Imaging oligometastatic cancer before local treatment

The term oligometastases is in common clinical use, but remains poorly defined. As novel treatment strategies widen the therapeutic window for patients defined as having oligometastatic cancer, improved biomarkers to reliably define patients who benefit from these treatments are needed. Multimodal imaging should be optimized to comprehensively assess the metastatic sites, disease burden and response to neoadjuvant treatment in each disease setting. These features will likely remain important prognostic biomarkers, and are critical in planning multidisciplinary treatment. There are opportunities to extract additional phenotypic information from conventional imaging, while novel imaging techniques can also image specific aspects of tumour biology. Imaging can both characterise and localise the phenotypic heterogeneity of multiple tumour sites. Novel approaches to existing imaging datasets, and correlation with tumour biology, will be important in realizing the potential of imaging to guide treatment in the oligometastatic setting. This article discusses the current status and future directions of imaging in patients with extracranial oligometastases

Tumour subregion analysis of colorectal liver metastases using semi-automated clustering based on DCE-MRI: Comparison with histological subregions and impact on pharmacokinetic parameter analysis.

PURPOSE: To use a novel segmentation methodology based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to define tumour subregions of liver metastases from colorectal cancer (CRC), to compare these with histology, and to use these to compare extracted pharmacokinetic (PK) parameters between tumour subregions. MATERIALS AND METHODS: This ethically-approved prospective study recruited patients with CRC and ≥1 hepatic metastases scheduled for hepatic resection. Patients underwent DCE-MRI pre-metastasectomy. Histological sections of resection specimens were spatially matched to DCE-MRI acquisitions and used to define histological subregions of viable and non-viable tumour. A semi-automated voxel-wise image segmentation algorithm based on the DCE-MRI contrast-uptake curves was used to define imaging subregions of viable and non-viable tumour. Overlap of histologically-defined and imaging subregions was compared using the Dice similarity coefficient (DSC). DCE-MRI PK parameters were compared for the whole tumour and histology-defined and imaging-derived subregions. RESULTS: Fourteen patients were included in the analysis. Direct histological comparison with imaging was possible in nine patients. Mean DSC for viable tumour subregions defined by imaging and histology was 0.738 (range 0.540-0.930). There were significant differences between Ktrans and kep for viable and non-viable subregions (p < 0.001) and between whole lesions and viable subregions (p < 0.001). CONCLUSION: We demonstrate good concordance of viable tumour segmentation based on pre-operative DCE-MRI with a post-operative histological gold-standard. This can be used to extract viable tumour-specific values from quantitative image analysis, and could improve treatment response assessment in clinical practice

Heterogenous mean-field analysis of a generalized voter-like model on networks

We propose a generalized framework for the study of voter models in complex networks at the the heterogeneous mean-field (HMF) level that (i) yields a unified picture for existing copy/invasion processes and (ii) allows for the introduction of further heterogeneity through degree-selectivity rules. In the context of the HMF approximation, our model is capable of providing straightforward estimates for central quantities such as the exit probability and the consensus/fixation time, based on the statistical properties of the complex network alone. The HMF approach has the advantage of being readily applicable also in those cases in which exact solutions are difficult to work out. Finally, the unified formalism allows one to understand previously proposed voter-like processes as simple limits of the generalized model

Physiological and biochemical adaptations to training in Rana pipiens

Fifteen Rana pipiens were trained on a treadmill thrice weekly for 6.5 weeks to assess the effects of training on an animal that supports activity primarily through anaerobiosis. Endurance for activity increased 35% in these frogs as a result of training ( P =0.006, Fig. 1). This increased performance was not due to enhanced anaerobiosis. Total lactate produced during exercise did not differ significantly for the trained or untrained animals in either gastrocnemius muscle (2.77±0.21 and 2.82±0.13 mg/g, respectively) or whole body (1.32±0.10 and 1.47±0.06 mg/g, respectively). Glycogen depletion also did not differ between the two groups (Fig. 2c). The primary response to training appeared to involve augmentation of aerobic metabolism, a response similar to that reported for mammals. Gastrocnemius muscles of trained frogs underwent a 38% increase over those of untrained individuals in the maximum activity of citrate synthase (14.5±1.0 and 10.5±0.9 μmoles/(g wet wt·min); P =0.008). This enzyme was also positively correlated with the level of maximum performance for all animals tested ( r =0.61, P <0.01) and with the degree of improvement in the trained animals ( r =0.72, P <0.05). In addition to an increased aerobic capacity, the trained animals demonstrated a greater removal of lactate from the muscle 15 min after fatigue (Fig. 2b).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47124/1/360_2004_Article_BF00710002.pd

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe