A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer.

BACKGROUND: Xentuzumab-a humanised IgG1 monoclonal antibody-binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). METHODS: Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). RESULTS: MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3-not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7-9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57-1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05-0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). CONCLUSIONS: Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). TRIAL REGISTRATION: ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.

Chromatographic Approach to Isolate Exfoliated Graphene.

A chromatographic approach for separating exfoliated graphene from natural flake graphite is presented. Graphene is an extremely strong, electrically and thermally conductive two-dimensional hexagonal array of carbon atoms with the potential to transform applications such as supercapacitors, composites, biosensors, ultra-thin touchscreens, and solar cells. However, many of these applications require the use of exfoliated graphene, and the current cost of this material can be prohibitive. The most cost-effective source of graphene is exfoliated graphite, and numerous approaches have been proposed for exfoliating graphite to graphene. Solution approaches are the most common, with graphite often exfoliated by extended sonication treatment followed by separation of graphene from graphite using centrifugation. This time-consuming approach results in low concentrations of small lateral dimension graphene, often in high-boiling-point organic solvents or containing stabilizers. In this study, a chromatographic approach is used in combination with a solvent interface trapping method of graphite exfoliation to isolate graphene. The interface trapping exfoliation approach uses a hydrophobic/hydrophilic solvent interface to spontaneously exfoliate graphite and form a graphene-stabilized water-in-oil emulsion. This emulsion contains both graphene and graphite, and when added to water-wet glass beads, graphene adsorbs onto the glass surface, leaving graphite in the hydrophobic mobile phase, where it is removed by washing with an additional oil phase. The efficiency of this scalable approach to separation is demonstrated by Raman spectroscopy, scanning electron microscopy, transmission electron microscopy, and Tyndall effect scattering.

Ninjaflex vs Superflab: A comparison of dosimetric properties, conformity to the skin surface, Planning Target Volume coverage and positional reproducibility for external beam radiotherapy.

BACKGROUND AND PURPOSE: When planning and delivering radiotherapy, ideally bolus should be in direct contact with the skin surface. Varying air gaps between the skin surface and bolus material can result in discrepancies between the intended and delivered dose. This study assessed a three-dimensional (3D) printed flexible bolus to determine whether it could improve conformity to the skin surface, reduce air gaps, and improve planning target volume coverage, compared to a commercial bolus material, Superflab. MATERIALS AND METHODS: An anthropomorphic head phantom was CT scanned to generate photon and electron treatment plans using virtual bolus. Two 3D printing companies used the material Ninjaflex to print bolus for the head phantom, which we designated Ninjaflex1 and Ninjaflex2. The phantom was scanned a further 15 more times with the different bolus materials in situ allowing plan comparison of the virtual to physical bolus in terms of planning target volume coverage, dose at the prescription point, skin dose, and air gap volumes. RESULTS: Superflab produced a larger volume and a greater number of air gaps compared to both Ninjaflex1 and Ninjaflex2, with the largest air gap volume of 12.02 cm3 . Our study revealed that Ninjaflex1 produced the least variation from the virtual bolus clinical goal values for all modalities, while Superflab displayed the largest variances in conformity, positional accuracy, and clinical goal values. For PTV coverage Superflab produced significant percentage differences for the VMAT and Electron3 plans when compared to the virtual bolus plans. Superflab also generated a significant difference in prescription point dose for the 3D conformal plan. CONCLUSION: Compared to Superflab, both Ninjaflex materials improved conformity and reduced the variance between the virtual and physical bolus clinical goal values. Results illustrate that custom-made Ninjaflex bolus could be useful clinically and may improve the accuracy of the delivered dose.

Effect of Aqueous Anions on Graphene Exfoliation.

Ion partitioning behavior in electrolyte solutions plays an important role in drug delivery and therapeutics, protein folding, materials science, filtration, and energy applications such as supercapacitors. Here, we show that the segregation of ions in solutions also plays an important role in the exfoliation of natural flake graphite to pristine graphene. Polarizable anions such as iodide and acetate segregate to the interfacial region of the aqueous phase during solvent interfacial trapping exfoliation of graphene. Ordered water layers and accumulated charges near the graphene surface aid in separating graphene sheets from bulk graphite, and, more importantly, reduce the reversibility of the exfoliation event. The observed phenomenon results not only in the improved stability of graphene-stabilized emulsions but also in a low-cost and environmentally friendly way of enhancing the production of graphene.

Pristine Graphene Microspheres by the Spreading and Trapping of Graphene at an Interface.

The interfacial spreading and exfoliation of graphene was used to create low-density, hollow microspheres defined by a thin shell of graphene. The spheres were templated by a thermodynamically driven self-assembly process in which graphite spontaneously exfoliated and spread at the high-energy interfaces of a water-in-oil emulsion. Graphene thus acted as a 2D surfactant to stabilize the dispersed water droplets utilized as polymerization templates. Using a mixture of organic solvent and monomer as the emulsion oil phase, polystyrene-coated hollow graphene microspheres were created. These spheres were characterized by optical and electron microscopy, thermo-gravimetric analysis, nanoindentation, and particle sizing. The mechanism leading to the microsphere surface morphology and shape is discussed, with the oil phase composition shown to play a critical role.

Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer.

BACKGROUND: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. METHODS: Patients were randomised (2 : 1) to IMM-101 (10 mg ml(-l) intradermally)+GEM (1000 mg m(-2) intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. RESULTS: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44-1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33-0.87, P=0.01). CONCLUSIONS: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.

Towards predicting the response of a solid tumour to chemotherapy and radiotherapy treatments: clinical insights from a computational model.

In this paper we use a hybrid multiscale mathematical model that incorporates both individual cell behaviour through the cell-cycle and the effects of the changing microenvironment through oxygen dynamics to study the multiple effects of radiation therapy. The oxygenation status of the cells is considered as one of the important prognostic markers for determining radiation therapy, as hypoxic cells are less radiosensitive. Another factor that critically affects radiation sensitivity is cell-cycle regulation. The effects of radiation therapy are included in the model using a modified linear quadratic model for the radiation damage, incorporating the effects of hypoxia and cell-cycle in determining the cell-cycle phase-specific radiosensitivity. Furthermore, after irradiation, an individual cell's cell-cycle dynamics are intrinsically modified through the activation of pathways responsible for repair mechanisms, often resulting in a delay/arrest in the cell-cycle. The model is then used to study various combinations of multiple doses of cell-cycle dependent chemotherapies and radiation therapy, as radiation may work better by the partial synchronisation of cells in the most radiosensitive phase of the cell-cycle. Moreover, using this multi-scale model, we investigate the optimum sequencing and scheduling of these multi-modality treatments, and the impact of internal and external heterogeneity on the spatio-temporal patterning of the distribution of tumour cells and their response to different treatment schedules.

Stabilization of graphene sheets by a structured benzene/hexafluorobenzene mixed solvent.

Applications requiring pristine graphene derived from graphite demand a solution stabilization method that utilizes an easily removable media. Using a combination of molecular dynamics simulations and experimental techniques, we investigate the solublization/suspension of pristine graphene sheets by an equimolar mixture of benzene and hexafluorobenzene (C(6)H(6)/C(6)F(6)) that is known to form an ordered structure solidifying at 23.7 °C. Our simulations show that the graphene surface templates the self-assembly of the mixture into periodic layers extending up to 30 Å from both sides of the graphene sheet. The solvent structuring is driven by quadrupolar interactions and consists of stacks of alternating C(6)H(6)/C(6)F(6) molecules rising from the surface of the graphene. These stacks result in density oscillations with a period of about 3.4 Å. The high affinity of the 1:1 C(6)H(6)/C(6)F(6) mixture with graphene is consistent with observed hysteresis in Wilhelmy plate measurements using highly ordered pyrolytic graphite (HOPG). AFM, SEM, and TEM techniques verify the state of the suspended material after sonication. As an example of the utility of this mixture, graphene suspensions are freeze-dried at room temperature to produce a sponge-like morphology that reflects the structure of the graphene sheets in solution.

Topoisomerase IIα levels and G2 radiosensitivity in T-lymphocytes of women presenting with breast cancer.

Previous studies from our laboratory have identified a link between intracellular topoisomerase IIα (topo IIα) levels and chromosomal radiosensitivity, as measured by the frequencies of chromatid breaks in the so-called G2-assay. Lower topo IIα levels were associated with reduced chromosomal radiosensitivity in cultured human cells. These findings supported a model, in which it is proposed that such chromatid breaks are the result of radiation-induced errors made by topoisomerase IIα during decatenation of chromatids. Studies from our and other laboratories, using the G2-assay, have shown that phytohaemagglutinin (PHA)-stimulated peripheral blood T-lymphocytes from 40% of female breast cancer cases show elevated chromatid break frequencies when exposed to a small standard dose of ionizing radiation, i.e. elevated above the 90th percentile of a group of female control samples. In the present study we have used a modified G2-assay to test whether elevated frequency of chromatid breaks in breast cancer cases is linked with elevated intracellular topo IIα level in PHA-stimulated T-lymphocytes, and also whether there is a general correlation between chromosomal radiosensitivity and topo IIα level. Our results confirm previous studies that 40% of breast cancer cases show elevated radiosensitivity as compared with controls. Also, the mean chromatid break frequency in breast cancer cases was significantly higher than in controls (P = 0.0001). We found that the mean topo IIα level in the cohort of breast cancer cases studied was significantly raised, as compared with controls (P = 0.0016), which could indicate a genetic propensity towards a raised intracellular production of topo IIα in these individuals. There was no direct correlation between chromosomal radiosensitivity and topo IIα level for individual samples either in the breast cancer cohort or in controls. However, a comparison between control and breast cancer samples shows a higher mean topo IIα level in breast cancer samples that correlates with the elevated mean chromatid break frequency seen in these patient samples. We found no meaningful correlations between either chromatid break frequency or topo IIα level and either tumour grade or hormone status. We conclude that elevated intracellular topo IIα level is likely to be a significant factor in determining the chromosomal response of stimulated T-lymphocytes from certain breast cancer cases.

Solvent-Free Direct PEGylation of Collagen Fibers.

The addition of poly(ethylene glycol) (PEG) to biomolecules and biomaterials is a well-established approach to modify their properties for therapeutic applications. For biomaterials, the approach is typically to blend or electrospray the synthetic polymer with the biomaterial. Effective surface modification approaches such as surface-initiated polymer brushes are challenging since the harsh solvents required for brush synthesis may destroy the biomaterial. Herein, we describe the PEGylation of collagen fibers by surface-initiated PEG brushes using a living anionic grafting-from mechanism. This brush synthesis is done in the absence of solvents to minimize the degradation of the native collagen structure. We quantify the effect the brush synthesis has on the native structure of the collagen fiber using differential scanning calorimetry (DSC) and find that even at long reaction times a significant fraction of the native structure remains. Dynamic mechanical analysis indicates the collagen undergoes only modest structural degradation, while adhesion studies find a significant improvement of antifouling properties. Further, our approach opens the way for further chemistry, as the growing polymer chain is a potassium alkoxy group that can be functionalized by termination or by subsequent reaction by a wide variety of molecules.

Mirels' score for upper limb metastatic lesions: do we need a different cutoff for recommending prophylactic fixation?

Hypothesis: The aim of this study was to investigate the reproducibility, reliability, and accuracy of Mirels' score in upper limb bony metastatic disease and validate its use in predicting pathologic fractures. Methods: Forty-five patients with upper limb bony metastases met the inclusion criteria (62% male 28/45). The mean age was 69 years (SD 9.5), and the most common primaries were lung (29%, 13/45), followed by prostate and hematological (each 20%, 9/45). The most commonly affected bone was the humerus (76%, 35/45), followed by the ulna (6.5%, 3/45). Mirels' score was calculated in 32 patients; with plain radiographs at index presentation scored using Mirels' system by 6 raters. The radiological aspects (lesion size and appearance) were scored twice by each rater (2 weeks apart). Intraobserver and interobserver reliability were calculated using Fleiss' kappa test. Bland-Altman plots compared the variances of both individual components and the total Mirels' score. Results: The overall fracture rate of upper limb metastatic lesions was 76% (35/46) with a mean follow-up of 3.6 years (range 11 months-6.8 years). Where time from diagnosis to fracture was known (n = 20), fractures occurred at a median 19 days (interquartile range 60-10), and 80% (16/20) occurred within 3 months of diagnosis.Mirels' score of ≥9 did not accurately predict lesions that fractured (fracture rate 11%, 5/46, for Mirels' ≥ 9 vs. 65%, 30/46, for Mirels' ≤ 8, P < .001). Sensitivity was 14%, and specificity was 73%. When Mirels' cutoff was lowered to ≥7, patients were more likely to fracture than not (48%, 22/46, vs. 28%, 13/46, P = .045); sensitivity rose to 63%, but specificity fell to 55%.Kappa values for interobserver variability were κ = 0.358 (fair, 95% confidence interval [CI] 0.288-0.429) for lesion size, κ = 0.107 (poor, 95% CI 0.02-0.193) for radiological appearance, and κ = 0.274 (fair, 95% CI 0.229-0.318) for total Mirels' score. Values for intraobserver variability were κ = 0.716 (good, 95% CI 0.432-0.999) for lesion size, κ = 0.427 (moderate, 95% CI 0.195-0.768) for radiological appearance, and κ = 0.580 (moderate, 95% CI 0.395-0.765) for total Mirels' score. Conclusions: This study demonstrates moderate to substantial agreement between and within raters using Mirels' score on upper limb radiographs. However, Mirels' score had a poor sensitivity and specificity in predicting upper extremity fractures. Until a more valid scoring system has been developed, based on our study, we recommend a Mirels' threshold of ≥7/12 for considering prophylactic fixation of impending upper limb pathologic fractures. This contrasts with the current ≥9/12 cutoff, which is recommended for lower limb pathologic fractures.

Palliative radiotherapy combined with stent insertion to reduce recurrent dysphagia in oesophageal cancer patients: the ROCS RCT.

BACKGROUND: Most patients with oesophageal cancer present with incurable disease. For those with advanced disease, the mean survival is 3-5 months. Treatment emphasis is therefore on effective palliation, with the majority of patients requiring intervention for dysphagia. Insertion of a self-expanding metal stent provides rapid relief but dysphagia may recur within 3 months owing to tumour progression. Evidence reviews have called for trials of interventions combined with stenting to better maintain the ability to swallow. OBJECTIVES: The Radiotherapy after Oesophageal Cancer Stenting (ROCS) study examined the effectiveness of palliative radiotherapy, combined with insertion of a stent, in maintaining the ability to swallow. The trial also examined the impact that the ability to swallow had on quality of life, bleeding events, survival and cost-effectiveness. DESIGN: A pragmatic, multicentre, randomised controlled trial with follow-up every 4 weeks for 12 months. An embedded qualitative study examined trial experiences in a participant subgroup. SETTING: Participants were recruited in secondary care, with all planned follow-up at home. PARTICIPANTS: Patients who were referred for stent insertion as the primary management of dysphagia related to incurable oesophageal cancer. INTERVENTIONS: Following stent insertion, the external beam radiotherapy arm received palliative oesophageal radiotherapy at a dose of 20 Gy in five fractions or 30 Gy in 10 fractions. MAIN OUTCOME MEASURES: The primary outcome was the difference in the proportion of participants with recurrent dysphagia, or death, at 12 weeks. Recurrent dysphagia was defined as deterioration of ≥ 11 points on the dysphagia scale of the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire oesophago-gastric module questionnaire. Secondary outcomes included quality of life, bleeding risk and survival. RESULTS: The study recruited 220 patients: 112 were randomised to the usual-care arm and 108 were randomised to the external beam radiotherapy arm. There was no evidence that radiotherapy reduced recurrence of dysphagia at 12 weeks (48.6% in the usual-care arm compared with 45.3% in the external beam radiotherapy arm; adjusted odds ratio 0.82, 95% confidence interval 0.40 to 1.68; p = 0.587) and it was less cost-effective than stent insertion alone. There was no difference in median survival or key quality-of-life outcomes. There were fewer bleeding events in the external beam radiotherapy arm. Exploration of patient experience prompted changes to trial processes. Participants in both trial arms experienced difficulty in managing the physical and psychosocial aspects of eating restriction and uncertainties of living with advanced oesophageal cancer. LIMITATIONS: Change in timing of the primary outcome to 12 weeks may affect the ability to detect a true intervention effect. However, consistency of results across sensitivity analyses is robust, including secondary analysis of dysphagia deterioration-free survival. CONCLUSIONS: Widely accessible palliative external beam radiotherapy in combination with stent insertion does not reduce the risk of dysphagia recurrence at 12 weeks, does not have an impact on survival and is less cost-effective than inserting a stent alone. Reductions in bleeding events should be considered in the context of patient-described trade-offs of fatigue and burdens of attending hospital. Trial design elements including at-home data capture, regular multicentre nurse meetings and qualitative enquiry improved recruitment/data capture, and should be considered for future studies. FUTURE WORK: Further studies are required to identify interventions that improve stent efficacy and to address the multidimensional challenges of eating and nutrition in this patient population. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12376468 and Clinicaltrials.gov NCT01915693. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 31. See the NIHR Journals Library website for further project information.

Most people are diagnosed with oesophageal (gullet) cancer when it is already at an advanced stage. Losing the ability to swallow food and even fluids is very common when patients are approaching the last months of life. Placing a flexible metal tube, or stent, in the gullet opens it up and improves the ability to swallow quickly. Unfortunately this can fail after around 3 months because the cancer grows and presses on the stent. We designed this trial to see if giving a small dose of radiotherapy alongside insertion of the stent would allow more people to remain swallowing well after 3 months. This could then improve their quality of life and reduce hospitalisation towards the end of life. It may also reduce bleeding from the gullet, as well as other symptoms. We recruited 220 people across the UK, randomly assigning them to have the stent as usual or the stent and a low dose of radiotherapy. We collected a lot of information from the participants at home on how the cancer, the stent and the radiotherapy affected their ability to swallow and their quality of life. Overall, the study showed that the radiotherapy did not improve the ability to swallow 3 months following stent insertion and was less cost-effective than stent insertion alone. It seemed to reduce the risk of bleeding from the tumour itself, but patients found that radiotherapy made them tired and attending extra hospital visits could be troublesome. We also learned that, even after a stent was inserted, patients still struggled with food and needed more support with managing daily life with the stent. The trial results are important. They show that, to answer questions such as these, studies should use different ways of assessing what works, particularly focusing on patients' and families' viewpoints. The results will guide doctors to not routinely give radiotherapy in this situation. The results also suggest that, after the insertion of a stent, patients need extra help in managing their diet, their worries about the stent and their worries about the future.

Palliative radiotherapy after oesophageal cancer stenting (ROCS): a multicentre, open-label, phase 3 randomised controlled trial.

BACKGROUND: Patients with advanced oesophageal cancer have a median survival of 3-6 months, and most require intervention for dysphagia. Self-expanding metal stent (SEMS) insertion is the most typical form of palliation in these patients, but dysphagia deterioration and re-intervention are common. This study examined the efficacy of adjuvant external beam radiotherapy (EBRT) compared with usual care alone in preventing dysphagia deterioration and reducing service use after SEMS insertion. METHODS: This was a multicentre, open-label, phase 3 randomised controlled trial based at cancer centres and acute care hospitals in England, Scotland, and Wales. Patients (aged ≥16 years) with incurable oesophageal carcinoma receiving stent insertion for primary management of dysphagia were randomly assigned (1:1) to receive usual care alone or EBRT (20 Gy in five fractions or 30 Gy in ten fractions) plus usual care after stent insertion. Usual care was implemented according to need as identified by the local multidisciplinary team (MDT). Randomisation was via the method of minimisation stratified by treating centre, stage at diagnosis (I-III vs IV), histology (squamous or non-squamous), and MDT intent to give chemotherapy (yes vs no). The primary outcome was difference in proportions of participants with dysphagia deterioration (>11 point decrease on patient-reported European Organisation for Research and Treatment of Cancer quality of life questionnaire-oesophagogastric module [QLQ-OG25], or a dysphagia-related event consistent with such a deterioration) or death by 12 weeks in a modified intention-to-treat (ITT) population, which excluded patients who did not have a stent inserted and those without a baseline QLQ-OG25 assessment. Secondary outcomes included survival, quality of life (QoL), morbidities (including time to first bleeding event or hospital admission for bleeding event and first dysphagia-related stent complications or re-intervention), and cost-effectiveness. Safety analysis was undertaken in the modified ITT population. The study is registered with the International Standard Randomised Controlled Trial registry, ISRCTN12376468, and ClinicalTrials.gov, NCT01915693, and is completed. FINDINGS: 220 patients were randomly assigned between Dec 16, 2013, and Aug 24, 2018, from 23 UK centres. The modified ITT population (n=199) comprised 102 patients in the usual care group and 97 patients in the EBRT group. Radiotherapy did not reduce dysphagia deterioration, which was reported in 36 (49%) of 74 patients receiving usual care versus 34 (45%) of 75 receiving EBRT (adjusted odds ratio 0·82 [95% CI 0·40-1·68], p=0·59) in those with complete data for the primary endpoint. No significant difference was observed in overall survival: median overall survival was 19·7 weeks (95% CI 14·4-27·7) with usual care and 18·9 weeks (14·7-25·6) with EBRT (adjusted hazard ratio 1·06 [95% CI 0·78-1·45], p=0·70; n=199). Median time to first bleeding event or hospital admission for a bleeding event was 49·0 weeks (95% CI 33·3-not reached) with usual care versus 65·9 weeks (52·7-not reached) with EBRT (adjusted subhazard ratio 0·52 [95% CI 0·28-0·97], p=0·038; n=199). No time versus treatment interaction was observed for prespecified QoL outcomes. We found no evidence of differences between trial group in time to first stent complication or re-intervention event. The most common (grade 3-4) adverse event was fatigue, reported in 19 (19%) of 102 patients receiving usual care alone and 22 (23%) of 97 receiving EBRT. On cost-utility analysis, EBRT was more expensive and less efficacious than usual care. INTERPRETATION: Patients with advanced oesophageal cancer having SEMS insertion for the primary management of their dysphagia did not gain additional benefit from concurrent palliative radiotherapy and it should not be routinely offered. For a minority of patients clinically considered to be at high risk of tumour bleeding, concurrent palliative radiotherapy might reduce bleeding risk and the need for associated interventions. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Fluorescent polymeric nanoparticles: aggregation and phase behavior of pyrene and amphotericin B molecules in nanoparticle cores.

The state of aggregation of compounds, especially drugs, in the cores of nanoparticles (NPs) formed by rapid precipitation is a significant unresolved issue. The state can control the dissolution kinetics from the NP, bioavailability, and chemical stability of the compound. A block-copolymer-directed rapid precipitation process is used to form ≈100 nm NPs comprising mixtures of hydrophobic species including fluorescent probe molecules. Fluorescence measurements are used to probe the state of aggregation and dynamics of rearrangement of pyrene (Py), Hostasol Yellow (HosY), and amphotericin B (AmpB) in NP cores. The Flory-Huggins theory of mixing is used to predict the miscibility or phase separation of the fluorophores from the host NP core material (polystyrene, cholesterol, or polycaprolactone). For Py, excimer fluorescence shows an initial microphase separation in the polystyrene core. Over time the Py redistributes more uniformly with a decrease in excimer and increase in monomer fluorescence. The Flory-Huggins theory predicts the miscibility. For HosY, the fluorescence quenching is not time-dependent, thus indicating stability of the microphase-separated fluorophores, which is consistent with the Flory-Huggins theory calculations. For the drug compound AmpB, the amphiphilic character of the molecule creates unusual "anti-Ostwald" ripening behavior in which the size distribution decreases and narrows over time, and the fluorescence demonstrates an increased ordering in the NP core over time--opposite to the behavior observed for Py.

Stabilization of the nitric oxide (NO) prodrugs and anticancer leads, PABA/NO and Double JS-K, through incorporation into PEG-protected nanoparticles.

We report the stabilization of the nitric oxide (NO) prodrugs and anticancer lead compounds, PABA/NO (O(2)-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) and "Double JS-K" 1,5-bis-{1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diol-2-ato}-2,4-dinitrobenzene, through their incorporation into polymer-protected nanoparticles. The prodrugs were formulated in block copolymer-stabilized nanoparticles with sizes from 220 to 450 nm by a novel rapid precipitation process. The block copolymers, with polyethylene glycol (PEG) soluble blocks, provide a steric barrier against NO prodrug activation by glutathione. Too rapid activation and NO release has been a major barrier to effective administration of this class of compounds. The nanoparticle stabilized PABA/NO are protected from attack by glutathione as evidenced by a significant increase in time taken for 50% decomposition from 15 min (unformulated) to 5 h (formulated); in the case of Double JS-K, the 50% decomposition time was extended from 4.5 min (unformulated) to 40 min (formulated). The more hydrophobic PABA/NO produced more stable nanoparticles and correspondingly more extended release times in comparison with Double JS-K. The hydrophobic blocks of the polymer were either polystyrene or polylactide. Both blocks produced nanoparticles of approximately the same size and release kinetics. This combination of PEG-protected nanoparticles with sizes appropriate for cancer targeting by enhanced permeation and retention (EPR) and delayed release of NO may afford enhanced therapeutic benefit.

PolyHIPE foams from pristine graphene: Strong, porous, and electrically conductive materials templated by a 2D surfactant.

Graphene is attractive as a functional 2D surfactant for polymerized high internal phase emulsions (polyHIPEs) due to its remarkable mechanical and electrical properties. We have developed polyHIPEs stabilized by pristine, unoxidized graphene via the spontaneous exfoliation of graphite at high-energy aqueous/organic interfaces. The exfoliated graphene self-assembles into a percolating network and incorporates into the polyHIPE cell walls as verified by TEM. The resulting composites showed compressive strengths of 7.0 MPa at densities of 0.22 g/cm3 and conductivities up to 0.36 S/m. Systematically reducing the concentration of monomer in the oil phase by dilution with a porogenic-acting solvent increased the porosity and lowered the density of the polyHIPEs. Characterization of these composites indicated that graphene's high compressive strength and modulus was transferred to the polyHIPEs and provided mechanical reinforcement even at low polymer content. SEM showed that the morphology of the polymer changed with decreasing monomer content while the graphene lined cells retained their shape. Moreover, we show that the polyHIPEs contain a continuous graphene percolating network resulting in electrically conductive materials at low graphene loading.

Interface-exfoliated graphene-based conductive screen-printing inks: low-loading, low-cost, and additive-free.

Paper diagnostics are of growing interest due to their low cost and easy accessibility. Conductive inks, necessary for manufacturing the next generation diagnostic devices, currently face challenges such as high cost, high sintering temperatures, or harsh conditions required to remove stabilizers. Here we report an effective, inexpensive, and environmentally friendly approach to graphene ink that is suitable for screen printing onto paper substrates. The ink formulation contains only pristine graphite, water, and non-toxic alkanes formed by an interfacial trapping method in which graphite spontaneously exfoliates to graphene. The result is a viscous graphene stabilized water-in-oil emulsion-based ink. This ink does not require sintering, but drying at 90 °C or brief microwaving can improve the conductivity. The production requires only 40 s of shaking to form the emulsion. The sheet resistance of the ink is approximately 600 Ω/sq at a thickness of less than 6 µm, and the ink can be stabilized by as little as 1 wt% graphite.

The Metastatic Early Prognostic (MEP) score.

AIMS: The early mortality in patients with hip fractures from bony metastases is unknown. The objectives of this study were to quantify 30- and 90-day mortality in patients with proximal femoral metastases, and to create a mortality prediction tool based on biomarkers associated with early death. METHODS: This was a retrospective cohort study of consecutive patients referred to the orthopaedic department at a UK trauma centre with a proximal femoral metastasis (PFM) over a seven-year period (2010 to 2016). The study group were compared to a matched control group of non-metastatic hip fractures. Minimum follow-up was one year. RESULTS: There was a 90-day mortality of 46% in patients with metastatic hip fractures versus 12% in controls (89/195 and 24/192, respectively; p < 0.001). Mean time to surgery was longer in symptomatic metastases versus complete fractures (9.5 days (SD 19.8) and 3.4 days (SD 11.4), respectively; p < 0.05). Albumin, urea, and corrected calcium were all independent predictors of early mortality and were used to generate a simple tool for predicting 90-day mortality, titled the Metastatic Early Prognostic (MEP) score. An MEP score of 0 was associated with the lowest risk of death at 30 days (14%, 3/21), 90 days (19%, 4/21), and one year (62%, 13/21). MEP scores of 3/4 were associated with the highest risk of death at 30 days (56%, 5/9), 90 days (100%, 9/9), and one year (100%, 9/9). Neither age nor primary cancer diagnosis was an independent predictor of mortality at 30 and 90 days. CONCLUSION: This score could be used to predict early mortality and guide perioperative counselling. The delay to surgery identifies a potential window to intervene and correct these abnormalities with the aim of improving survival. Cite this article: Bone Joint J. 2020;102-B(1):72-81.