Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two-staged, adaptive placebo-controlled trial (APRICOT).

BACKGROUND: Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease that affects the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1. OBJECTIVES: To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit in PPP. METHODS: This was a randomized (1 : 1), double-blind, two-staged, adaptive, UK multicentre, placebo-controlled trial [ISCRTN13127147 (registered 1 August 2016); EudraCT number: 2015-003600-23 (registered 1 April 2016)]. Participants had a diagnosis of PPP (> 6 months) requiring systemic therapy. Treatment was 8 weeks of anakinra or placebo via daily, self-administered subcutaneous injections. Primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. RESULTS: A total of 374 patients were screened; 64 were enrolled (31 in the anakinra arm and 33 in the placebo arm) with a mean (SD) baseline PPPASI of 17·8 (10·5) and a PPP investigator's global assessment of severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in the intention-to-treat analysis [-1·65, 95% confidence interval (CI) -4·77 to 1·47; P = 0·30]. Similarly, secondary objective measures, including fresh pustule count (2·94, 95% CI -26·44 to 32·33; favouring anakinra), total pustule count (-30·08, 95% CI -83·20 to 23·05; favouring placebo) and patient-reported outcomes, did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect for an individual who received ≥ 90% of the total treatment (48% in the anakinra group) was -3·80 (95% CI -10·76 to 3·16; P = 0·285). No serious adverse events occurred. CONCLUSIONS: No evidence for the superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

Correlation between Ki-67 immunohistochemistry and 18F-fluorothymidine uptake in patients with cancer: A systematic review and meta-analysis.

BACKGROUND: Positron emission tomography (PET) imaging using the radiotracer 18F-Fluorothymidine (FLT) has been proposed as an imaging biomarker of tumour proliferation. If FLT-PET can be established as such it will provide a non-invasive, quantitative measurement of tumour proliferation across the entire tumour. Results from validation studies have so far been conflicting with some studies confirming a good correlation between FLT uptake and Ki-67 score and others presenting negative results. METHODS: Firstly we performed a systematic review of published studies between 1998 and 2011 that explored the correlation between FLT uptake and Ki-67 score and examined possible variations in the methods used. Studies were eligible if they: (a) included patients with cancer, (b) investigated the correlation between Ki-67 measured by immunohistochemistry and FLT uptake measured with PET scanning, and (c) were published as a full paper in a peer-reviewed scientific journal. Secondly a meta-analysis of the correlation coefficient values reported from each study was performed. Correlation coefficient (r) values were extracted from each study and 95% confidence intervals (CIs) were calculated after applying Fisher's z transformation. For subgroup analysis, studies were classified by the index used to characterise Ki-67 expression (average or maximum expression), the nature of the sample (whole specimen or biopsy) and the cancer type. FINDINGS: Twenty-seven studies were identified as eligible for the meta-analysis. In the studies we examined there were variations in aspects of the methods and reporting. The meta-analysis showed that given an appropriate study design the FLT/Ki-67 correlation is significant and independent of cancer type. Specifically subgroup analysis showed that FLT/Ki-67 correlation was high in studies measuring the Ki-67 average expression regardless of use of surgery or biopsy samples (r=0.70, 95% CI=0.43-0.86, p<0.001). Of the studies that measured Ki-67 maximum expression, only those that used the whole surgical specimen provided a significant r value (r=0.72, 95% CI=0.54-0.84, p<0.001). Studies that used biopsy samples for Ki-67 maximum measurements did not produce a significant r value (r=0.04, 95% CI=-0.18-0.26, p=0.71). In terms of the cancer type subgroup analysis there is sufficient data to support a strong FLT/Ki-67 correlation for brain, lung and breast cancer. No publication bias was detected. INTERPRETATION: This systematic review and meta-analysis highlights the importance of the methods used in validation studies comparing FLT-PET imaging with the biomarker Ki-67. The correlation is significant and independent of cancer type provided a study design that uses Ki-67 average measurements, regardless of nature of sample, or whole surgical samples when measuring Ki-67 maximum expression. Sufficient data to support a strong correlation for brain, lung and breast cancer exist. However, larger, prospective studies with improved study design are warranted to validate these findings for the rest of the cancer types.

Paediatric nutrition risk scores in clinical practice: children with inflammatory bowel disease.

BACKGROUND: There has been increasing interest in the use of nutrition risk assessment tools in paediatrics to identify those who need nutrition support. Four non-disease specific screening tools have been developed, although there is a paucity of data on their application in clinical practice and the degree of inter-tool agreement. METHODS: The concurrent validity of four nutrition screening tools [Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP), Screening Tool for Risk On Nutritional status and Growth (STRONGkids), Paediatric Yorkhill Malnutrition Score (PYMS) and Simple Paediatric Nutrition Risk Score (PNRS)] was examined in 46 children with inflammatory bowel disease. Degree of malnutrition was determined by anthropometry alone using World Health Organization International Classification of Diseases (ICD-10) criteria. RESULTS: There was good agreement between STAMP, STRONGkids and PNRS (kappa > 0.6) but there was only modest agreement between PYMS and the other scores (kappa = 0.3). No children scored low risk with STAMP, STRONGkids or PNRS; however, 23 children scored low risk with PYMS. There was no agreement between the risk tools and the degree of malnutrition based on anthropometric data (kappa < 0.1). Three children had anthropometry consistent with malnutrition and these were all scored high risk. Four children had body mass index SD scores < -2, one of which was scored at low nutrition risk. CONCLUSIONS: The relevance of nutrition screening tools for children with chronic disease is unclear. In addition, there is the potential to under recognise nutritional impairment (and therefore nutritional risk) in children with inflammatory bowel disease.

Valproate for the treatment of acute bipolar depression: systematic review and meta-analysis.

BACKGROUND: Our aim was to analyse existing data on the efficacy and tolerability of valproate for the treatment of acute bipolar depression. METHODS: Randomized controlled trials comparing valproate with placebo were identified using searches of electronic databases in October 2008. Outcomes investigated were depression, anxiety, hypomania, attrition, and adverse events. Trial quality was assessed, and data were summarized using meta-analyses. RESULTS: Four randomized, controlled, doubleblind trials of 142 participants were included. Trial quality was good, although individual study sample sizes were small. Study duration was six weeks (2 studies) and eight weeks (2 studies). Meta-analysis showed a significant difference in favour of valproate for reduction in depressive symptoms, both on depression symptom scales (standardized mean difference (SMD) -0.35 (95% confidence interval, -0.69, -0.02)), and participants with at least 50% improvement in symptoms - relative risk (RR) 2.00 (1.13, 3.53). Effects on anxiety symptoms were small, SMD -0.32 (-0.72, 0.08) and inconclusive (p=0.12). No evidence of a difference in mania symptoms, withdrawal for any reason, lack of effectiveness or adverse events was detected. Nausea occurred more frequently with valproate compared with placebo though the difference was not significant, RR 2.01 (0.98, 4.11). Other adverse events occurring more frequently with valproate (somnolence, fatigue/muscle weakness, headache, diarrhoea and dry mouth) did not differ significantly between treatment groups. LIMITATIONS: Sample sizes were small warranting a larger study to confirm or disprove these findings. CONCLUSIONS: Valproate is effective for the reduction of depressive symptoms of acute bipolar depression, and was well tolerated.

Systematic reviews of adverse effects of drug interventions: a survey of their conduct and reporting quality.

PURPOSE: There is a need for high quality evidence on the adverse effects of medical interventions to inform policy, practice and research. Methods to systematically review adverse effects have not been fully developed. We aimed to assess the current methods and reporting used by such reviews. METHODS: Survey of general medical, drug safety and pharmacology journals published in 2006. Methods including: searching, inclusion criteria, quality assessment and meta-analysis were assessed. RESULTS: Forty three systematic reviews from 2704 abstracts in 16 journals were included. The search strategy was not reported by 10 (23%) of reviews. The collection and reporting of the adverse effects from primary studies was described by 4/37 (12%) reviews and the quality of included studies was assessed by 15 (35%) of reviews. Meta-analysis on rare outcomes and handling of zero event data were inconsistent. A polarity in the standard of reporting between reviews was observed. The reporting standard we found was similar to another survey of systematic reviews. CONCLUSION: Reporting was poor with respect to searching and definition/collection of adverse effects and guidelines such as QUOROM and MOOSE could be employed by authors. Comprehensive and clear reporting should be enforced by journals. The low proportion of reviews assessing quality, and the inconsistencies observed when modelling rare event data reflect the need for empirical research to underpin methods in these areas.