Contrast‐Enhanced Echocardiographic Evaluation of a Giant Saphenous Vein Graft Aneurysm

A 61‐year‐old man presented with unstable angina 16 years after undergoing coronary artery bypass grafting with a left internal mammary artery graft to the left anterior descending coronary artery and a sequential saphenous vein graft (SVG) to the right coronary artery and an obtuse marginal branch. Transthoracic echocardiography (TTE) with a Philips iE33 machine and an S5 transducer revealed a 5.3 cm × 4.6 cm mass with a central echolucent area, surrounded by a peripheral zone of increased echodensity adjacent to, and partially compressing, the right atrium. Contrast echocardiography following an intravenous bolus injection of Definity revealed late appearance of contrast within the mass consistent with a giant SVG aneurysm. Coronary artery bypass graft angiography revealed a giant aneurysm in the SVG proximal to the RCA anastomosis; the distal limb of the graft to the obtuse marginal branch was occluded. Under intravascular ultrasound guidance, a 7‐mm spider filter was placed in the distal graft; then, a 6 mm × 10 cm Viabahn self‐expanding nitinol polyethylene terephthalate‐covered stent was deployed in the SVG with good seal zones proximally and distally. A follow‐up contrast‐enhanced transthoracic echocardiogram 1 day postprocedure revealed partial thrombosis of the aneurysm cavity. Ultrasound contrast did not appear in the aneurysm following intravenous injection, consistent with complete exclusion from the systemic circulation. This is the first report demonstrating feasibility of contrast‐enhanced transthoracic echocardiography for the diagnosis of SVG aneurysm and confirming procedural success by documenting exclusion from the systemic circulation following intervention.     

Alosetron versus traditional pharmacotherapy in clinical practice: effects on resource use,health-related quality of life,safety and symptom improvement in women with severe diarrhea-predominant irritable bowel syndrome

Objective: Severe diarrhea-predominant irritable bowel syndrome (IBS-D) is associated with decreased health-related quality of life (HRQOL) and increased health care costs. Treatment recommendations for IBS-D often start with traditional pharmacotherapy (TP), with escalation to alosetron, rifaximin or eluxadoline if there is no success. There has been no previous head-to-head clinical trial comparing IBS-D treatment outcome for alosetron versus TP. This study, GSK protocol S3B30020, evaluated resource use, work productivity, health-related quality of life and global symptom response in women with IBS-D who were treated with alosetron or TP.

Methods: A total of 1956 patients who met criteria for severe IBS-D were randomized to treatment with alosetron 1?mg twice daily (BID) or only TP for up to 24 weeks. Work productivity and resource use were evaluated by standard questionnaires, HRQOL by the IBSQOL instrument and IBS symptoms by the Global Improvement Scale (GIS).

Results: Compared to only TP, alosetron-treated patients reported: (1) fewer clinic/office visits for any health problem (p?=?.0181) or for IBS-D (p?=?.0004); (2) reduced use of over-the-counter medications for IBS-D (p < .0001); (3) fewer days of lost work productivity (p < .0001); (4) decreased restriction of social and outdoor activities (p < .0001); and (5) greater global improvement in IBS-D symptoms (p < .0001). Alosetron treatment improved HRQOL scores for all domains (p < .0001). Incidence of adverse events during alosetron use was not remarkable and was similar to that previously reported.

Conclusions: Alosetron 1?mg BID significantly reduced health care utilization and lost productivity, and significantly improved global IBS symptoms, HRQOL, and participation in outdoor and social activities compared with treatment response to TP.     

The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model

NPM-ALK⁺ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK⁺ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK⁺ solid tumors. However, NPM-ALK⁺ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK⁺ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK⁺ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK⁺ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK⁺ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials.     

Combining the ‘bottom up’ and ‘top down’ approaches in pharmacokinetic modelling: fitting PBPK models to observed clinical data

Pharmacokinetic models range from being entirely exploratory and empirical, to semi-mechanistic and ultimately complex physiologically based pharmacokinetic (PBPK) models. This choice is conditional on the modelling purpose as well as the amount and quality of the available data. The main advantage of PBPK models is that they can be used to extrapolate outside the studied population and experimental conditions. The trade-off for this advantage is a complex system of differential equations with a considerable number of model parameters. When these parameters cannot be informed from in vitro or in silico experiments they are usually optimized with respect to observed clinical data. Parameter estimation in complex models is a challenging task associated with many methodological issues which are discussed here with specific recommendations. Concepts such as structural and practical identifiability are described with regards to PBPK modelling and the value of experimental design and sensitivity analyses is sketched out. Parameter estimation approaches are discussed, while we also highlight the importance of not neglecting the covariance structure between model parameters and the uncertainty and population variability that is associated with them. Finally the possibility of using model order reduction techniques and minimal semi-mechanistic models that retain the physiological-mechanistic nature only in the parts of the model which are relevant to the desired modelling purpose is emphasized. Careful attention to all the above issues allows us to integrate successfully information from in vitro or in silico experiments together with information deriving from observed clinical data and develop mechanistically sound models with clinical relevance.     

Comparison of efficacy and safety of intralesional triamcinolone and combination of triamcinolone with 5-fluorouracil in the treatment of keloids and hypertrophic scars: Randomised control trial

The treatment of keloid and hypertrophic scar is challenging with no universally accepted mode for permanent ablation. Conventional therapies yield unpredictable results, significant complications and require elaborate hardware.

Poor patient-reported outcome after shoulder replacement in young patients with cuff-tear arthropathy: a matched-pair analysis from the Danish Shoulder Arthroplasty Registry

Background and purpose — Reverse shoulder arthroplasty (RSA) has become the treatment of choice for cuff-tear arthropathy. There are, however, concerns about the longevity and the outcome of an eventual revision procedure. Thus, resurfacing hemiarthroplasty (RHA) with extended articular surface has been suggested for younger patients. We compared the patient-reported outcome of these arthroplasty designs for cuff-tear arthropathy.

Patients and methods — We included patients operated on because of cuff-tear arthropathy and reported to the Danish Shoulder Arthroplasty Registry (DSR) from January 1, 2006 to December 31, 2013. 117 RHA cases were matched by age and sex with 233 RSA controls. 34 of the RHAs were conventional and 67 were RHAs with extended articular surface. The Western Ontario Osteoarthritis of the Shoulder (WOOS) Index at 1 year was used as primary outcome. The score was converted to a percentage of a maximum score. Revision, defined as removal or exchange of any component or the addition of a glenoid component, was used as secondary outcome.

Results — Median WOOS was 49 (30–81) for RHA and 77 (50–92) for RSA (p < 0.001). For patients younger than 65 years, median WOOS was 58 (44–80) after RHA, similar to the 54 after RSA (37–85). For patients older than 65 years, median WOOS was 48 (28–82) after RHA and 79 (55–92) after RSA (p < 0.001).

Interpretation — In all patients RSA had a clinically and statistically better patient-reported outcome than RHA. However, in patients younger than 65 years the functional outcome was similar and poor for either arthroplasty type. The optimal treatment of CTA in young patients remains a challenge.     

Therapeutic approaches for targeting receptor tyrosine kinase like orphan receptor-1 in cancer cells

Introduction: There is a high expression of receptor tyrosine kinase like orphan receptor-1 (ROR-1), a tyrosine kinase receptor, in various tumor-cell types. ROR-1 is involved in many key processes in cancer including proliferation, survival and metastasis. Hence, ROR-1 is an attractive and promising therapeutic target. There are many therapeutic approaches that target ROR-1 and these include specific monoclonal antibodies (mAbs), modified T cells (CART cell), miRNAs and tyrosine kinase inhibitors (TKI).

Areas covered: This review examines ROR-1 structure and function, immunotherapeutic strategies including specific chimeric antigen receptor (CARs) T cells and miRNAs and other targeted approaches such as the use of tyrosine kinase inhibitors.

Expert opinion: Chimeric antibodies, CARs T cells, bi-specific T cell engagers (BiTEs), miRNAs and TKIs are used to target the ROR-1 marker on cancer cell lines. By selecting the most favorable therapeutic approaches regarding ROR-1 in vivo, anti-ROR-1 antibodies or CAR T cells can be also used for diagnosis of ROR-1⁺ cancer cells in new technologies such as biosensors. Moreover, ROR-1 targeted combination therapy with other cancer biomarkers could be considered a novel therapeutic strategy for cancer treatment.     

Effects of upper-body resistance exercise training on serum nesfatin-1 level,insulin resistance,and body composition in obese paraplegic men

Background

As a recently discovered adipokine, nesfatin-1 is conducive to insulin sensitivity, lipid profile, energy balance, and probably obesity.