Intensity-modulated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): 2-year toxicity results from an open-label, randomised, phase 3, non-inferiority trial.

BACKGROUND: Localised prostate cancer is commonly treated with external beam radiotherapy and moderate hypofractionation is non-inferior to longer schedules. Stereotactic body radiotherapy (SBRT) allows shorter treatment courses without impacting acute toxicity. We report 2-year toxicity findings from PACE-B, a randomised trial of conventionally fractionated or moderately hypofractionated radiotherapy versus SBRT. METHODS: PACE is an open-label, multicohort, randomised, controlled, phase 3 trial conducted at 35 hospitals in the UK, Ireland, and Canada. In PACE-B, men aged 18 years and older with a WHO performance status 0-2 and low-risk or intermediate-risk histologically-confirmed prostate adenocarcinoma (Gleason 4 + 3 excluded) were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group to control radiotherapy (CRT; 78 Gy in 39 fractions over 7·8 weeks or, following protocol amendment on March 24, 2016, 62 Gy in 20 fractions over 4 weeks) or SBRT (36·25 Gy in five fractions over 1-2 weeks). Androgen deprivation was not permitted. Co-primary outcomes for this toxicity analysis were Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicity at 24 months after radiotherapy. Analysis was by treatment received and included all patients with at least one fraction of study treatment assessed for late toxicity. Recruitment is complete. Follow-up for oncological outcomes continues. The trial is registered with ClinicalTrials.gov, NCT01584258. FINDINGS: We enrolled and randomly assigned 874 men between Aug 7, 2012, and Jan 4, 2018 (441 to CRT and 433 to SBRT). In this analysis, 430 patients were analysed in the CRT group and 414 in the SBRT group; a total of 844 (97%) of 874 randomly assigned patients. At 24 months, RTOG grade 2 or worse genitourinary toxicity was seen in eight (2%) of 381 participants assigned to CRT and 13 (3%) of 384 participants assigned to SBRT (absolute difference 1·3% [95% CI -1·3 to 4·0]; p=0·39); RTOG grade 2 or worse gastrointestinal toxicity was seen in 11 (3%) of 382 participants in the CRT group versus six (2%) of 384 participants in the SBRT group (absolute difference -1·3% [95% CI -3·9 to 1·1]; p=0·32). No serious adverse events (defined as RTOG grade 4 or worse) or treatment-related deaths were reported within the analysis timeframe. INTERPRETATION: In the PACE-B trial, 2-year RTOG toxicity rates were similar for five fraction SBRT and conventional schedules of radiotherapy. Prostate SBRT was found to be safe and associated with low rates of side-effects. Biochemical outcomes are awaited. FUNDING: Accuray.

VinCaP: a phase II trial of vinflunine in locally advanced and metastatic squamous carcinoma of the penis.

BACKGROUND: We investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit. METHODS: Twenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming-A'Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m2, given every 21 days. Primary endpoint was clinical benefit rate (CBR: objective responses plus stable disease) assessed after 4 cycles. Seven or more objective responses or disease stabilisations observed in 22 evaluable participants would exclude a CBR of <15%, with a true CBR of >40% being probable. RESULTS: Twenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression. CONCLUSIONS: Pre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease. TRIAL REGISTRATION: NCT02057913.

Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.

BACKGROUND: Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer. METHODS: PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0-2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1-2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT01584258. PACE-B recruitment is complete and follow-up is ongoing. FINDINGS: Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference -1·9 percentage points, 95% CI -6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference -4·2 percentage points, 95% CI -10·0 to 1·7; p=0·16). No treatment-related deaths occurred. INTERPRETATION: Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity. FUNDING: Accuray and National Institute of Health Research.

BOXIT-A Randomised Phase III Placebo-controlled Trial Evaluating the Addition of Celecoxib to Standard Treatment of Transitional Cell Carcinoma of the Bladder (CRUK/07/004).

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) has a significant risk of recurrence despite adjuvant intravesical therapy. OBJECTIVE: To determine whether celecoxib, a cyclo-oxygenase 2 inhibitor, reduces the risk of recurrence in NMIBC patients receiving standard treatment. DESIGN, SETTING, AND PARTICIPANTS: BOXIT (CRUK/07/004, ISRCTN84681538) is a double-blinded, phase III, randomised controlled trial. Patients aged ≥18 yr with intermediate- or high-risk NMIBC were accrued across 51 UK centres between 1 November 2007 and 23 July 2012. INTERVENTION: Patients were randomised (1:1) to celecoxib 200mg twice daily or placebo for 2 yr. Patients with intermediate-risk NMIBC were recommended to receive six weekly mitomycin C instillations; high-risk NMIBC cases received six weekly bacillus Calmette-Guérin and maintenance therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was time to disease recurrence. Analysis was by intention to treat. RESULTS AND LIMITATIONS: A total of 472 patients were randomised (236:236). With median follow-up of 44 mo (interquartile range: 36-57), 3-yr recurrence-free rate (95% confidence interval) was as follows: celecoxib 68% (61-74%) versus placebo 64% (57-70%; hazard ratio [HR] 0.82 [0.60-1.12], p=0.2). There was no difference in high-risk (HR 0.77 [0.52-1.15], p=0.2) or intermediate-risk (HR 0.90 [0.55-1.48], p=0.7) NMIBC. Subgroup analysis suggested that time to recurrence was longer in pT1 NMIBC patients treated with celecoxib compared with those receiving placebo (HR 0.53 [0.30-0.94], interaction test p=0.04). The 3-yr progression rates in high-risk patients were low: 10% (6.5-17%) and 9.7% (6.0-15%) in celecoxib and placebo arms, respectively. Incidence of serious cardiovascular events was higher in celecoxib (5.2%) than in placebo (1.7%) group (difference +3.4% [-0.3% to 7.2%], p=0.07). CONCLUSIONS: BOXIT did not show that celecoxib reduces the risk of recurrence in intermediate- or high-risk NMIBC, although celecoxib was associated with delayed time to recurrence in pT1 NMIBC patients. The increased risk of cardiovascular events does not support the use of celecoxib. PATIENT SUMMARY: Celecoxib was not shown to reduce the risk of recurrence in intermediate- or high-risk non-muscle-invasive bladder cancer (NMIBC), although celecoxib was associated with delayed time to recurrence in pT1 NMIBC patients. The increased risk of cardiovascular events does not support the use of celecoxib.

Implementation of an Interdisciplinary Communication Workgroup on an Acute Psychiatric Unit.

Communication among Interdisciplinary Healthcare Teams is an essential component of providing optimal patient care. Staff members at one U. S. Department of Veterans Affairs on an Acute Psychiatric Unit identified fragmented communication on the unit and expressed interest in forming an interdisciplinary communication workgroup. This quality improvement (QI) project was designed to enhance communication among the Interdisciplinary Healthcare Team on the Acute Psychiatric Unit. A workgroup was formed and met four times at 1-hour intervals. A pre/post-test was used to determine the initial effectiveness of the intervention. The results of the intervention suggested increased communication among the Interdisciplinary Healthcare Team as an upward trend of the mean scores was noted.

Effect of volumetric water content and clover (Trifolium incarnatum) on the survival of Escherichia coli O157:H7 in a soil matrix.

Studies aimed at understanding Escherichia coli O157:H7 soil survival dynamics are paramount due to their inevitable introduction into the organic vegetable production systems via animal manure-based fertilizer. Therefore, a greenhouse study was conducted to determine the survival of E. coli O157:H7 in highly controlled soil matrices subjected to two variable environmental stressors: (1) soil volumetric water content (25 or 45 % VWC), and (2) the growth of clover (planted or unplanted). During the 7-week study, molecular-based qPCR analyses revealed that E. coli O157:H7 survival was significantly lower in soils maintained at either near water-holding capacity (45 % VWC) or under clover growth. The significant reduction under clover growth was only observed when E. coli populations were determined relative to all bacteria, indicating the need to further study the competition between E. coli O157:H7 and the total bacterial community in organic soils. Given the significant effect of clover on E. coli O157:H7 survival under different moisture conditions in this greenhouse-based study, this work highlights the antimicrobial potential of clover exudates in arable soils, and future work should concentrate on their specific mechanisms of inhibition; ultimately leading to the development of crop rotations/production systems to improve pre-harvest food safety and security in minimally processed, ready-to-eat and organic production systems.

Auditory short-term memory capacity correlates with gray matter density in the left posterior STS in cognitively normal and dyslexic adults.

A central feature of auditory STM is its item-limited processing capacity. We investigated whether auditory STM capacity correlated with regional gray and white matter in the structural MRI images from 74 healthy adults, 40 of whom had a prior diagnosis of developmental dyslexia whereas 34 had no history of any cognitive impairment. Using whole-brain statistics, we identified a region in the left posterior STS where gray matter density was positively correlated with forward digit span, backward digit span, and performance on a "spoonerisms" task that required both auditory STM and phoneme manipulation. Across tasks and participant groups, the correlation was highly significant even when variance related to reading and auditory nonword repetition was factored out. Although the dyslexics had poorer phonological skills, the effect of auditory STM capacity in the left STS was the same as in the cognitively normal group. We also illustrate that the anatomical location of this effect is in proximity to a lesion site recently associated with reduced auditory STM capacity in patients with stroke damage. This result, therefore, indicates that gray matter density in the posterior STS predicts auditory STM capacity in the healthy and damaged brain. In conclusion, we suggest that our present findings are consistent with the view that there is an overlap between the mechanisms that support language processing and auditory STM.

Cognitive neuroscience: distinguishing self from other.

Neurons in medial frontal cortex have been found to distinguish between whether an animal or its partner is responding on a turn-taking task, but are they really the basis of a social learning mechanism?

The social brain in adolescence: evidence from functional magnetic resonance imaging and behavioural studies.

Social cognition is the collection of cognitive processes required to understand and interact with others. The term 'social brain' refers to the network of brain regions that underlies these processes. Recent evidence suggests that a number of social cognitive functions continue to develop during adolescence, resulting in age differences in tasks that assess cognitive domains including face processing, mental state inference and responding to peer influence and social evaluation. Concurrently, functional and structural magnetic resonance imaging (MRI) studies show differences between adolescent and adult groups within parts of the social brain. Understanding the relationship between these neural and behavioural observations is a challenge. This review discusses current research findings on adolescent social cognitive development and its functional MRI correlates, then integrates and interprets these findings in the context of hypothesised developmental neurocognitive and neurophysiological mechanisms.

Pubertal development of the understanding of social emotions: Implications for education.

Recent developmental cognitive neuroscience research has supported the notion that puberty and adolescence are periods of profound socio-emotional development. The current study was designed to investigate whether the onset of puberty marks an increase in the awareness of complex, or "mixed," emotions. Eighty-three female participants (aged 9-16 years) were divided into three groups according to a self-report measure of puberty stage (early-, mid- and post-puberty). Participants were presented with emotional scenarios, and used four linear scales to rate their emotional response to each scenario. Scenarios were designed to evoke social emotions (embarrassment or guilt) or basic emotions (anger or fear), where social emotions are defined as those which require the representation of others' mental states. We measured the relative complexity or "mixedness" of emotional responses, that is, the degree to which participants reported feeling more than one emotion for a given scenario. We found that mixed emotion reporting increased between early- and post-puberty for social emotion scenarios, and showed no relationship with age, whereas there was no change in mixed emotion reporting for basic emotion scenarios across age or puberty groups. This suggests that the awareness of mixed emotions develops during the course of puberty, and that this development is specific to social emotions. Results are discussed in the context of brain development across puberty and adolescence, with speculation regarding the potential implications for education.

The patient lock model©: a continuum of care.

Nursing as a profession has the responsibility to society to protect and promote the health of individuals and communities. The intent of this conceptual model is to center the patient in his or her environment while allowing qualified, expert health professionals to provide timely, effective, cost-efficient care within their levels of competence and expertise. Significant shortages of registered nurses and other health professionals delay timely provision of quality care and affect the effectiveness of care. Care management issues are due to the complexity of individual patient's health care needs, limited access to providers, inability to afford treatment, and delay in seeking care. These challenges to the system slow efficiency in the provision of care across all settings. In presenting this conceptual model, there will be a review of nursing and the internal and external forces that affect the profession. This is an initial development phase of the model: The Patient Lock Model.

Adolescents' heightened risk-seeking in a probabilistic gambling task.

This study investigated adolescent males' decision-making under risk, and the emotional response to decision outcomes, using a probabilistic gambling task designed to evoke counterfactually mediated emotions (relief and regret). Participants were 20 adolescents (aged 9-11), 26 young adolescents (aged 12-15), 20 mid-adolescents (aged 15-18) and 17 adults (aged 25-35). All were male. The ability to maximize expected value improved with age. However, there was an inverted U-shaped developmental pattern for risk-seeking. The age at which risk-taking was highest was 14.38 years. Although emotion ratings overall did not differ across age, there was an increase between childhood and young adolescence in the strength of counterfactually mediated emotions (relief and regret) reported after receiving feedback about the gamble outcome. We suggest that continuing development of the emotional response to outcomes may be a factor contributing to adolescents' risky behaviour.

Feeling, caring, knowing: different types of empathy deficit in boys with psychopathic tendencies and autism spectrum disorder.

BACKGROUND: Empathy dysfunction is one of the hallmarks of psychopathy, but it is also sometimes thought to characterise autism spectrum disorders (ASD). Individuals with either condition can appear uncaring towards others. This study set out to compare and contrast directly boys with psychopathic tendencies and boys with ASD on tasks assessing aspects of affective empathy and cognitive perspective taking. The main aim of the study was to assess whether a distinct profile of empathy deficits would emerge for boys with psychopathic tendencies and ASD, and whether empathy deficits would be associated with conduct problems in general, rather than psychopathic tendencies or ASD specifically. METHODS: Four groups of boys aged between 9 and 16 years (N = 96) were compared: 1) psychopathic tendencies, 2) ASD, 3) conduct problems and 4) comparison. Tasks were included to probe attribution of emotions to self, empathy for victims of aggression and cognitive perspective-taking ability. RESULTS: Boys with psychopathic tendencies had a profile consistent with dysfunctional affective empathy. They reported experiencing less fear and less empathy for victims of aggression than comparison boys. Their cognitive perspective-taking abilities were not statistically significantly different from those of comparison boys. In contrast, boys with ASD had difficulties with tasks requiring cognitive perspective taking, but reported emotional experiences and victim empathy that were in line with comparison boys. Boys with conduct problems did not differ from comparison boys, suggesting that the affective empathy deficit seen in boys with psychopathic tendencies was specific to that group, rather than common to all boys with conduct problems. CONCLUSIONS: Although both groups can appear uncaring, our findings suggest that the affective/information processing correlates of psychopathic tendencies and ASD are quite different. Psychopathic tendencies are associated with difficulties in resonating with other people's distress, whereas ASD is characterised by difficulties in knowing what other people think.

The role of puberty in the developing adolescent brain.

Adolescence refers to the period of physical and psychological development between childhood and adulthood. The beginning of adolescence is loosely anchored to the onset of puberty, which brings dramatic alterations in hormone levels and a number of consequent physical changes. Puberty onset is also associated with profound changes in drives, motivations, psychology, and social life; these changes continue throughout adolescence. There is an increasing number of neuroimaging studies looking at the development of the brain, both structurally and functionally, during adolescence. Almost all of these studies have defined development by chronological age, which shows a strong-but not unitary-correlation with pubertal stage. Very few neuroimaging studies have associated brain development with pubertal stage, and yet there is tentative evidence to suggest that puberty might play an important role in some aspects of brain and cognitive development. In this paper we describe this research, and we suggest that, in the future, developmental neuroimaging studies of adolescence should consider the role of puberty.

The development of adolescent social cognition.

Adolescence has long been considered a turbulent time; beginning with large changes in hormonal levels and consequent bodily changes, as well as changes in behavior. Recently, neuroscience studies have contributed to this picture of turbulence. We now know that the brain undergoes profound transformation during the teenage years. This paper focuses on how the social brain--the network of brain regions involved in understanding other people and self-awareness--develops during adolescence.

Functional connectivity during a social emotion task in adolescents and in adults.

In this fMRI study we investigated functional connectivity between components of the mentalising system during a social emotion task, using psychophysiological interaction (PPI) analysis. Ten adults (22-32 years) and 18 adolescents (11-18 years) were scanned while thinking about scenarios in which a social or a basic emotion would be experienced. Unlike basic emotions (such as disgust and fear), social emotions (such as embarrassment and guilt) require the representation of another's mental states. In both adults and adolescents, an anterior rostral region of medial prefrontal cortex (arMPFC) involved in mentalising showed greater connectivity with the posterior superior temporal sulcus (pSTS) bordering on the temporo-parietal junction (TPJ) and with anterior temporal cortex (ATC) during social than during basic emotion. This result provides novel evidence that components of the mentalising system interact functionally during a social emotion task. Furthermore, functional connectivity differed between adolescence and adulthood. The adolescent group showed stronger connectivity between arMPFC and pSTS/TPJ during social relative to basic emotion than did the adult group, suggestive of developmental changes in functional integration within the mentalising system.

Development during adolescence of the neural processing of social emotion.

In this fMRI study, we investigated the development between adolescence and adulthood of the neural processing of social emotions. Unlike basic emotions (such as disgust and fear), social emotions (such as guilt and embarrassment) require the representation of another's mental states. Nineteen adolescents (10-18 years) and 10 adults (22-32 years) were scanned while thinking about scenarios featuring either social or basic emotions. In both age groups, the anterior rostral medial prefrontal cortex (MPFC) was activated during social versus basic emotion. However, adolescents activated a lateral part of the MPFC for social versus basic emotions, whereas adults did not. Relative to adolescents, adults showed higher activity in the left temporal pole for social versus basic emotions. These results show that, although the MPFC is activated during social emotion in both adults and adolescents, adolescents recruit anterior (MPFC) regions more than do adults, and adults recruit posterior (temporal) regions more than do adolescents.

Development of the self-concept during adolescence.

Adolescence is a period of life in which the sense of 'self' changes profoundly. Here, we review recent behavioural and neuroimaging studies on adolescent development of the self-concept. These studies have shown that adolescence is an important developmental period for the self and its supporting neural structures. Recent neuroimaging research has demonstrated that activity in brain regions associated with self-processing, including the medial prefrontal cortex, changes between early adolescence and adulthood. These studies indicate that neurocognitive development might contribute to behavioural phenomena characteristic of adolescence, such as heightened self-consciousness and susceptibility to peer influence. We attempt to integrate this recent neurocognitive research on adolescence with findings from developmental and social psychology.

Genome-wide genetic association of complex traits in heterogeneous stock mice.

Difficulties in fine-mapping quantitative trait loci (QTLs) are a major impediment to progress in the molecular dissection of complex traits in mice. Here we show that genome-wide high-resolution mapping of multiple phenotypes can be achieved using a stock of genetically heterogeneous mice. We developed a conservative and robust bootstrap analysis to map 843 QTLs with an average 95% confidence interval of 2.8 Mb. The QTLs contribute to variation in 97 traits, including models of human disease (asthma, type 2 diabetes mellitus, obesity and anxiety) as well as immunological, biochemical and hematological phenotypes. The genetic architecture of almost all phenotypes was complex, with many loci each contributing a small proportion to the total variance. Our data set, freely available at http://gscan.well.ox.ac.uk, provides an entry point to the functional characterization of genes involved in many complex traits.

A protocol for high-throughput phenotyping, suitable for quantitative trait analysis in mice.

Whole-genome genetic association studies in outbred mouse populations represent a novel approach to identifying the molecular basis of naturally occurring genetic variants, the major source of quantitative variation between inbred strains of mice. Measuring multiple phenotypes in parallel on each mouse would make the approach cost effective, but protocols for phenotyping on a large enough scale have not been developed. In this article we describe the development and deployment of a protocol to collect measures on three models of human disease (anxiety, type II diabetes, and asthma) as well as measures of mouse blood biochemistry, immunology, and hematology. We report that the protocol delivers highly significant differences among the eight inbred strains (A/J, AKR/J, BALBc/J, CBA/J, C3H/HeJ, C57BL/6 J, DBA/2 J, and LP/J), the progenitors of a genetically heterogeneous stock (HS) of mice. We report the successful collection of multiple phenotypes from 2000 outbred HS animals. The phenotypes measured in the protocol form the basis of a large-scale investigation into the genetic basis of complex traits in mice designed to examine interactions between genes and between genes and environment, as well as the main effects of genetic variants on phenotypes.