Colon cancer prevention currently relies on colonoscopy using white light to detect and remove polyps, but small and flat polyps are difficult to detect and frequently missed when using this technique. Fluorescence colonoscopy combined with a fluorescent probe specific for a polyp biomarker may improve polyp detection. Here we describe GE-137, a water-soluble probe consisting of a 26-amino acid cyclic peptide that binds the human tyrosine kinase c-Met conjugated to a fluorescent cyanine dye. Intravenous administration of GE-137 leads to its accumulation specifically in c-Met-expressing tumors in mice, and it is safe and well tolerated in humans. Fluorescence colonoscopy in patients receiving intravenous GE-137 enabled visualization of all neoplastic polyps that were visible with white light (38), as well as an additional nine polyps that were not visible with white light. This first-in-human pilot study shows that molecular imaging using an intravenous fluorescent agent specific for c-Met is feasible and safe, and that it may enable the detection of polyps missed by other techniques.

Background Economic evaluation can inform whether strategies designed to improve the quality of health care delivery and the uptake of evidence-based practices represent a cost-effective use of limited resources. We report a systematic review and critical appraisal of the application of health economic methods in improvement/implementation research. Method A systematic literature search identified 1668 papers across the Agris, Embase, Global Health, HMIC, PsycINFO, Social Policy and Practice, MEDLINE and EconLit databases between 2004 and 2016. Abstracts were screened in Rayyan database, and key data extracted into Microsoft Excel. Evidence was critically appraised using the Quality of Health Economic Studies (QHES) framework. Results Thirty studies were included—all health economic studies that included implementation or improvement as a part of the evaluation. Studies were conducted mostly in Europe (62%) or North America (23%) and were largely hospital-based (70%). The field was split between improvement ( N = 16) and implementation ( N = 14) studies. The most common intervention evaluated (43%) was staffing reconfiguration, specifically changing from physician-led to nurse-led care delivery. Most studies ( N = 19) were ex-post economic evaluations carried out empirically—of those, 17 were cost effectiveness analyses. We found four cost utility analyses that used economic modelling rather than empirical methods. Two cost-consequence analyses were also found. Specific implementation costs considered included costs associated with staff training in new care delivery pathways, the impacts of new processes on patient and carer costs and the costs of developing new care processes/pathways. Over half (55%) of the included studies were rated ‘good’ on QHES. Study quality was boosted through inclusion of appropriate comparators and reporting of incremental analysis (where relevant); and diminished through use of post-hoc subgroup analysis, limited reporting of the handling of uncertainty and justification for choice of discount rates. Conclusions The quantity of published economic evaluations applied to the field of improvement and implementation research remains modest; however, quality is overall good. Implementation and improvement scientists should work closely with health economists to consider costs associated with improvement interventions and their associated implementation strategies. We offer a set of concrete recommendations to facilitate this endeavour.

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contrast-enhanced ultrasound; gene therapy; microbubble drug delivery PRESENTLY, CONTRAST-ENHANCED ultrasound (CEUS) imaging focuses on diagnostic clinical applications. In the future, however, therapeutic uses of CEUS will create a paradigm shift for patient care and the pharmaceutical industry. Ultrasound contrast agents (UCAs) are composed of shelled microbubbles that serve as superior diagnostic agents while traversing the smallest of blood vessels resulting in unparalleled, real-time spatial and temporal imaging of intact tissues and organs. These microscopic, gas-filled microspheres acting as intravascular indicators represent ideal carrier vehicles for local delivery of ultrasound-directed drug and gene therapies. The conceptually simple application of external acoustic energy in the transformation of these inert, microspheres into powerful therapeutic systems has seemingly unlimited potential.Brief history of CEUS. All diagnostic imaging modalities use and require contrast effects to increase signal-to-noise ratios, permitting enhanced discrimination of the targets. Examples include the use of radiopaque contrast agents to create discrete image patterns using X-ray methods (ionizing radiation), thus creating enhanced detection of objects within the image plane. Similar to X-ray, positron emission tomography and radionuclide imaging procedures rely on radioactive emitters to highlight anatomy and provide information on cellular metabolism and physiology.

Proof of principle for local drug delivery with Acoustic Cluster Therapy (ACT) was demonstrated in a human prostate adenocarcinoma growing in athymic mice, using near infrared (NIR) dyes as model molecules. A dispersion of negatively charged microbubble/positively charged microdroplet clusters are injected i.v., activated within the target pathology by diagnostic ultrasound (US), undergo an ensuing liquid-to-gas phase shift and transiently deposit 20-30 µm large bubbles in the microvasculature, occluding blood flow for ~ 5-10 min. Further application of low frequency US induces biomechanical effects that increase the vascular permeability, leading to a locally enhanced extravasation of components from the vascular compartment (e.g. released or co-administered drugs). Results demonstrated deposition of activated bubbles in tumor vasculature. Following ACT treatment, a significant and tumor specific increase in the uptake of a co-administered macromolecular NIR dye was shown. In addition, ACT compound loaded with a lipophilic NIR dye to the microdroplet component was shown to facilitate local release and tumor specific uptake. Whereas the mechanisms behind the observed increased and tumor specific uptake are not fully elucidated, it is demonstrated that the ACT concept can be applied as a versatile technique for targeted drug delivery.

Acoustic cluster therapy (ACT) is a novel approach for ultrasound mediated, targeted drug delivery. In the current study, we have investigated ACT in combination with paclitaxel and Abraxane® for treatment of a subcutaneous human prostate adenocarcinoma (PC3) in mice. In combination with paclitaxel (12 mg/kg given i.p)., ACT induced a strong increase in therapeutic efficacy; 120 days after study start, 42% of the animals were in stable, complete remission vs. 0% for the paclitaxel only group and the median survival was increased by 86%. In combination with Abraxane® (12 mg paclitaxel/kg given i.v.), ACT induced a strong increase in the therapeutic efficacy; 60 days after study start 100% of the animals were in stable, remission vs. 0% for the Abraxane® only group, 120 days after study start 67% of the animals were in stable, complete remission vs. 0% for the Abraxane® only group. For the ACT + Abraxane group 100% of the animals were alive after 120 days vs. 0% for the Abraxane® only group. Proof of concept for Acoustic Cluster Therapy has been demonstrated; ACT markedly increases the therapeutic efficacy of both paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice.

BackgroundAnimal studies have suggested that the hippocampus may play an important role in anxiety as part of the Behavioural Inhibition System (BIS), which mediates reactivity to threat and punishment and can predict an individual’s response to anxiety-relevant cues in a given environment. The aim of the present structural magnetic resonance imaging (MRI) study was to examine the relationship between individual differences in BIS and hippocampal structure, since this has not received sufficient attention in non-clinical populations. Thirty healthy right-handed participants with no history of alcohol or drug abuse, neurological or psychiatric disorders, or traumatic brain injury were recruited (16 male, 14 female, age 18 to 32 years). T1-weighted structural MRI scans were used to derive estimates of total intracranial volume, and hippocampal and amygdala gray matter volume using FreeSurfer. To relate brain structure to Gray’s BIS, participants completed the Sensitivity to Punishment questionnaire. They also completed questionnaires assessing other measures potentially associated with hippocampal volume (Beck Depression Inventory, Negative Life Experience Survey), and two other measures of anxiety (Spielberger Trait Anxiety Inventory and the Beck Anxiety Inventory).ResultsWe found that high scores on the Sensitivity to Punishment scale were positively associated with hippocampal volume, and that this phenomenon was lateralized to the right side. In other words, greater levels of behavioural inhibition (BIS) were positively associated with right hippocampal volume.ConclusionsOur data suggest that hippocampal volume is related to the cognitive and affective dimensions of anxiety indexed by the Sensitivity to Punishment, and support the idea that morphological differences in the hippocampal formation may be associated with behavioural inhibition contributions to anxiety.

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