Dupilumab Drug Survival and Associated Predictors in Patients With Moderate to Severe Atopic Dermatitis Long-term Results From the Daily Practice BioDay Registry

IMPORTANCE Long-term data on dupilumab drug survival in patients with atopic dermatitis (AD) are scarce. Furthermore, little is known about the factors associated with drug survival of dupilumab in AD.OBJECTIVE To describe the drug survival of dupilumab in patients with AD and to identify associated predictors.DESIGN, SETTING, AND PARTICIPANTS This cohort studywas based on data from the multicenter prospective daily practice BioDay registry, in which 4 university and 10 nonuniversity hospitals in the Netherlands participated. Analysis included patients (age &gt;= 18 years) participating in the BioDay registry with a follow-up of at least 4 weeks. The first patient treated with dupilumab was recorded in the BioDay registry in October 2017; data lock took place in December 2020, and data analysis was performed from October 2017 to December 2020.MAIN OUTCOMES AND MEASURES Drug survivalwas analyzed by Kaplan-Meier survival curves and associated characteristics by using univariate and multivariate Cox regression analysis.RESULTS A total of 715 adult patients with AD (mean [SD] age, 41.8 [16.0] years; 418 [58.5%] were male) were included with a 1-year, 2-year, and 3-year overall dupilumab drug survival of 90.3%, 85.9%, and 78.6%, respectively. Characteristics associated with shorter drug survival owing to ineffectiveness were the use of immunosuppressant drugs at baseline (hazard ratio [HR], 2.64; 95% CI, 1.10-6.37) and being a nonresponder at 4 weeks (HR, 8.68; 95% CI, 2.97-25.35). Characteristics associated with shorter drug survival owing to adverse effects were the use of immunosuppressant drugs at baseline (HR, 2.69; 95% CI, 1.32-5.48), age 65 years or older (HR, 2.94; 95% CI, 1.10-7.87), and Investigator Global Assessment score of very severe AD (HR, 3.51; 95% CI, 1.20-10.28).CONCLUSIONS AND RELEVANCE This cohort study demonstrated a good overall 1-year, 2-year, and 3-year dupilumab drug survival. Patients using immunosuppressive therapy at baseline and those with an absence of treatment effect at week 4 tended to discontinue treatment owing to ineffectiveness more frequently. Using immunosuppressant drugs at baseline, older age, and Investigator Global Assessment score of very severe AD were characteristics associated with an increased risk for discontinuation owing to adverse effects. These data provide more insight and new perspectives regarding dupilumab treatment in AD and can contribute to the optimization of patient outcomes.</p

Multi-modal image registration: matching MRI with histology

Spatial correspondence between histology and multi sequence MRI can provide information about the capabilities of non-invasive imaging to characterize cancerous tissue. However, shrinkage and deformation occurring during the excision of the tumor and the histological processing complicate the co registration of MR images with histological sections. This work proposes a methodology to establish a detailed 3D relation between histology sections and in vivo MRI tumor data. The key features of the methodology are a very dense histological sampling (up to 100 histology slices per tumor), mutual information based non-rigid B-spline registration, the utilization of the whole 3D data sets, and the exploitation of an intermediate ex vivo MRI. In this proof of concept paper, the methodology was applied to one tumor. We found that, after registration, the visual alignment of tumor borders and internal structures was fairly accurate. Utilizing the intermediate ex vivo MRI, it was possible to account for changes caused by the excision of the tumor: we observed a tumor expansion of 20%. Also the effects of fixation, dehydration and histological sectioning could be determined: 26% shrinkage of the tumor was found. The annotation of viable tissue, performed in histology and transformed to the in vivo MRI, matched clearly with high intensity regions in MRI. With this methodology, histological annotation can be directly related to the corresponding in vivo MRI. This is a vital step for the evaluation of the feasibility of multi-spectral MRI to depict histological ground-truth

Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? - A preclinical assessment in vitro and in vivo

BACKGROUND: Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors such as bortezomib. METHODS AND RESULTS: In this study, we assessed several combined treatment modalities in vitro and in vivo. By cell-based functional analyses, in a 3D in ovo and an orthotopic mouse model, we demonstrated sensitizing effects of bortezomib combined with cisplatin, radiation and peptide receptor radionuclide therapy (PRRT). By gene expression profiling and western blot, we explored the underlying mechanisms, which resulted in an impaired DNA damage repair. Therapy-induced DNA damage triggered extrinsic proapoptotic signaling as well as the induction of cell cycle arrest, leading to a decreased vital tumor volume and altered tissue composition shown by magnetic resonance imaging and F-18-FDG-PET in vivo, however with no significant additional benefit related to PRRT alone. CONCLUSIONS: We demonstrated that bortezomib has short-term sensitizing effects when combined with DNA damaging therapy by interfering with DNA repair in vitro and in ovo. Nevertheless, due to high tumor heterogeneity after PRRT in long-term observations, we were not able to prove a therapeutic advantage of bortezomib-combined PRRT in an in vivo mouse model

Cardiac magnetic resonance imaging parameters as surrogate endpoints in clinical trials of acute myocardial infarction

Cardiac magnetic resonance (CMR) offers a variety of parameters potentially suited as surrogate endpoints in clinical trials of acute myocardial infarction such as infarct size, myocardial salvage, microvascular obstruction or left ventricular volumes and ejection fraction. The present article reviews each of these parameters with regard to the pathophysiological basis, practical aspects, validity, reliability and its relative value (strengths and limitations) as compared to competitive modalities. Randomized controlled trials of acute myocardial infarction which have used CMR parameters as a primary endpoint are presented

Atopic dermatitis and vitamin D: facts and controversies

Patients with atopic dermatitis have genetically determined risk factors that affect the barrier function of the skin and immune responses that interact with environmental factors. Clinically, this results in an intensely pruriginous and inflamed skin that allows the penetration of irritants and allergens and predisposes patients to colonization and infection by microorganisms. Among the various etiological factors responsible for the increased prevalence of atopic diseases over the past few decades, the role of vitamin D has been emphasized. As the pathogenesis of AD involves a complex interplay of epidermal barrier dysfunction and dysregulated immune response, and vitamin D is involved in both processes, it is reasonable to expect that vitamin D's status could be associated with atopic dermatitis' risk or severity. Such association is suggested by epidemiological and experimental data. in this review, we will discuss the evidence for and against this controversial relationship, emphasizing the possible etiopathogenic mechanisms involved.Univ Brasilia UNB, Brasilia, DF, BrazilFed Dist Hlth State Dept SES DF, Brasilia, DF, BrazilUniv Brasilia HUB UNB, Brasilia Univ Hosp, Brasilia, DF, BrazilSão Paulo Fed Univ UNIFESP, Brasilia, DF, BrazilSão Paulo Fed Univ UNIFESP, Brasilia, DF, BrazilWeb of Scienc

Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? – A preclinical assessment in vitro and in vivo

Background: Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors suc

Quantity and quality of childcare and children’s educational outcomes

Policy-makers wanting to support child development can choose to adjust the quantity or quality of publicly funded universal pre-school. To assess the impact of such changes, we estimate the effects of an increase in free pre-school education in England of about 3.5 months at age 3 on children’s school achievement at age 5. We exploit date-of-birth discontinuities that create variation in the length and starting age of free pre-school using administrative school records linked to nursery characteristics. Estimated effects are small overall, but the impact of the additional term is substantially larger in settings with the highest inspection quality rating but not in settings with highly qualified staff. Estimated effects fade out by age 7

The joint evaluated fission and fusion nuclear data library, JEFF-3.3

The joint evaluated fission and fusion nuclear data library 3.3 is described. New evaluations for neutron-induced interactions with the major actinides $^{235}$U, $^{238}$U and $^{239}$Pu, on $^{241}$Am and $^{23}$Na, $^{59}$Ni, Cr, Cu, Zr, Cd, Hf, W, Au, Pb and Bi are presented. It includes new fission yields, prompt fission neutron spectra and average number of neutrons per fission. In addition, new data for radioactive decay, thermal neutron scattering, gamma-ray emission, neutron activation, delayed neutrons and displacement damage are presented. JEFF-3.3 was complemented by files from the TENDL project. The libraries for photon, proton, deuteron, triton, helion and alpha-particle induced reactions are from TENDL-2017. The demands for uncertainty quantification in modeling led to many new covariance data for the evaluations. A comparison between results from model calculations using the JEFF-3.3 library and those from benchmark experiments for criticality, delayed neutron yields, shielding and decay heat, reveals that JEFF-3.3 performes very well for a wide range of nuclear technology applications, in particular nuclear energy