Using Bayesian Evidence Synthesis Methods to Incorporate Real-World Evidence in Surrogate Endpoint Evaluation.

Objective Traditionally, validation of surrogate endpoints has been carried out using randomized controlled trial (RCT) data. However, RCT data may be too limited to validate surrogate endpoints. In this article, we sought to improve the validation of surrogate endpoints with the inclusion of real-world evidence (RWE). Methods We use data from comparative RWE (cRWE) and single-arm RWE (sRWE) to supplement RCT evidence for the evaluation of progression-free survival (PFS) as a surrogate endpoint to overall survival (OS) in metastatic colorectal cancer (mCRC). Treatment effect estimates from RCTs, cRWE, and matched sRWE, comparing antiangiogenic treatments with chemotherapy, were used to inform surrogacy patterns and predictions of the treatment effect on OS from the treatment effect on PFS. Results Seven RCTs, 4 cRWE studies, and 2 matched sRWE studies were identified. The addition of RWE to RCTs reduced the uncertainty around the estimates of the parameters for the surrogate relationship. The addition of RWE to RCTs also improved the accuracy and precision of predictions of the treatment effect on OS obtained using data on the observed effect on PFS. Conclusion The addition of RWE to RCT data improved the precision of the parameters describing the surrogate relationship between treatment effects on PFS and OS and the predicted clinical benefit of antiangiogenic therapies in mCRC.</p

A Deletion in <i>FOXN1</i> Is Associated with a Syndrome Characterized by Congenital Hypotrichosis and Short Life Expectancy in Birman Cats

<div><p>An autosomal recessive syndrome characterized by congenital hypotrichosis and short life expectancy has been described in the Birman cat breed (<i>Felis silvestris catus</i>). We hypothesized that a <i>FOXN1</i> (<i>forkhead box N1</i>) loss-of-function allele, associated with the nude phenotype in humans, mice and rats, may account for the syndrome observed in Birman cats. To the best of our knowledge, spontaneous mutations in <i>FOXN1</i> have never been described in non-human, non-rodent mammalian species. We identified a recessive c.1030_1033delCTGT deletion in <i>FOXN1</i> in Birman cats. This 4-bp deletion was associated with the syndrome when present in two copies. Percentage of healthy carriers in our French panel of genotyped Birman cats was estimated to be 3.2%. The deletion led to a frameshift and a premature stop codon at position 547 in the protein. In silico, the truncated FOXN1 protein was predicted to lack the activation domain and critical parts of the forkhead DNA binding domain, both involved in the interaction between FOXN1 and its targets, a mandatory step to promote normal hair and thymic epithelial development. Our results enlarge the panel of recessive <i>FOXN1</i> loss-of-function alleles described in mammals. A DNA test is available; it will help owners avoid matings at risk and should prevent the dissemination of this morbid mutation in domestic felines.</p></div

Genotypes for the c.[1030_1033delCTGT] deletion in 16 breeds of cats.

<p>* Chartreux (n = 21), Sphynx (n = 20), British SH and LH (n = 20), Norwegian Forest Cat (n = 20), Maine Coon (n = 15), Abyssinian and Somali (n = 15), Bengal (n = 13), Domestic SH and LH (n = 11), Devon Rex (n = 10), Siberian (n = 6), Russian and Nebelung (n = 4), Bombay (n = 1).</p><p><i>N</i>: no deletion. <i>del</i>: CTGT deletion. SH: shorthair, LH: longhair</p><p>Genotypes for the c.[1030_1033delCTGT] deletion in 16 breeds of cats.</p

Hypotrichosis phenotype in Birman kittens.

<p>Hairless kittens among normal littermates, born to longhaired colourpoint mitted parents (A, B). A hairless 3-week-old kitten showing wrinkled skin (C). A 12-week-old hairless kitten displaying a sparse short fur with attenuated whiskers (D). Pictures A and C depict the same proband male, born in 2013. Pictures B and D depict a 12-week-old female kitten, born in 2004 and which is a proband relative.</p

What do research ethics committees say about applications to do cancer trials?

The European Clinical Trials Directive 2001/20/EC aimed to harmonise standards for clinical trials throughout the European Union, and was implemented in UK law by the Medicines for Human Use (Clinical Trials) Regulations 2004. As a result, all trials of investigational medicinal products must comply with the Guidelines for Good Clinical Practice issued by the European Medicines Agency, and undertaking a trial now requires a range of approvals from different agencies. These approvals are generally sought in parallel. Clinical trial authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA; London, UK) is required, but before applying to the MHRA, the approval of the trial sponsor must be obtained, and the trial must be registered with the European Clinical Trials Database. Research governance approval from the UK National Health Service (NHS) organisations in which the trial is to be done must be given. An important requirement is a favourable opinion from a Research Ethics Committee (REC). A REC application involves completion of a form and submission of supporting documentation, which is then considered at a REC meeting to which applicants will be invited to attend. Details of success rates of applications to RECs specifically to undertake cancer trials are unknown, but numbers from the National Research Ethics Service (NRES), which coordinates the REC system, suggest that only 17% of all applications receive a favourable opinion at first review by a REC in the UK.1 Most (66%) of opinions are provisional and require further response and modification before a final decision is rendered, whereas 8% of all submissions receive an unfavourable opinion (the remainder are withdrawn or otherwise deferred)

Wild type and mutant FOXN1 proteins.

<p>Alignment of partial amino acids sequences of FOXN1, translated from the wild type alleles reported in human (Homo, ENSP00000226247), mouse (Mus, ENSMUSP00000103929), cat [Felis (WT), ENSFCAP00000007665] and the c.[1030_1033delCTGT] mutated allele identified in hairless Birman cats (hairless). Amino acids encoded by exons 1 to 5 are omitted and alignment start with amino acid number 310 in human and mouse proteins, or amino acid number 309 in the feline protein. Human FOXN1 sequence was used as the reference sequence. Dashes represent identical amino acids compared to the reference sequence. FOXN1 structural features were depicted according to [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120668#pone.0120668.ref026" target="_blank">26</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120668#pone.0120668.ref029" target="_blank">29</a>].</p

Vers une réforme de la taxe professionnelle ?

<p>Totals reflect progress through 2012. Percentage figures represent the achieved proportion of the target of 80% coverage among males ages 15–49, but totals include circumcisions done for all age groups, regardless of the age-range target. Data obtained from WHO 2012 VMMC report <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001641#pmed.1001641-WHOAFRO1" target="_blank">[38]</a>.</p

Scale-up of voluntary medical male circumcision program and coverage in 14 priority countries, aggregate, 2008–2013.

<p>Number of circumcisions completed each year in millions. Source of 2008–2012 data is the WHO 2012 VMMC report <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001641#pmed.1001641-WHOAFRO1" target="_blank">[38]</a>. 2013 numbers have been estimated using data from PEPFAR and the Bill & Melinda Gates Foundation. *CAGR, compound annual growth rate, calculated based on the average proportional growth each year. CAGR (t₀,t_n)  =  (V(t_n)/V(t₀))^{1/(tn − to)} −1, where V(t₀) is the start value and V(t_n) is the finish value and t_n − t₀ is the number of years.</p

Manhattan plot of the genome-wide association study for dilated cardiomyopathy in Irish wolfhounds from Europe using a general linear model analysis.

<p>The genome-wide p-values (–log10 p-values) for the SNP effect are plotted against marker position on each chromosome. X-axis indicates marker number. Chromosomes are differentiated by colours. Colours are given below the plot. Red line indicates threshold value of probabilit<i>y</i> for significant association with DCM. Blue line indicates threshold value of probability for suggestive association with DCM.</p

New paradigms to assess consequences of long-term low-dose curcumin exposure in lung cancer cells.

Curcumin has been investigated extensively for cancer prevention, but it has been proposed that long-term treatments may promote clonal evolution and gain of cellular resistance, potentially rendering cancer cells less sensitive to future therapeutic interventions. Here, we used long-term, low-dose treatments to determine the potential for adverse effects in non-small cell lung cancer (NSCLC) cells. IC50s for curcumin, cisplatin, and pemetrexed in A549, PC9, and PC9ER NSCLC cells were evaluated using growth curves. IC50s were subsequently re-assessed following long-term, low-dose curcumin treatment and a three-month treatment withdrawal period, with a concurrent assessment of oncology-related protein expression. Doublet cisplatin/pemetrexed-resistant cell lines were created and the IC50 for curcumin was determined. Organotypic NSCLC-fibroblast co-culture models were used to assess the effects of curcumin on invasive capacity. Following long-term treatment/treatment withdrawal, there was no significant change in IC50s for the chemotherapy drugs, with chemotherapy-resistant cell lines exhibiting similar sensitivity to curcumin as their non-resistant counterparts. Curcumin (0.25–0.5 µM) was able to inhibit the invasion of both native and chemo-resistant NSCLC cells in the organotypic co-culture model. In summary, long-term curcumin treatment in models of NSCLC neither resulted in the acquisition of pro-carcinogenic phenotypes nor caused resistance to chemotherapy agents