Prognostic models for predicting overall survival in metastatic castration-resistant prostate cancer: a systematic review.

PURPOSE: Prognostic models are developed to estimate the probability of the occurrence of future outcomes incorporating multiple variables. We aimed to identify and summarize existing multivariable prognostic models developed for predicting overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: The protocol was prospectively registered (CRD42017064448). We systematically searched Medline and reference lists up to May 2018 and included experimental and observational studies, which developed and/or internally validated prognostic models for mCRPC patients and were further externally validated or updated. The outcome of interest was overall survival. Two authors independently performed literature screening and quality assessment. RESULTS: We included 12 studies that developed models including 8750 patients aged 42-95 years. Models included 4-11 predictor variables, mostly hemoglobin, baseline PSA, alkaline phosphatase, performance status, and lactate dehydrogenase. Very few incorporated Gleason score. Two models included predictors related to docetaxel and mitoxantrone treatments. Model performance after internal validation showed similar discrimination power ranging from 0.62 to 0.73. Overall survival models were mainly constructed as nomograms or risk groups/score. Two models obtained an overall judgment of low risk of bias. CONCLUSIONS: Most models were not suitable for clinical use due to methodological shortcomings and lack of external validation. Further external validation and/or model updating is required to increase prognostic accuracy and clinical applicability prior to their incorporation in clinical practice as a useful tool in patient management.

Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story: Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015.

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.

Evidence-based management of vitiligo: summary of a Cochrane systematic review.

Vitiligo affects around 1% of the world's population. Despite it being relatively common, there is still no effective treatment. The objective of this study was to update the Cochrane systematic review of randomized clinical trials (RCTs) to evaluate the efficacy of treatments for vitiligo. We carried out searches of a range of databases to October 2013 for RCTs of interventions for vitiligo regardless of language or publication status. At least two reviewers independently assessed study eligibility and methodological quality and extracted data using data extraction forms approved by the Cochrane Skin Group. Our primary outcomes of interest were quality of life, > 75% repigmentation and adverse effects. We retrieved 96 studies, of which 39 were new studies, with an overall total of 4512 participants. Repigmentation was assessed in all studies, although only five reported on all three of our primary outcomes. Regarding our two secondary outcomes, six studies measured cessation of spread but none assessed long-term permanence of repigmentation at 2 years' follow-up. Most of the studies evaluated combination treatments, which generally showed better repigmentation than monotherapies. Of the new studies, seven were surgical interventions. The majority of the studies had fewer than 50 participants. The quality of the studies was poor to moderate at best. Very few studies specifically included children or participants with segmental vitiligo. Five years after the last update of this review, there are still important variations in study design and outcome measures in clinical trials for vitiligo, limiting the evidence for the efficacy of different therapeutic options. The best evidence from individual trials showed short-term benefit from topical corticosteroids and various forms of ultraviolet radiation combined with topical preparations. Long-term follow-up and patient-rated outcomes should be incorporated into study design, and more studies should assess psychological interventions.

Report from the kick-off meeting of the Cochrane Skin Group Core Outcome Set Initiative (CSG-COUSIN).

A major obstacle of evidence-based clinical decision making is the use of nonstandardized, partly untested outcome measurement instruments. Core Outcome Sets (COSs) are currently developed in different medical fields to standardize and improve the selection of outcomes and outcome measurement instruments in clinical trials, in order to pool results of trials or to allow indirect comparison between interventions. A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials of a specific disease or trial population. The international, multidisciplinary Cochrane Skin Group Core Outcome Set Initiative (CSG-COUSIN) aims to develop and implement COSs in dermatology, thus making trial evidence comparable and, herewith, more useful for clinical decision making. The inaugural meeting of CSG-COUSIN was held on 17-18 March 2015 in Dresden, Germany, as the exclusive theme of the Annual Cochrane Skin Group Meeting. In total, 29 individuals representing a broad mix of different stakeholder groups, professions, skills and perspectives attended. This report provides a description of existing COS initiatives in dermatology, highlights current methodological challenges in COS development, and presents the concept, aims and structure of CSG-COUSIN.

Phenotyping asthma, rhinitis and eczema in MeDALL population-based birth cohorts: an allergic comorbidity cluster.

BACKGROUND: Asthma, rhinitis and eczema often co-occur in children, but their interrelationships at the population level have been poorly addressed. We assessed co-occurrence of childhood asthma, rhinitis and eczema using unsupervised statistical techniques. METHODS: We included 17 209 children at 4 years and 14 585 at 8 years from seven European population-based birth cohorts (MeDALL project). At each age period, children were grouped, using partitioning cluster analysis, according to the distribution of 23 variables covering symptoms 'ever' and 'in the last 12 months', doctor diagnosis, age of onset and treatments of asthma, rhinitis and eczema; immunoglobulin E sensitization; weight; and height. We tested the sensitivity of our estimates to subject and variable selections, and to different statistical approaches, including latent class analysis and self-organizing maps. RESULTS: Two groups were identified as the optimal way to cluster the data at both age periods and in all sensitivity analyses. The first (reference) group at 4 and 8 years (including 70% and 79% of children, respectively) was characterized by a low prevalence of symptoms and sensitization, whereas the second (symptomatic) group exhibited more frequent symptoms and sensitization. Ninety-nine percentage of children with comorbidities (co-occurrence of asthma, rhinitis and/or eczema) were included in the symptomatic group at both ages. The children's characteristics in both groups were consistent in all sensitivity analyses. CONCLUSION: At 4 and 8 years, at the population level, asthma, rhinitis and eczema can be classified together as an allergic comorbidity cluster. Future research including time-repeated assessments and biological data will help understanding the interrelationships between these diseases.

Are allergic multimorbidities and IgE polysensitization associated with the persistence or re-occurrence of foetal type 2 signalling? The MeDALL hypothesis.

Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono- and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention.

Single and repeated bleomycin intratracheal instillations lead to different biomechanical changes in lung tissue.

Single dose of bleomycin induces acute alveolitis followed by a reparative process whilst a repeated dose results in progressive fibrosis, which may lead to distinct lung tissue biomechanical changes. To test this hypothesis, rats were intratracheally instilled with saline (N=11) or bleomycin (2.5U/kg) once (SD, N=8) or three times (RD, N=9) one week apart, and sacrificed 28 days after challenge. Forced oscillatory mechanics as well as the amount of collagen fibre and myeloperoxidase content (MPO(L)) were studied in lung tissue strips. Both elastic modulus (H), tissue damping (G), and MPO(L) increased only in RD-challenged rats. Although fibroblast focus was found in RD, collagen fibre content increased in both challenged groups. However, the amount of collagen fibre in SD group was not enough to induce lung tissue mechanical changes. In conclusion, repeated doses of bleomycin induce inflammatory and fibrogenic behaviour with biomechanical changes mimicking interstitial lung disease in humans.

Inflammatory related changes in lung tissue mechanics after bleomycin-induced lung injury.

The impact of lung remodelling in respiratory mechanics has been widely studied in bleomycin-induced lung injury. However, little is known regarding the relationship between the amount of lung inflammation and pulmonary tissue mechanics. For this purpose, rats were intratracheally instilled with bleomycin (n=29) or saline (n=8) and sacrificed at 3, 7, or 15 days. Forced oscillatory mechanics as well as indices of remodelling (elastic fibre content and hydroxyproline) and inflammation (myeloperoxidase content, total cell count, alveolar wall thickness, and lung water content) were studied in lung tissue strips. Tissue resistance increased significantly at day 15, while hysteresivity was significantly higher in bleomycin group compared to control at all time points. Elastic fibres, hydroxyproline and myeloperoxidase contents augmented after bleomycin at days 7 and 15. Tissue resistance and hysteresivity were significantly correlated with myeloperoxidase, elastic fibre and lung water content. In conclusion, inflammatory structural changes and elastogenesis are the main determinants for hysteretic changes in this 2-week bleomycin-induced lung injury model.

Is there a sex-shift in prevalence of allergic rhinitis and comorbid asthma from childhood to adulthood? A meta-analysis.

BACKGROUND: Allergic rhinitis and asthma as single entities affect more boys than girls in childhood but more females in adulthood. However, it is unclear if this prevalence sex-shift also occurs in allergic rhinitis and concurrent asthma. Thus, our aim was to compare sex-specific differences in the prevalence of coexisting allergic rhinitis and asthma in childhood, adolescence and adulthood. METHODS: Post-hoc analysis of systematic review with meta-analysis concerning sex-specific prevalence of allergic rhinitis. Using random-effects meta-analysis, we assessed male-female ratios for coexisting allergic rhinitis and asthma in children (0-10 years), adolescents (11-17) and adults (> 17). Electronic searches were performed using MEDLINE and EMBASE for the time period 2000-2014. We included population-based observational studies, reporting coexisting allergic rhinitis and asthma as outcome stratified by sex. We excluded non-original or non-population-based studies, studies with only male or female participants or selective patient collectives. RESULTS: From a total of 6539 citations, 10 studies with a total of 93,483 participants met the inclusion criteria. The male-female ratios (95% CI) for coexisting allergic rhinitis and asthma were 1.65 (1.52; 1.78) in children (N = 6 studies), 0.61 (0.51; 0.72) in adolescents (N = 2) and 1.03 (0.79; 1.35) in adults (N = 2). Male-female ratios for allergic rhinitis only were 1.25 (1.19; 1.32, N = 5) in children, 0.80 (0.71; 0.89, N = 2) in adolescents and 0.98 (0.74; 1.30, N = 2) in adults, respectively. CONCLUSIONS: The prevalence of coexisting allergic rhinitis and asthma shows a clear male predominance in childhood and seems to switch to a female predominance in adolescents. This switch was less pronounced for allergic rhinitis only.

In vivo and in vitro lung mechanics by forced oscillations: effect of bleomycin challenge.

Bleomycin injury causes biomechanical changes secondary to inflammation, tissue remodeling and surfactant changes. We compared lung mechanics in open chest (OC) and tissue strip (TS) to better understand the pathophysiology of the alveolar interface between lung tissue and conducting airways. Thirty nine rats were studied at days 3, 7, and 15 after receiving saline or bleomycin (2.5 Ukg(-1)) intratracheally. Normalized elastance (E), hysteresivity (η) and exponent (ß) of the power frequency dependence of elastance were determined in OC (lung parenchyma) and TS. Remodeling (hydroxyproline) and inflammation (myeloperoxidase and lung water) parameters were determined. E, η and ß were higher in OC both in saline and bleomycin groups. The difference (OC-TS) of η and ß correlated with myeloperoxidase and lung water but not with hydroxyproline. We concluded that differences between lung parenchyma and tissue mechanics are due to mechanical effects of inhomogeneities in saline animals. Changes at the alveolar interface after bleomycin are related to oxidative stress and extravascular lung water.

In vitro determination of prebiotic properties of oligosaccharides derived from an orange juice manufacturing by-product stream.

Fermentation properties of oligosaccharides derived from orange peel pectin were assessed in mixed fecal bacterial culture. The orange peel oligosaccharide fraction contained glucose in addition to rhamnogalacturonan and xylogalacturonan pectic oligosaccharides. Twenty-four-hour, temperature- and pH-controlled, stirred anaerobic fecal batch cultures were used to determine the effects that oligosaccharides derived from orange products had on the composition of the fecal microbiota. The effects were measured through fluorescent in situ hybridization to determine changes in bacterial populations, fermentation end products were analyzed by high-performance liquid chromatography to assess short-chain fatty acid concentrations, and subsequently, a prebiotic index (PI) was determined. Pectic oligosaccharides (POS) were able to increase the bifidobacterial and Eubacterium rectale numbers, albeit resulting in a lower prebiotic index than that from fructo-oligosaccharide metabolism. Orange albedo maintained the growth of most bacterial populations and gave a PI similar to that of soluble starch. Fermentation of POS resulted in an increase in the Eubacterium rectale numbers and concomitantly increased butyrate production. In conclusion, this study has shown that POS can have a beneficial effect on the fecal microflora; however, a classical prebiotic effect was not found. An increase in the Eubacterium rectale population was found, and butyrate levels increased, which is of potential benefit to the host.