Patients treated with romiplostim had a higher rate of a platelet response, lower incidence of treatment failure and splenectomy, less bleeding and fewer blood transfusions, and a higher quality of life than patients treated with the standard of care. ( ClinicalTrials.gov number, NCT00415532.).
We propose a comprehensive pattern recognition procedure that will achieve best discrimination between two or more sets of subjects with data in the same coordinate system. Applying the procedure to MS data of proteomic analysis of serum from ovarian cancer patients and serum from cancer-free individuals in the Food and Drug Administration͞National Cancer Institute Clinical Proteomics Database, we have achieved perfect discrimination (100% sensitivity, 100% specificity) of patients with ovarian cancer, including early-stage disease, from normal controls for two independent sets of data. Our procedure identifies the best subset of proteomic biomarkers for optimal discrimination between the groups and appears to have higher discriminatory power than other methods reported to date. For large-scale screening for diseases of relatively low prevalence such as ovarian cancer, almost perfect specificity and sensitivity of the detection system is critical to avoid unmanageably high numbers of false-positive cases. discriminant analysis ͉ random field ͉ resampling ͉ statgram
Romiplostim is the TPOra for which the longest duration of safety data is available. Our data demonstrate that long-term romiplostim treatment is well tolerated, with no new safety signals, even in patients treated for up to 5 yr.
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by platelet destruction and insufficient platelet production. The resulting thrombocytopenia reduces patient health-related quality of life (HRQOL). In a randomized, open-label, 52-week study of nonsplenectomized ITP patients treated with romiplostim or medical standard of care (SOC), patients completed the 10-scale ITP-patient assessment questionnaire (PAQ) at the start of the study and after 12, 24, 36, 48, and 52 weeks of treatment. HRQOL changes were examined for all patients in both treatment groups and by responder status, splenectomy status, and after the use of rituximab. Patients in both groups showed marked increases in all HRQOL scales over 52 weeks of treatment. These change scores exceeded the minimally important difference values (a measure of clinical relevance) for most of these scales, especially in responders to treatment. Compared with baseline, patients receiving romiplostim showed statistically significant improvements compared to SOC over 52 weeks for the ITP-PAQ scales of Symptoms, Bother, Activity, Psychological Health, Fear, Overall QOL, and Social QOL. Overall, treatment of ITP was associated with improvement in HRQOL. Patients receiving romiplostim had greater HRQOL improvements than those receiving SOC, but the magnitude of the difference is of uncertain clinical benefit.Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by persistent thrombocytopenia due to antibody binding to platelet antigen(s) causing their premature destruction by the reticuloendothelial system, particularly in the spleen [1]. In addition, recent evidence suggests that there is also insufficient platelet production, possibly immune-mediated [2]. The resulting thrombocytopenia places patients at risk for bruising and bleeding.Recent international practice guidelines recommend that initial ITP treatment include glucocorticoids, intravenous immunoglobulin (IVIg), or intravenous anti-D. Second-line treatment includes splenectomy or medical therapies such as azathioprine, danazol, rituximab, or the thrombopoietin (TPO) receptor agonists [3,4]. Many of these second-line treatments are associated with significant toxicities or cost [3,4].Romiplostim is a novel TPO receptor agonist that binds to and stimulates the TPO receptor. It has been shown to increase platelet counts with few adverse events [5]. In two randomized studies, an overall platelet response (weekly platelet counts 50 3 10 9 /L during 4 or more weeks of the 24-week study) was achieved by 83% of patients receiving romiplostim versus 7% of patients receiving placebo (P < 0.0001) [6]. In addition, 87% of romiplostim versus 38% of placebo patients were able to reduce or discontinue their concurrent ITP medication, including corticosteroids and IVIg [6]. Continuous long-term (up to 156 weeks) treatment with romiplostim produced a platelet response (platelet counts 50 3 10 9 /L) in 87% of 142 ITP patients [7]. Finally, romiplostim treatment led to fewer bleeding events, tran...
Humans exhibit considerable variation in how they value their own interest relative to the interests of others. Deciphering the neural codes representing potential rewards for self and others is crucial for understanding social decision-making. Here we integrate computational modeling with fMRI to investigate the neural representation of social value and the modulation by oxytocin, a nine-amino acid neuropeptide, in participants evaluating monetary allocations to self and other (self-other allocations). We found that an individual's preferred self-other allocation serves as a reference-point for computing the value of potential self-other allocations. In more-prosocial participants, amygdala activity encoded a social-value-distance signal, i.e. the value dissimilarity between potential and preferred allocations. Intranasal oxytocin administration amplified this amygdala representation and increased prosocial behavior in more-individualist participants but not in more-prosocial ones. Our results reveal a neurocomputational mechanism underlying social-value representations and suggest that oxytocin may promote prosociality by modulating social-value representations in the amygdala.
A safety analysis of pooled data from clinical studies of romiplostim, a thrombopoietin (TPO) receptor agonist, in which patients with immune thrombocytopaenia (ITP) received romiplostim, placebo, or medical standard of care (SOC) Rodeghiero et al. (Eur J Haematol 91:423-436, 2013), has been updated. Included are data from 14 trials spanning 2002-2011; placebo- and SOC-arm data are pooled. Most patients (n = 1059) were female (61 %) and Caucasian (85 %); 38 % had undergone splenectomy; 23 were children. Mean (SD) baseline platelet count was 20.6 (16.5) × 10(9)/L. Mean (SD) weekly dose of romiplostim was 4.2 (2.8) µg/kg; total exposure was 1520 patient-years. Overall, 921 patients received romiplostim only, 65 received placebo/SOC only, and 73 received placebo/SOC followed by romiplostim. Rates of haemorrhage (romiplostim, 205/100 patient-years; placebo/SOC, 263/100), thrombosis (both, 5.5/100 patient-years), haematological malignancy/myelodysplastic syndrome (romiplostim, 0.5/100 patient-years; placebo/SOC, 2.7/100), and non-haematological tumours (romiplostim, 2.2/100 patient-years; placebo/SOC, 3.6/100) were comparable among groups. Bone marrow reticulin was reported in 17 patients and collagen in one patient receiving romiplostim; one patient receiving placebo/SOC had reticulin reported. Three patients developed neutralizing antibodies to romiplostim, but not to endogenous TPO. This integrated analysis of the safety profile of romiplostim in patients with ITP is consistent with previously reported studies; no new safety concerns emerged.
The effects of romiplostim on bone marrow morphology were evaluated in adults with immune thrombocytopenia (ITP). Patients with platelet counts <50 × 109/L, ≥1 prior ITP therapies, and no collagen at baseline received weekly subcutaneous romiplostim starting at 1 μg/kg, adjusted to maintain platelet counts between 50 and 200 × 109/L. Biopsies were scheduled after 1, 2, or 3 years of romiplostim (cohorts 1, 2, and 3, respectively). Irrespective of scheduled time, biopsies were performed earlier if patients discontinued or failed to achieve/maintain a response to romiplostim. Reticulin (silver stain) and collagen (trichrome stain) were graded by two hematopathologists using the modified Bauermeister scale (0–4). Of 169 patients, 131 had evaluable biopsies; 9/131 (6.9 %) had increases of ≥2 grades on the modified Bauermeister scale (cohort 1: 0/34; cohort 2: 2/39; cohort 3: 7/58), including two with collagen. Three of the nine patients had follow-up biopsies, including one patient with collagen; changes were reversible after romiplostim discontinuation. Of the nine patients, one had neutropenia detected by laboratory test and two had adverse events of anemia, both non-serious and not treatment-related. By actual exposure (as some biopsies did not occur as scheduled), the number of patients with grade increases ≥2 were year 1: 3/41, year 2: 1/38, year 3: 5/52. Twenty-four patients sustained platelet counts ≥50 × 109/L for ≥6 months with no ITP medications after discontinuing romiplostim, i.e., they entered clinical remission of their ITP. In conclusion, in patients with ITP receiving romiplostim, bone marrow changes were observed in a small proportion of patients.ClinicalTrials.gov identifier: NCT#00907478Electronic supplementary materialThe online version of this article (doi:10.1007/s00277-016-2682-2) contains supplementary material, which is available to authorized users.
Primary immune thrombocytopenia is an autoimmune disorder characterized by increased platelet destruction and insufficient platelet production without another identified underlying disorder. Splenectomy may alter responsiveness to treatment and/or increase the risk of thrombosis, infection, and pulmonary hypertension. The analysis herein evaluated the safety and efficacy of the thrombopoietin receptor agonist romiplostim in splenectomized and nonsplenectomized adults with primary immune thrombocytopenia. Data were pooled across 13 completed clinical studies in adults with immune thrombocytopenia from 2002–2014. Adverse event rates were adjusted for time of exposure. Results were considered different when 95% confidence intervals were non-overlapping. Safety was analyzed for 1111 patients (395 splenectomized; 716 nonsplenectomized) who received romiplostim or control (placebo or standard of care). At baseline, splenectomized patients had a longer median duration of immune thrombocytopenia and a lower median platelet count, as well as a higher proportion with >3 prior immune thrombocytopenia treatments versus nonsplenectomized patients. In each treatment group, splenectomized patients used rescue medications more often than nonsplenectomized patients. Platelet response rates (≥50×109/L) for romiplostim were 82% (310/376) for splenectomized and 91% (592/648) for nonsplenectomized patients (P<0.001 by Cochran-Mantel-Haenszel test). Platelet responses were stable over time in both subgroups. Exposure-adjusted adverse event rates were higher for control versus romiplostim for both splenectomized (1857 versus 1226 per 100 patient-years) and nonsplenectomized patients (1052 versus 852 per 100 patient-years). In conclusion, responses to romiplostim were seen in both splenectomized and nonsplenectomized patients, and romiplostim was not associated with an increase in the risk of adverse events in splenectomized patients. clinicaltrials.gov Identifier: 00111475(A)(B), 00117143, 00305435, 01143038, 00102323, 00102336, 00415532, 00603642, 00508820, 00907478, 00116688, and 00440037.
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