Treatment of Epithelioid Sarcoma at the Royal Marsden Hospital

Purpose: The aim of this study was to assess treatment and outcome with respect to clinical and pathological features

Investigations in vivo of the effects of carbogen breathing on 5-fluorouracil pharmacokinetics and physiology of solid rodent tumours

Purpose: We have shown previously that carbogen (95% 02, 5% CO2) breathing by rodents can increase uptake of anticancer drugs into tumours. The aim of this study was to extend these observations to other rodent models using the anticancer drug 5-fluorouracil (5FU). 5FU pharmacokinetics in tumour and plasma and physiological effects on the tumour by carbogen were investigated to determine the locus of carbogen action on augmenting tumour uptake of 5FU. Methods: Two different tumour models were used, rat GH3 prolactinomas xenografted s.c. into nude mice and rat H9618a hepatomas grown s.c. in syngeneic Buffalo rats. Uptake and metabolism of 5FU in both tumour models with or without host carbogen breathing was studied non-invasively using fluorine-19 magnetic resonance spectroscopy (19F-MRS), while plasma samples from Buffalo rats were used to construct a NONMEM pharmacokinetic model. Physiological effects of carbogen on tumours were studied using 31P-MRS for energy status (NTP/Pi) and pH, and gradient-recalled echo magnetic resonance imaging (GRE-MRI) for blood flow and oxygenation. Results: In both tumour models, carbogan-induced GRE-MRI signal intensity increases of ∼60% consistent with an increase in tumour blood oxygenation and/or flow. In GH3 xenografts, 19F-MRS showed that carbogen had no significant effect on 5FU uptake and metabolism by the tumours, and 31P-MRS showed there was no change in the NTP/Pi ratio. In H9618a hepatomas, 19F-MRS showed that carbogen had no effect on tumour 5FU uptake but significantly (p=0.0003) increased 5FU elimination from the tumour (i.e. decreased the t1/2) and significantly (p=0.029) increased (53%) the rate of metabolism to cytotoxic fluoronucleotides (FNuct). The pharmacokinetic analysis showed that carbogen increased the rate of tumour uptake of 5FU from the plasma but also increased the rate of removal. 31P-MRS showed there were significant (p≤0.02) increases in the hepatoma NTP/Pi ratio of 49% and transmembrane pH gradient of 0.11 units. Conclusions: We suggest that carbogen can transiently increase tumour blood flow, but this effect alone may not increase uptake of anticancer drugs without a secondary mechanism operating. In the case of the hepatoma, the increase in tumour energy status and pH gradient may be sufficient to augment 5FU metabolism to cytotoxic FNuct, while in the GH3 xenografts this was not the case. Thus carbogen breathing does not universally lead to increased uptake of anticancer drug

Can Mindfulness Address Maladaptive Eating Behaviors? Why Traditional Diet Plans Fail and How New Mechanistic Insights May Lead to Novel Interventions

Emotional and other maladaptive eating behaviors develop in response to a diversity of triggers, from psychological stress to the endless external cues in our modern food environment. While the standard approach to food- and weight-related concerns has been weight-loss through dietary restriction, these interventions have produced little long-term benefit, and may be counterproductive. A growing understanding of the behavioral and neurobiological mechanisms that underpin habit formation may explain why this approach has largely failed, and pave the way for a new generation of non-pharmacologic interventions. Here, we first review how modern food environments interact with human biology to promote reward-related eating through associative learning, i.e., operant conditioning. We also review how operant conditioning (positive and negative reinforcement) cultivates habit-based reward-related eating, and how current diet paradigms may not directly target such eating. Further, we describe how mindfulness training that targets reward-based learning may constitute an appropriate intervention to rewire the learning process around eating. We conclude with examples that illustrate how teaching patients to tap into and act on intrinsic (e.g., enjoying healthy eating, not overeating, and self-compassion) rather than extrinsic reward mechanisms (e.g., weighing oneself), is a promising new direction in improving individuals\u27 relationship with food

In-beam fast-timing measurements in 103,105,107Cd

Fast-timing measurements were performed recently in the region of the medium-mass 103,105,107Cd isotopes, produced in fusion evaporation reactions. Emitted gamma-rays were detected by eight HPGe and five LaBr3:Ce detectors working in coincidence. Results on new and re-evaluated half-lives are discussed within a systematic of transition rates. The $7/2_1^+$ states in 103,105,107Cd are interpreted as arising from a single-particle excitation. The half-life analysis of the $11/2_1^-$ states in 103,105,107Cd shows no change in the single-particle transition strength as a function of the neutron number

The Large Enriched Germanium Experiment for Neutrinoless Double Beta Decay (LEGEND)

The observation of neutrinoless double-beta decay (0${\nu}{\beta}{\beta}$) would show that lepton number is violated, reveal that neutrinos are Majorana particles, and provide information on neutrino mass. A discovery-capable experiment covering the inverted ordering region, with effective Majorana neutrino masses of 15 - 50 meV, will require a tonne-scale experiment with excellent energy resolution and extremely low backgrounds, at the level of $\sim$0.1 count /(FWHM$\cdot$t$\cdot$yr) in the region of the signal. The current generation $^{76}$Ge experiments GERDA and the MAJORANA DEMONSTRATOR utilizing high purity Germanium detectors with an intrinsic energy resolution of 0.12%, have achieved the lowest backgrounds by over an order of magnitude in the 0${\nu}{\beta}{\beta}$ signal region of all 0${\nu}{\beta}{\beta}$ experiments. Building on this success, the LEGEND collaboration has been formed to pursue a tonne-scale $^{76}$Ge experiment. The collaboration aims to develop a phased 0${\nu}{\beta}{\beta}$ experimental program with discovery potential at a half-life approaching or at $10^{28}$ years, using existing resources as appropriate to expedite physics results.Comment: Proceedings of the MEDEX'17 meeting (Prague, May 29 - June 2, 2017

Safety and efficacy of Pazopanib in advanced soft tissue sarcoma: PALETTE (EORTC 62072) subgroup analyses.

Background PALETTE is a phase 3 trial that demonstrated single-agent activity of pazopanib in advanced soft tissue sarcomas (aSTS). We performed retrospective subgroup analyses to explore potential relationships between patient characteristics, prior lines of therapy, dose intensity, and dose modifications on safety and efficacy of pazopanib in aSTS.Methods PALETTE compared pazopanib with placebo in patients with aSTS (age ≥ 18 years) whose disease had progressed during or following prior chemotherapy. In these subgroup analyses, median progression-free survival (mPFS) among patients receiving pazopanib was the efficacy outcome of interest. Adverse events (AEs) were also compared within subgroups. All analyses were descriptive and exploratory.Results A total of 246 patients received pazopanib in the PALETTE study. The mPFS was longer in patients who had only 1 prior line versus 2+ prior lines of therapy (24.7 vs 18.9 weeks, respectively); AE rates were similar regardless of number of prior lines of therapy. The mPFS was similar in patients aged < 65 and ≥ 65 y (20.0 and 20.1 weeks, respectively). Although AEs leading to study discontinuation were higher in older patients (≥65 y, 30%; < 65 y, 17%), rates of dose reductions, dose interruptions, and serious AEs were similar between the 2 age groups. No reduction in mPFS was noted in patients requiring dose reductions or dose interruptions to manage toxicities.Conclusions Longer mPFS was observed in patients receiving pazopanib following only 1 line of therapy. Additionally, mPFS with pazopanib was maintained regardless of patient age or dose modifications used to manage toxicity.Trial registration NCT00753688 , first posted September 16, 2008 (registered prospectively)

Characterisation of a CZT detector for dosimetry of molecular radiotherapy

A pixelated cadmium zinc telluride (CZT) detector has been characterised for the purpose of developing a quantitative single photon emission computed tomography (SPECT) system for dosimetry of molecular radiotherapy (MRT). This is the aim of the Dosimetric Imaging with CZT (DEPICT) project, which is a collaboration between the University of Liverpool, The Royal Marsden Hospital, The Royal Liverpool and Broadgreen University Hospital, and the commercial partner Kromek. CZT is a direct band gap semiconductor with superior energy resolution and stopping power compared to scintillator detectors used in current SPECT systems. The inherent detector properties have been investigated and operational parameters such as bias voltage and peaking time have been selected to optimise the performance of the system. Good energy resolution is required to discriminate γ-rays that are scattered as they are emitted from the body and within the collimator, and high photon throughput is essential due to the high activities of isotopes administered in MRT. The system has an average measured electronic noise of 3.31 keV full width at half maximum (FWHM), determined through the use of an internal pulser. The energy response of the system was measured across the energy region of interest 59.5 keV to 364.5 keV and found to be linear. The reverse bias voltage and peaking time producing the optimum FWHM and maximum photon throughput were 600 V and 0.5 μs respectively. The average dead time of the system was measured as 4.84 μs and charge sharing was quantified to be 0.71 % at 59.5 keV . A pixel sensitivity calibration map was created and planar images of the medical imaging isotopes 99mTc and 123I were acquired by coupling the device to a prototype collimator, thereby demonstrating the suitability of the detector for the DEPICT project