A Multicentre Retrospective Study of Fulvestrant Use and Efficacy in Advanced/Metastatic Breast Cancer.

AIMS: Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres. MATERIALS AND METHODS: Medical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored. RESULTS: Data from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21-95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0-1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0-5) prior lines of endocrine therapy and median 0 (range 0-6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1-88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0-88). CONCLUSIONS: This is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients.

Film clips smoking behavior and nicotine craving: The interrelationship between stress, smoking cues and craving.

Αn abundance of research has demonstrated that substance addicted individuals, when they are exposed to a substance related stimulus, show a positive correlation between physiological measurements, such as an increase in heart rate and sweating, and behavioral reactions, that include craving and substance use or consumption. Films depicting smoking behavior are regarded as cues to induce smoking behavior. The current study aimed to investigate the effects of smoking behavior portrayed in movies on actual craving experienced by smokers who watch on screen actors consume tobacco products. In addition, the effects of receiving orally administered nicotine (chewing gum), a regular chewing gum or no additional intervention were examined. In particular, the study aimed to investigate how these factors impact nicotine craving as well as the heart rate and sweating. The majority of the participants were University of Bedfordshire students and staff. Thirty smokers (12 males and 18 females) having received a nicotine gum, a regular chewing gum or no gum, were exposed to a digital video clip showing actors smoking. The participants chose the type of chewing gum they wanted. Heart rate (HR) and galvanic skin response (GSR) were measured during the course of the experiment. Prior to and after watching the movie clip participants completed the Brief Questionnaire of Smoking Urges (QSU-Brief) and the Perceived Stress Scale (PSS). According to the results, the craving was increased when compared to the baseline score (t=-3.76, p<0.001). Additionally, a correlation was found between the baseline level of craving and perceived stress before and after the movie (r=0.39). Nicotine chewing gum was found to have a significant impact on participants' heart rate (p<0.05) but not on GSR. A significant difference was found in participants in the normal chewing gum condition reporting higher levels of craving than the other two groups (p<0.05). Age was found to positively related to post-measures of nicotine craving which was found to be higher for young respondents (r=-0.47, p<0.01). The data further show that the depiction of smoking behavior in the media is likely to have a significant impact on smoking craving, smoking behavior and nicotine consumption. The current study confirms and replicates some of the previous findings within the field of smoking behavior and nicotine craving such as high susceptibility of younger adults to media influence.

A study of urgent and emergency referrals from NHS Direct within England.

OBJECTIVES: The presented study aimed to explore referral patterns of National Health Service (NHS) Direct to determine how patients engage with telephone-based healthcare and how telephone-based healthcare can manage urgent and emergency care. SETTING: NHS Direct, England, UK PARTICIPANTS: NHS Direct anonymised call data (N=1,415,472) were extracted over a representative 1-year period, during the combined month periods of July 2010, October 2010, January 2011 and April 2011. Urgent and emergency calls (N=269,558; 19.0%) were analysed by call factors and patient characteristics alongside symptom classification. Categorical data were analysed using the χ(2) test of independence with cross-tabulations used to test within-group differences. PRIMARY AND SECONDARY OUTCOME MEASURES: Urgent and emergency referrals to 999; accident and emergency or to see a general practitioner urgently, which are expressed as call rate per 100 persons per annum. Outcomes related to symptom variations by patient characteristics (age, gender, ethnicity and deprivation) alongside differences by patient characteristics of call factors (date and time of day). RESULTS: Urgent and emergency referrals varied by a range of factors relating to call, patient and symptom characteristics. For young children (0-4), symptoms related to 'crying' and 'colds and flu' and 'body temperature change' represented the significantly highest referrals to 'urgent and emergency' health services symptoms relating to 'mental health' alongside 'pain' and 'sensation disorders' represented the highest referrals to urgent and emergency health services for adults aged 40+ years. CONCLUSIONS: This study has highlighted characteristics of 'higher likelihood' referrals to urgent and emergency care through the delivery of a national nurse-led telephone healthcare service. This research can help facilitate an understanding of how patients engage with both in and out of hours care and the role of telephone-based healthcare within the care pathway.

Young people's use of NHS Direct: a national study of symptoms and outcome of calls for children aged 0-15.

OBJECTIVES: National Health Service (NHS) Direct provides 24/7 expert telephone-based healthcare information and advice to the public in England. However, limited research has explored the reasons to why calls are made on behalf of young people, as such this study aimed to examine call rate (CR) patterns in younger people to enable a better understanding of the needs of this population in England. SETTING: NHS Direct, England, UK. PARTICIPANTS AND METHODS: CRs (expressed as calls/100 persons/annum) were calculated for all calls (N=358 503) made to NHS Direct by, or on behalf of, children aged 0-15 during the combined four '1-month' periods within a year (July 2010, October 2010, January 2011 and April 2011). χ² Analysis was used to determine the differences between symptom, outcome and date/time of call. RESULTS: For infants aged <1, highest CRs were found for 'crying' for male (n=14, 440, CR=13.61) and female (n=13 654, CR=13.46) babies, which is used as a universal assessment applied to all babies. High CRs were also found for symptoms relating to 'skin/hair/nails' and 'colds/flu/sickness' for all age groups, whereby NHS Direct was able to support patients to self-manage and provide health information for these symptoms for 59.7% and 51.4% of all cases, respectively. Variations in CRs were found for time and age, with highest peaks found for children aged 4-15 in the 15:00-23:00 period and in children aged <1 in the 7:00-15:00 period. CONCLUSIONS: This is the first study to examine the symptoms and outcome of calls made to NHS Direct for and on behalf of young children. The findings revealed how NHS Direct has supported a range of symptoms through the provision of health information and self-care support which provides important information about service planning and support for similar telephone-based services.

Epithelial ovarian cancer: a review of current management.

Epithelial ovarian cancer is the most lethal gynaecological cancer among women worldwide, with 6000 new cases diagnosed in the UK each year. Most women present with advanced disease, but, despite a good initial response to treatment, most relapse. The overall 5-year survival rate is 46%, although this drops to about 13% in women with advanced disease. Transvaginal ultrasound and the tumour marker CA125 are being investigated for screening in ongoing randomised trials. Treatment of ovarian cancer is dependent on clinical stage, and should always be managed within a multidisciplinary team. Most cases will require a pelvic clearance and adjuvant chemotherapy. Current guidelines by the National Institute of Clinical Excellence (NICE) recommend that first-line chemotherapy should include a platinum-based regimen with or without paclitaxel. Relapsed ovarian cancer is incurable; however, chemotherapy can improve quality of life and survival. Gene therapy, immunotherapy and signal transduction inhibitors are all potential future therapies, and are being investigated in ongoing clinical research. In this paper we review the literature on the epidemiology, pathology, clinical features and the current treatment options in epithelial ovarian cancer.

A phase II study of sequential carboplatin, paclitaxel and topotecan in patients with previously untreated advanced ovarian cancer.

We evaluated the sequential use of carboplatin, paclitaxel and topotecan in patients with advanced, previously untreated ovarian cancer. In total, 43 patients with advanced ovarian cancer and >1 cm residual disease were treated with sequential carboplatin (area-under-the-curve (AUC) 5 days 1 and 22), paclitaxel (175 mg m(-2) days 43 and 64) and topotecan (1.5 mg m(-2) daily for 5 days from days 85, 106, 127 and 148). Median age of patients was 61 years. Median follow-up was 22.2 months (range 0.76-50.6 months). In all, 34 (79%) patients received all eight cycles of treatment and nine (21%) withdrew. Of the 29 evaluable patients, 19 (66%) responded according to WHO and 30 of 36 (83%) patients according to CA125. The best overall response (CA125 and/or WHO) was 77% (33 of 43 patients). The response rates to sequential drugs based on >50% fall in CA125 were as follows: carboplatin, 77% (30 of 39 patients); paclitaxel, 65% (15 of 23 patients); topotecan, 38% (five of 13 patients). Two patients responded to paclitaxel and one to topotecan after failure to respond to preceding chemotherapy. Median survival and time to progression was 22.24 and 10.61 months, respectively. This study demonstrates that sequential chemotherapy with just two initial courses of carboplatin is a reasonable way to introduce new agents into first-line therapy for poor prognostic ovarian cancer patients.

The role of surveillance CT scans in patients with diffuse large B-cell non-Hodgkin's lymphoma.

The use of routine surveillance computed tomography (CT) scans in the follow-up of patients with diffuse large B-cell lymphoma may allow the detection of early asymptomatic relapse. On this basis, CT scans are frequently included in follow-up schedules, but the utility of this investigation in this setting has never been determined. This study evaluated the effectiveness of routine surveillance CT scans performed 3 and 12 months after completion of chemotherapy in patients with diffuse large B-cell lymphoma who had achieved a complete response. One hundred and seventeen patients with diffuse large B-cell lymphoma achieved complete remission at the Royal Marsden Hospital using first line combination chemotherapy between January 1992 and January 2000. The median follow-up was 4.6 years and 35 patients subsequently relapsed. Relapse was associated with the development of new symptoms and/or signs in 86% of cases. Only 5.7% of relapses were detected in asymptomatic patients using surveillance CT scans. Routine surveillance CT scans are of limited value in detecting asymptomatic early relapse and other approaches are required in order to identify patients destined to relapse at an earlier stage.

CA125 response: can it replace the traditional response criteria in ovarian cancer?

CA125 is well established as an accurate and reliable means of monitoring response to treatment and confirming relapse in ovarian cancer patients. Its role in follow-up after initial treatment is less certain and the subject of a current clinical trial. Measuring response with computerized tomography scans is futile in the majority of patients, as disease is often nonmeasurable at presentation, e.g., ascites or peritoneal deposits, or all measurable disease has been removed at the time of surgery. Serial changes in CA125 can be used as a reliable indicator of disease response or progression so that patients can be classified as responding or progressing according to either standard or CA125 criteria. These precise definitions are currently being prospectively validated in conjunction with the new response evaluation criteria in solid tumor response guidelines and are being incorporated into all future clinical trials.

Individual differences, exercise and leisure activity in predicting affective well-being in young adults.

This study focuses on the prevalence of exercise and health-related leisure activities (smoking, drinking), across groups of subjects, defined by personality and gender, in relation to subjective well-being. Results from a cross-sectional survey of 187 participants are reported. Males (n = 80) reported more drinking (p < 0.001) and smoking (p < 0.001) than females, though they also reported higher habitual physical activity levels (p < 0.001). Females (n = 107) reported more frequent use of social support coping (p < 0.01). There was a positive association between extraversion and self-reported habitual physical activity as well as alcohol consumption (even when controlling for gender). Neuroticism was not related to any of the exercise and leisure activity variables. Multiple regression analyses predicted 34% of variance for the depression-enthusiasm and 39% of the variance for the anxiety-contentment measures of affective well-being. Neuroticism (p < 0.001) and avoidance coping (p < 0.05) were the only significant predictors of both anxiety-contentment and depression-enthusiasm. It is concluded that the influence of individual differences such as personality and gender on coping behaviour and well-being is consistent with social learning theory research. Limitations of cross-sectional research designs necessitate caution with inferring causal paths. Recommendations for future research are presented concerning the use and value of repeated measures designs within research into exercise and well-being.

Stressors, locus of control, and social support as consequences of affective psychological well-being.

Tests of the influence of affective psychological well-being on stressors, locus of control, and social support in a 1-month follow-up study of 210 male and 34 female British accountants is reported. There was a marginally significant association between the level of psychological symptoms and subsequent reports of intensity of quantitative workload stressors. A significant interaction between psychological symptoms and a measure of depression-enthusiasm was found to predict subsequent locus of control. The results indicate a differential pattern of associations between aspects of affective well-being and subsequent reports of social support. The results also indicate that initially more frequent stressors are associated with subsequently less intense stressors of the same type. The findings highlight the dynamic and reciprocal nature of the occupational stress process.

Drivers' biased perceptions of the adverse consequences of drink-driving.

The decision to drink and drive may involve the subjective process of weighing the perceived risks of adverse consequences of the behaviour against perceived utility components. Deterrence theory proposes that an individual will refrain from drink-driving if the perceived chances of experiencing negative outcomes associated with the behaviour are high. Previous research has demonstrated that there may be a mechanism of judgmental bias which influences individuals' perceived probabilities of rarely occurring events. In general driver age and gender have been shown independently to be both indicative and non-indicative for the operation of the bias in terms of subjective perceptions of driver skill, safety and accident involvement. Little evidence has been presented to describe the nature of the bias in the specific domain of drink-driving. Responses from more than 1000 UK drivers were examined to establish whether a system of bias operated for judgments of the likelihood of experiencing several possible adverse consequences of drink-driving across males/females, age groups and offenders/non-offenders. In general drivers were found to perceive themselves as less likely than the average driver to be accident involved while impaired and non-impaired by alcohol. Drivers reporting previous drink-driving behaviour indicated the greatest bias. The age and gender of the driver, independently and in interaction, were not shown to be important in the operation of these perceptual inconsistencies. Findings are discussed for implications of deterrence based drink-driving counter-measures.

Speeding in relation to perceptions of risk, utility and driving style by British company car drivers.

Results are presented of a questionnaire survey of speed-related risk-taking performed on 572 British company car drivers. Reported risk-taking was examined in relation to risk and utility perceptions as well as perceived control and driver self-perceptions. The data revealed that over half the sample reported often exceeding the motorway speed limit by at least 10 mph (16 km/h). It was found that drivers who more frequently exceeded the speed limit on motorways were less likely to view speeding as an important risk factor and were much more likely to view being on time for appointments as desirable. They were also likely to view themselves as less aware, less sociable and more confident. The importance of the perceived utility of arriving at appointments on time, in relation to speeding over the legal limit, suggests that some organizational measures to reduce perceived time pressure within company vehicle drivers could be beneficial.

The interactionist nature of drinking and driving: a structural model.

A structural model is described that examines the contributions of personal and situational determinants (interactionist theory) for the elicitation of previous self-reported drink-driving offending. Responses of 1011 UK driver's licence holders to 57 questions concerning demographics, driving experience/exposure, deterrence issues, attitudinal factors and situation specific drink-driving behaviour were subjected to a series of multiple regression analyses. Seven variables (five personal and two situational) accounting for 46% of the sample variance were shown to be significantly predictive of undetected offending behaviour. Of these age and safe driving consumption estimates were found to be best described in terms of their direct effects on offending behaviour. The relationships between general alcohol consumption and exposure to secondary level enforcement (breath test) with drink-driving behaviour have both direct and indirect effects. Two attitudinal factors referring to a belief of deterrence if random breath testing were introduced into the UK, and arranging alternative transport on a drinking occasion, as well as exposure to a drink-driving charge, show approximately proportional direct and spurious links with offending. Findings are discussed i n terms of the utility of an interactionist approach for the study of drink-driving behaviour, previous attempts at modelling drink-driving behaviour, and the implications that such results have for counter-measure development.

Behavior and perceptions related to drink-driving among an international sample of company vehicle drivers.

OBJECTIVE: The study examined reported behavior, perceptions and attitudes related to drink-driving among company vehicle drivers located across eight countries. An additional aim of the research was to identify important predictors of drink-driving. METHOD: A cross-sectional mailshot questionnaire survey was undertaken on all drivers of company vehicle identified by the collaborating companies. Responses to items concerning reported drink-driving, perceived consumption limits, perceived risk and reported restraint were examined for a total of 600 male drivers, representing an overall response rate of 55%. RESULTS: Driving after any alcohol consumption was found to be relatively common across most of the sample, while driving when over the legal limit at least once in the previous 12 months was reported by approximately one-third of the drivers. Multiple regression analysis indicated that the strongest predictors of reported drink-driving behavior were associated with perceived limits of personal alcohol consumption and a "moral attachment" to non-drink-driving associated with alcohol consumption restraint. This general prediction model seemed to be relatively consistent across the different national groups. CONCLUSIONS: The results suggest that longer term cognitive components of decision making such as "moral attachment" may form fundamental elements in the decision to drive after excessive drinking. It was suggested that company-based policies and programs may have a useful role in promoting safer driving practices, particularly in relation to driving after drinking.

Drivers' differential perceptions of legal and safe driving consumption.

UK drink-drive countermeasures have been grounded in deterrence theory and more specifically through per se legislation. Education and information campaigns to stimulate inhibitory behavioural systems have emphasized the legal limit in terms of "driving safeness". This study examined the relationship between subjective perceptions of safe driving and legal driving consumption limits and other factors important in the decision to drive after drinking. Responses from over 900 drivers established that those who perceived safe consumption levels to be greater than that required to break the law indicated reduced moral commitment to present and possible future countermeasures. These drivers also had previous experience of being breath tested (but not charged with a drink-driving offence), reported comparatively lower estimates of their chances of apprehension and accident involvement when over the legal limit, showed higher consumption levels on a driving trip and greater self-reported driving while impaired by alcohol. The implications of the findings for the development and delivery of measures to counter drink-driving are discussed.

Subjective probability of accident and apprehension in relation to self-other bias, age, and reported behavior.

Responses from over 900 male drivers were examined on items measuring the subjective probability of two adverse driving scenarios (accident and apprehension) for a number of speeding and drink-driving-related events. The items were constructed to focus on self versus average referent driver comparisons. Respondents were categorised into "offenders" and "non-offenders" according to their reported behaviour concerning speeding and drink-driving. The data were analysed using repeated measures analysis of variance. The results indicated that both accident and apprehension are seen as less probable when self is the reference compared to the average driver. There was evidence to suggest that this self-favouring bias did vary over presented scenarios. It was suggested that such perceptions may vary in relation to the perceived influence of driver skill within scenarios. Weak age effects were found, but it was concluded that, generally, self-favouring biases were common across all age groups. Concerning the offender/nonoffender classification, the results indicated that speeders and drink-drivers generally perceived the probability of apprehension and accident as being lower than did the nonoffender groups. There was no evidence to suggest that self-average driver biases were associated with offender/nonoffender grouping.

Frequency sensitivity and directional hearing in the gleaning bat, Plecotus auritus (Linnaeus 1758).

1. The neural audiogram of the common long-eared bat, Plecotus auritus was recorded from the inferior colliculus (IC). The most sensitive best frequency (BF) thresholds for single neurones are below 0 dB SPL between 7-20 kHz, reaching a best value of -20 dB SPL between 12-20 kHz. The lower and upper limits of hearing occur at 3 kHz and 63 kHz, respectively, based on BF thresholds at 80 dB SPL. BF threshold sensitivities are about 10 dB SPL between 25-50 kHz, corresponding to the energy band of the sonar pulse (26-78 kHz). The tonotopic organization of the central nucleus of the IC (ICC) reveals that neurones with BFs below 20 kHz are disproportionately represented, occupying about 30% of ICC volume, occurring in the more rostral and lateral regions of the nucleus. 2. The acoustical gain of the external ear reaches a peak of about 20 dB between 8-20 kHz. The gain of the pinna increases rapidly above 4 kHz, to a peak of about 15 dB at 7-12 kHz. The pinna gain curve is similar to that of a simple, finite length acoustic horn; expected horn gain is calculated from the average dimensions of the pinna. 3. The directional properties of the external ear are based on sound diffraction by the pinna mouth, which, to a first approximation, is equivalent to an elliptical opening due to the elongated shape of the pinna. The spatial receptive field properties for IC neurones are related to the directional properties of the pinna. The position of the acoustic axis of the pinna and the best position (BP) of spatial receptive fields are both about 25 degrees from the midline between 8-30 kHz but approach the midline to 8 degrees at 45 kHz. In elevation, the acoustic axis and the BP of receptive fields move upwards by 20 degrees between 9-25 kHz, remaining stationary for frequencies up to 60 kHz. 4. The extremely high auditory sensitivity shown by the audiogram and the directionality of hearing are discussed in terms of the adaptation of the auditory system to low frequencies and the role of a large pinna in P. auritus. The functional significance of low frequency hearing in P. auritus is discussed in relation to hunting for prey by listening and is compared to other gleaning species.

The effects of alcohol on speed perception in a closed-course driving situation.

The present study examined the effect of alcohol on the perception of speed in a closed-course driving situation. Male subjects (N = 24) classified with respect to previous drinking experience were used in the experiment. Each subject was tested on a speed estimation task at blood alcohol levels (BALs) of 0 and 100 mg/dl. Subjects were required to decelerate from a constant speed of 30 mph to a target speed of 20 mph under two conditions: using their speedometer and being deprived of its use. Of interest were the subjective judgments made under the latter conditions. Results show that there was no significant effect of alcohol on the perception of speed. The expected interaction between previous drinking experience and alcohol dose was found to be nonsignificant. Overall, a significant difference in performance between the two speedometer conditions indicated that subjects overestimated the target speed when they were not given access to their speedometer. Possible explanations and implications of these findings are discussed and future directions for research are suggested.