On the road to improved outcomes by capturing leiomyosarcoma patients' views.

An international collaborative project set up as a 'priority setting partnership' used a questionnaire to capture the views of patients, carers and clinicians about the sarcoma research agenda. Responses from 25 patients with leiomyosarcoma (LMS) in eight countries provided useful insight from the patient's perspective. Unmet needs identified by patients were in the areas of: LMS-specific trial design; exploring new therapeutic avenues; avoiding morcellation; exploring the immune system in LMS; investigating circulating tumor DNA; implementing molecular characterization of LMS; conducting basic research and a translational pipeline; evaluating imaging modalities; improving early diagnosis; identifying patient-reported outcomes; improving communication, information and support; and addressing survivorship and end-of-life care. Each of the unmet needs is described in more detail

Correlations, Fluctuations, and Flow Measurements from the STAR Experiment

New measurements of short-range and long-range two-particle correlations, azimuthal anisotropy, and event-by-event fluctuations from the STAR experiment for sqrt{s_{NN}}= 130 and 200 GeV Au+Au collisions are summarized. Striking evidence is presented for large, non-statistical fluctuations in mean transverse momentum. Descriptions of the data in terms of phenomenological source function models are also presented.Comment: 10 pages, 10 figures, Conference proceedin

Pathological Fracture due to pemphigus vulgaris: A case report

Pemphigus vulgaris is a rare but serious autoimmune mucocutaneous bullous disease.The two cardinal pathological processes at work are a split within the epidermis and loss of adhesion of epidermal cells (Acantholysis). It is due to deposition of pathogenic IgG on the Keratinocyte cell surface. The mainstay of treatment is systemic corticosteroids and bone complications have been noted to arise from this treatment. Pathological fracture due to pemphigus vulgaris before commencement of corticosteroid treatment has not been reported before in the world literature

Cassini detection of Enceladus' cold water-group plume ionosphere

This study reports direct detection by the Cassini plasma spectrometer of freshly-produced water-group ions (O+, OH+, H2O+, H3O+) and heavier water dimer ions (HxO(2))(+) very close to Enceladus where the plasma begins to emerge from the plume. The data were obtained during two close ( 52 and 25 km) flybys of Enceladus in 2008 and are similar to ion data in cometary comas. The ions are observed in detectors looking in the Cassini ram direction exhibiting energies consistent with the Cassini speed, indicative of a nearly stagnant plasma flow in the plume. North of Enceladus the plasma slowing commences about 4 to 6 Enceladus radii away, while south of Enceladus signatures of the plasma interaction with the plume are detected 22 Enceladus radii away. Citation: Tokar, R. L., R. E. Johnson, M. F. Thomsen, R. J. Wilson, D. T. Young, F. J. Crary, A. J. Coates, G. H. Jones, and C. S. Paty ( 2009), Cassini detection of Enceladus' cold water-group plume ionosphere, Geophys. Res. Lett., 36, L13203, doi:10.1029/2009GL038923

Development of a baseline-temperature correction methodology for electrochemical sensors and its implications for long-term stability

Recent studies have shown that (three-electrode) electrochemical sensors can be utilised for air quality monitoring and exposure assessment. The long-term performance of these sensors is however, often limited by the effects of ambient meteorological parameters on the sensor baseline, in particular temperature. If electrochemical (EC) sensors are to be adopted for air quality measurement over extended periods (months), this effect must be accounted for. Recent long-term, ambient measurements of CO, NO and NO$_2$ using EC sensors have revealed that temperature (and relative humidity (RH)) had an effect on the baseline which was more pronounced in the case of NO sensors with coefficient of determination, $R^2$ of 0.9 when compared to CO and NO$_2$ with $R^2$ < 0.2. In this paper we present a correction methodology that quantifies this effect (referred to here as fitted baseline), implementing these correction on the EC measurements. We found that EC sensors corrected for baseline-temperature effect using the method describe in this paper show good agreement when compared with traditional reference instrument. The coefficient of determination $R^2$ of 0.7-0.8 and gradient of 0.9 was observed for baseline-temperature corrected NO compared to $R^2$ = 0.02 prior to baseline-temperature correction. Furthermore, the correction methodology was validated by comparing the temperature-baseline with proxy temperature compensating measurements obtained from the fourth electrode of a set of novel four-electrode electrochemical sensors. A good agreement (R$^2$ = 0.9, with gradients = 0.7-1.08 for NO and 0.5 < R$^2$ < 0.73 for CO) was observed between temperature fitted baselines and outputs from the fourth electrodes (also known non-sensing/auxiliary electrode). Meanwhile, the long-term stability (calibrated signal output) of temperature-corrected data was evaluated by comparing the change in sensor gain to meteorological parameters including temperature, relative humidity, wind speed and wind direction. The results showed that there was no statistically significant change in sensitivity (two-sided $t$-test, p = 0.34) of the temperature-corrected electrochemical sensor with respect to these parameters (over several months). This work demonstrates that using the baseline-temperature correction methodology described in this paper, electrochemical sensors can be used for long-term (months), quantitative measurements of air quality gases at the parts per billion volume (ppb) mixing ratio level typical of ambient conditions in the urban environment.The authors would like to thank Cambridge Commonwealth Trust & Cambridge Overseas Trust and Dorothy Hodgkin Studentship for the PhD studentship awarded to Olalekan Popoola. We will like to thank NERC for funding the SNAQ Heathrow project as well as DfT and EPSRC for funding the MESSAGE project

Quasi-diffusion magnetic resonance imaging (QDI): A fast, high b-value diffusion imaging technique.

To enable application of non-Gaussian diffusion magnetic resonance imaging (dMRI) techniques in large-scale clinical trials and facilitate translation to clinical practice there is a requirement for fast, high contrast, techniques that are sensitive to changes in tissue structure which provide diagnostic signatures at the early stages of disease. Here we describe a new way to compress the acquisition of multi-shell b-value diffusion data, Quasi-Diffusion MRI (QDI), which provides a probe of subvoxel tissue complexity using short acquisition times (1-4 min). We also describe a coherent framework for multi-directional diffusion gradient acquisition and data processing that allows computation of rotationally invariant quasi-diffusion tensor imaging (QDTI) maps. QDI is a quantitative technique that is based on a special case of the Continuous Time Random Walk model of diffusion dynamics and assumes the presence of non-Gaussian diffusion properties within tissue microstructure. QDI parameterises the diffusion signal attenuation according to the rate of decay (i.e. diffusion coefficient, D in mm2 s-1) and the shape of the power law tail (i.e. the fractional exponent, α). QDI provides analogous tissue contrast to Diffusional Kurtosis Imaging (DKI) by calculation of normalised entropy of the parameterised diffusion signal decay curve, Hn, but does so without the limitations of a maximum b-value. We show that QDI generates images with superior tissue contrast to conventional diffusion imaging within clinically acceptable acquisition times of between 84 and 228 s. We show that QDI provides clinically meaningful images in cerebral small vessel disease and brain tumour case studies. Our initial findings suggest that QDI may be added to routine conventional dMRI acquisitions allowing simple application in clinical trials and translation to the clinical arena

Tropomyosin receptor kinase inhibitors in the management of sarcomas.

Purpose of review Genetic aberrations resulting in tropomyosin receptor kinase (TRK) fusion proteins can drive oncogenesis and are postulated to occur in up to 1% of solid tumours. However, TRK fusions in adult sarcomas are rare and there is a significant challenge in identifying patients with sarcomas harbouring TRK fusions in the clinical setting. Despite a recent European Society of Medical Oncology consensus article regarding screening of tumours for TRK fusions, economical and practical limitations present a barrier to widespread screening of sarcomas.Recent findings Larotrectinib and entrectinib are pan-TRK inhibitors which have both received FDA approval for the management of solid tumours harbouring NTRK fusions. Initial results of a number of clinical trials have demonstrated promising efficacy and safety data, including dramatic and durable responses in patients with sarcomas. As such, TRK inhibitors represent a promising treatment option in a small cohort of adult sarcoma patients, where currently treatment options are limited. The emergence of acquired resistance is a concern associated with TRK inhibitor therapy and a number of second-generation agents targeting TRK kinase mutations driving acquired resistance have entered early-phase clinical trials.Summary With the growing appreciation of the implications of TRK fusions, this review will summarize the emerging clinical trial data of TRK inhibitors in sarcomas. Although in their infancy, clinical trial results are encouraging, and as further results and analyses are released, we will have a greater understanding of their impact on clinical practice and the management of patients with sarcomas

Avapritinib in the treatment of PDGFRA exon 18 mutated gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GIST) can be molecularly classified based on different subtypes including mutations in KIT and PDGFRA. Patients with PDGFRA mutations are an important subgroup that commonly arise in the stomach and are associated with a more indolent disease course. Importantly, the most common PDGFRA molecular subtype, the D842V mutation in exon 18 of the gene which alters the activation loop, is imatinib insensitive in in vitro studies. Poor responses to imatinib have been seen clinically compared with PDGFRA exon 18 non-D842V-mutated GIST. Avapritinib (BLU-285) is a potent KIT and PDGFRA-specific tyrosine kinase inhibitor which has shown >90% response rates in patients with PDGFRA exon 18 D842V-mutated GIST. Results from the Phase I trial of avapritinib have indicated that this drug should be the standard of care for patients with PDGFRA exon 18 D842V-mutated GIST

Oligoclonal expansions of CD8(+) T cells in chronic HIV infection are antigen specific

Acute HIV infection is associated with a vigorous immune response characterized by the proliferation of selected T cell receptor V beta (BV)-expressing CD8(+) T cells. These 'expansions', which are commonly detected in the peripheral blood, can persist during chronic HIV infection and may result in the dominance of particular clones. Such clonal populations are most consistent with antigen-driven expansions of CD8(+) T cells. However, due to the difficulties in studying antigen-specific T cells in vivo, it has been hard to prove that oligoclonal BV expansions are actually HIV specific. The use of tetrameric major histocompatibility complex-peptide complexes has recently enabled direct visualization of antigen-specific T cells ex vivo but has not provided information on their clonal composition. We have now made use of these tetrameric complexes in conjunction with anti-BV chain-specific monoclonal antibodies and analysis of cytotoxic T lymphocyte lines/clones to show that chronically clonally expanded CD8(+) T cells are HIV specific in vivo

Ripretinib for the treatment of adult patients with advanced gastrointestinal stromal tumors.

INTRODUCTION: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Imatinib mesylate revolutionized the management of advanced/metastatic GIST, and remains the standard first-line therapy in this setting. Upon development of secondary resistance, sunitinib and regorafenib are used as subsequent treatments, although clinical benefit is often non-durable. Ripretinib is a type II kinase inhibitor targeting KIT and PDGFRA mutations and resistance through switching active I and inactive II forms. AREAS COVERED: This drug profile article provides an overview of the current state of the art treatment algorithm for advanced/metastatic GIST, focusing on the role of ripretinib in the fourth-line setting as defined by currently available clinical trials evidence. The mechanism of action, the safety profile, efficacy, and clinical application of ripretinib are presented. In addition, the Phase I study (NCT02571036) through which the optimal dose was established and the Phase III trials that assessed the efficacy and safety of ripretinib as fourth- (INVICTUS) and second-line treatment (INTRIGUE) are presented. EXPERT OPINION: Ripretinib is a safe and an effective therapy for the fourth-line setting in advanced/metastatic GIST. Future studies should evaluate combination schedules and the identification of markers predictive of benefit from ripretinib