Effects of 4-hydroxytamoxifen and a novel pure antioestrogen (ICI 182780) on the clonogenic growth of human breast cancer cells in vitro.

We have investigated the effects on breast cancer cell growth of 4-hydroxytamoxifen (4OHT), a conventional antioestrogen with agonist activity, and 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra- 1,3,5,(10)- triene-3,17 beta-diol (ICI 182780), a novel, pure antioestrogen, using established human breast cancer cell lines and cancer cells obtained directly from breast cancer patients with malignant pleural effusions who had relapsed on tamoxifen. The effects of the two agents were assessed using the Courtenay-Mills clonogenic assay, which measures the growth of single cancer cells as colonies suspended in soft agar. The standard assay was modified by the use of defined serum- and phenol red-free growth medium. The growth of oestrogen receptor (ER)-positive MCF-7 cells in the assay was oestrogen responsive. Both antioestrogens inhibited the stimulatory effects of 1 nM oestradiol, but ICI 182780 caused significantly greater inhibition than 4OHT at 0.1-1.0 microM concentrations. In the absence of oestradiol, 4OHT but not ICI 182780 caused significant stimulation of colony formation at low (0.01-1.00 nM) concentrations. Neither antioestrogen had any effects on colony formation by the ER-negative Hs578T cell line. Successful colony formation was obtained in primary cultures from six out of eight malignant effusions. Colony formation was significantly stimulated by 0.1 nM oestradiol in four cases and by 10 nM 40HT in two cases. In contrast, ICI 182780 exhibited no intrinsic stimulatory activity and significantly inhibited both oestradiol- and 4OHT-stimulated cell growth. We conclude that the agonist activity of 4OHT and other conventional antioestrogens may cause treatment failure in some patients by stimulating breast cancer cell growth. The new, pure antioestrogen ICI 182780 is a more potent oestrogen antagonist than 4OHT and exhibits no growth-stimulatory activity. This agent may therefore offer therapeutic advantages over conventional antioestrogens in patients with advanced breast cancer and may be effective after conventional agents have failed

Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer.

We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. The AUCs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Side-effects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed "no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer

Ki67 proliferation in core biopsies versus surgical samples - a model for neo-adjuvant breast cancer studies

Background: An increasing number of neo-adjuvant breast cancer studies are being conducted and a novel model for tumor biological studies, the "window-of-opportunity" model, has revealed several advantages. Change in tumor cell proliferation, estimated by Ki67-expression in pre-therapeutic core biopsies versus post-therapeutic surgical samples is often the primary end-point. The aim of the present study was to investigate potential differences in proliferation scores between core biopsies and surgical samples when patients have not received any intervening anti-cancer treatment. Also, a lack of consensus concerning Ki67 assessment may raise problems in the comparison of neo-adjuvant studies. Thus, the secondary aim was to present a novel model for Ki67 assessment. Methods: Fifty consecutive breast cancer cases with both a core biopsy and a surgical sample available, without intervening neo-adjuvant therapy, were collected and tumor proliferation (Ki67, MIB1 antibody) was assessed immunohistochemically. A theoretical model for the assessment of Ki67 was constructed based on sequential testing of the null hypothesis 20% Ki67-positive cells versus the two-sided alternative more or less than 20% positive cells.. Results: Assessment of Ki67 in 200 tumor cells showed an absolute average proliferation difference of 3.9% between core biopsies and surgical samples (p = 0.046, paired t-test) with the core biopsies being the more proliferative sample type. A corresponding analysis on the log-scale showed the average relative decrease from the biopsy to the surgical specimen to be 19% (p = 0.063, paired t-test on the log-scale). The difference was significant when using the more robust Wilcoxon matched-pairs signed-ranks test (p = 0.029). After dichotomization at 20%, 12 of the 50 sample pairs had discrepant proliferation status, 10 showed high Ki67 in the core biopsy compared to two in the surgical specimen (p = 0.039, McNemar's test). None of the corresponding results for 1000 tumor cells were significant - average absolute difference 2.2% and geometric mean of the ratios 0.85 (p = 0.19 and p = 0.18, respectively, paired t-tests, p = 0.057, Wilcoxon's test) and an equal number of discordant cases after dichotomization. Comparing proliferation values for the initial 200 versus the final 800 cancer cells showed significant absolute differences for both core biopsies and surgical samples 5.3% and 3.2%, respectively (p < 0.0001, paired t-test). Conclusions: A significant difference between core biopsy and surgical sample proliferation values was observed despite no intervening therapy. Future neo-adjuvant breast cancer studies may have to take this into consideration

Psychomotor control in a virtual laparoscopic surgery training environment: gaze control parameters differentiate novices from experts

Background: Surgical simulation is increasingly used to facilitate the adoption of technical skills during surgical training. This study sought to determine if gaze control parameters could differentiate between the visual control of experienced and novice operators performing an eye-hand coordination task on a virtual reality laparoscopic surgical simulator (LAP Mentor™). Typically adopted hand movement metrics reflect only one half of the eye-hand coordination relationship; therefore, little is known about how hand movements are guided and controlled by vision. Methods: A total of 14 right-handed surgeons were categorised as being either experienced (having led more than 70 laparoscopic procedures) or novice (having performed fewer than 10 procedures) operators. The eight experienced and six novice surgeons completed the eye-hand coordination task from the LAP Mentor basic skills package while wearing a gaze registration system. A variety of performance, movement, and gaze parameters were recorded and compared between groups. Results: The experienced surgeons completed the task significantly more quickly than the novices, but only the economy of movement of the left tool differentiated skill level from the LAP Mentor parameters. Gaze analyses revealed that experienced surgeons spent significantly more time fixating the target locations than novices, who split their time between focusing on the targets and tracking the tools. Conclusion: The findings of the study provide support for the utility of assessing strategic gaze behaviour to better understand the way in which surgeons utilise visual information to plan and control tool movements in a virtual reality laparoscopic environment. It is hoped that by better understanding the limitations of the psychomotor system, effective gaze training programs may be developed. © 2010 The Author(s).published_or_final_versionSpringer Open Choice, 01 Dec 201

Gaze training enhances laparoscopic technical skill acquisition and multi-tasking performance: A randomized, controlled study

Background: The operating room environment is replete with stressors and distractions that increase the attention demands of what are already complex psychomotor procedures. Contemporary research in other fields (e.g., sport) has revealed that gaze training interventions may support the development of robust movement skills. This current study was designed to examine the utility of gaze training for technical laparoscopic skills and to test performance under multitasking conditions. Methods: Thirty medical trainees with no laparoscopic experience were divided randomly into one of three treatment groups: gaze trained (GAZE), movement trained (MOVE), and discovery learning/control (DISCOVERY). Participants were fitted with a Mobile Eye gaze registration system, which measures eye-line of gaze at 25 Hz. Training consisted of ten repetitions of the "eye-hand coordination" task from the LAP Mentor VR laparoscopic surgical simulator while receiving instruction and video feedback (specific to each treatment condition). After training, all participants completed a control test (designed to assess learning) and a multitasking transfer test, in which they completed the procedure while performing a concurrent tone counting task. Results: Not only did the GAZE group learn more quickly than the MOVE and DISCOVERY groups (faster completion times in the control test), but the performance difference was even more pronounced when multitasking. Differences in gaze control (target locking fixations), rather than tool movement measures (tool path length), underpinned this performance advantage for GAZE training. Conclusions: These results suggest that although the GAZE intervention focused on training gaze behavior only, there were indirect benefits for movement behaviors and performance efficiency. Additionally, focusing on a single external target when learning, rather than on complex movement patterns, may have freed-up attentional resources that could be applied to concurrent cognitive tasks. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201

Superhydrophilic Functionalization of Microfiltration Ceramic Membranes Enables Separation of Hydrocarbons from Frac and Produced Water

The environmental impact of shale oil and gas production by hydraulic fracturing (fracking) is of increasing concern. The biggest potential source of environmental contamination is flowback and produced water, which is highly contaminated with hydrocarbons, bacteria and particulates, meaning that traditional membranes are readily fouled. We show the chemical functionalisation of alumina ceramic microfiltration membranes (0.22 μm pore size) with cysteic acid creates a superhydrophilic surface, allowing for separation of hydrocarbons from frac and produced waters without fouling. The single pass rejection coefficients was >90% for all samples. The separation of hydrocarbons from water when the former have hydrodynamic diameters smaller than the pore size of the membrane is due to the zwitter ionically charged superhydrophilic pore surface. Membrane fouling is essentially eliminated, while a specific flux is obtained at a lower pressure (<2 bar) than that required achieving the same flux for the untreated membrane (4–8 bar)

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

A randomized trial to assess the biological activity of short-term (pre-surgical) fulvestrant 500 mg plus anastrozole versus fulvestrant 500 mg alone or anastrozole alone on primary breast cancer

Introduction: Fulvestrant shows dose-dependent biological activity. Greater estrogen-receptor (ER) blockade may feasibly be achieved by combining fulvestrant with anastrozole. This pre-surgical study compared fulvestrant plus anastrozole versus either agent alone in patients with ER-positive breast cancer. Methods: In this double-blind, multicenter trial, 121 patients received: fulvestrant 500 mg on day 1 plus anastrozole 1 mg/day for 14-21 days (F+A); fulvestrant plus anastrozole placebo (F); or fulvestrant placebo plus anastrozole (A), 2-3 weeks before surgery. ER, progesterone-receptor (PgR), and Ki67 expression were determined from tumor biopsies before treatment and at surgery. Results: 103 paired samples were available (F, n = 35; F+A, n = 31; A, n = 37). All treatments significantly reduced mean ER expression from baseline (F: 41%, P = 0.0001; F+A: 39%, P = 0.0001; A: 13%, P = 0.0034). F and F+A led to greater reductions in ER versus A (both P = 0.0001); F+A did not lead to additional reductions versus F. PgR and Ki67 expression were significantly reduced with all treatments (means were 34% to 45%, and 75% to 85%, respectively; all P = 0.0001), with no differences between groups. Conclusions: In this short-term study, all treatments reduced ER expression, although F and F+A showed greater reductions than A. No significant differences were detected between the treatment groups in terms of PgR and Ki67 expression. No additional reduction in tumor biomarkers with combination treatment was observed, suggesting that F+A is unlikely to have further clinical benefit over F alone. Trial registration: Clinicaltrials.gov NCT00259090