monitoring board, data safety monitoring board Other; Biogen IDEC: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Pfiser: consultancy, data and safety monitoring board Other; Octapharma: Research Funding. Dunn:CSL Behring,: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Pfiser: Membership on an entity's Board of Directors or advisory committees. Iorio:Baxter: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; NovoNordisk: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Pfiser: Honoraria, Research Funding.

Beschreibung: Background: Bleeding frequency is an important outcome commonly used in hemophilia studies. There is variation in practice in how bleeding is measured and defined. We therefore performed a systematic review of the studies reporting bleeding frequency in hemophilia patients. Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Control Trials were searched from January 1990 to January 2014. We included all published studies that included patients with hemophilia A and/or B and reported some measure of bleeding. Two reviewers independently performed title and abstract screening, full-text review and data abstraction of the identified studies. Results: A total of 118 studies fulfilled the inclusion criteria. Study designs were randomized controlled trials [RCT] (16/118: 14%), cohort (80/118: 68%), cross-sectional (6/118: 5%) and others design (13/118: 11%). The median duration of follow-up (first quartile [Q1], third quartile [Q3]) was 20 (7.9, 50) months. Joint bleeding is the most common site of reported bleeding (66.9%). We found 10 different bleeding outcomes reported (absolute number of bleeding 60 (50.8%) studies, annualized bleeding rate 60 (50.8%) studies, bleed per month 10 (8.5%) studies and others (bleed per patient-year, bleed per week, bleed per season, etc.) 11 (9.3%) studies). Of these, 32 studies (27%) reported only mean or median without dispersion and 33 (28%) studies did not report any measures of central tendency (dispersion). Conclusions: There is substantial variation in definitions and measures of bleeding outcomes in the hemophilia literature. This creates difficulty and limitations in comparing the outcomes between studies and in performing meta-analysis. The hemophilia research community needs to develop a consensus definition of bleeding and how to address the limitations associated with variations in measures of bleeding between centers and studies. Table 1. Measures of bleeding frequency used in the studies Bleeding outcome measures n , (%) 1. Bleeding frequency# Absolute number of bleeds 60 (50.8) Annualized bleeding rate 60 (50.8) Bleed per month 10 (8.5) Bleed per 100 days 4 (3.4) Others (bleed per patient-year, bleed per week, bleed per 5 years, etc.) 11 (9.3) 2. Central tendency and dispersion# Mean with standard deviation 33 (28.0) Median with range or interquartile range 35 (27.0) Only mean or median 32 (27.1) Not reported 33 (28.0) #Studies could include more than one level of characteristics. Disclosures No relevant conflicts of interest to declare.