Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Patients' preferences for adjuvant sorafenib after resection of renal cell carcinoma in the SORCE trial: what makes it worthwhile?

Background: We sought to determine the survival benefits that patients judged sufficient to warrant adjuvant therapy with sorafenib for 1 year, or for 3 years after resection of renal cell carcinoma in the SORCE trial. Methods: SORCE participants from all sites in Australia and New Zealand, and selected sites in the UK, completed a validated preferences questionnaire at months 0, 3, 15, and 42 to elicit the minimum survival benefits they judged sufficient to warrant adjuvant sorafenib for 1 year (versus observation), or for 3 years (versus 1 year). The questionnaires used reference survival times of 5 and 15 years; and reference survival rates at 5 years of 65% and 85%. Results: The 233 participants had a median age of 57 years (range 29-78) and 71% were male. For 1 year of sorafenib versus no adjuvant therapy, the median benefits in survival times judged sufficient to warrant treatment were an extra 9 months beyond 5 years and an extra 1 year beyond 15 years; the median benefit in survival rates were an extra 4% beyond 65% and an extra 3% beyond 85% at 5 years. For 3 years of sorafenib versus 1 year of sorafenib, the median benefit in survival time judged sufficient to warrant extended treatment was an extra 1 year beyond both 5 and 15 years. Participants randomly allocated to treatment with sorafenib judged larger benefits necessary than those allocated to placebo. Participants' preferences were not associated with their baseline characteristics or the interval from randomisation. Conclusion: Most participants judged an extra year of survival necessary to warrant 1 year of adjuvant sorafenib worthwhile, and an additional year of survival to warrant extending the duration of sorafenib from 1 to 3 years. Patients' preferences are important in shared decision making. SORCE trial clinical trials number: NCT00492258.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Silicon 1s near edge X-ray absorption fine structure spectroscopy of functionalized silicon nanocrystals.

Silicon 1s Near Edge X-ray Absorption Fine Structure (NEXAFS) spectra of silicon nanocrystals have been examined as a function of nanocrystal size (3-100 nm), varying surface functionalization (hydrogen or 1-pentyl termination), or embedded in oxide. The NEXAFS spectra are characterized as a function of nanocrystal size and surface functionalization. Clear spectroscopic evidence for long range order is observed silicon nanocrystals that are 5-8 nm in diameter or larger. Energy shifts in the silicon 1s NEXAFS spectra of covalently functionalized silicon nanocrystals with changing size are attributed to surface chemical shifts and not to quantum confinement effects.

Description of an efficacious behavioral peer-driven intervention to reduce racial/ethnic disparities in AIDS clinical trials.

AIDS clinical trials (ACTs) are critical to the development of new treatments for HIV infection. However, people of color living with HIV/AIDS are involved in ACTs at disproportionally low rates, with African-Americans experiencing the greatest under-representation. In this article, we describe the core elements and key characteristics of a highly efficacious multi-component peer-driven intervention (PDI) designed to increase rates of screening for and enrollment into ACTs among African-American and Latino/Hispanic individuals, by addressing the main complex, multi-level barriers they experience to ACTs. We discuss the process of developing the intervention, the theoretical models guiding its delivery format and content, and provide an overview of the intervention's components. We then use brief case studies to illustrate a number of key issues that may arise during intervention implementation. Finally, we describe lessons learned and provide recommendations for the PDI's uptake in clinical and clinical trials settings.

2†Pathways to detection of non-infectious childhood uveitis in the UK: findings from the UNICORN cohort study.

INTRODUCTION: Prompt detection of childhood uveitis is key to minimising negative impact. From an internationally unique inception cohort, we report pathways to disease detection.UNICORNS is a national childhood non-infectious uveitis study with longitudinal collection of a standardised clinical dataset and patient reported outcomes. Descriptive analysis of baseline characteristics are reported.Amongst 150 recruited children (51% female, 31% non-white ethnicity) age at detection ranged from 2-18yrs (median 10). In 69%, uveitis was diagnosed following onset of symptoms: time from first symptoms to uveitis detection ranged from 0-739days (median 7days), with longer time to detection for those presenting initially to their general practitioner. Non symptomatic children were detected through JIA/other disease surveillance (16%), routine optometry review (5%) or child visual health screening (1%). Commonest underlying diagnoses at uveitis detection were JIA (17%), TINU (9%, higher than pre-pandemic reported UK disease frequency) and sarcoid (1%). 60% had no known systemic disease at uveitis detection. At disease detection, in at least one eye: 34% had structural complications (associated with greater time to detection - 17 days versus 4 days for uncomplicated presentation).The larger relative proportions of children with non-JIA uveitis reported here increase the importance of improving awareness of childhood uveitis amongst the wider clinical communities. There is scope for improvement of pathways to detection. Forthcoming analysis on the full cohort (251 recruited to date across 33 hospitals and 4 nations) will provide nationally representative data on management and the determinants of visual and broader developmental/well-being outcomes.

Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma.

BACKGROUND: Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFß and VEGF receptors that is licensed for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Current evidence-based post-nephrectomy management of individuals with localized RCC consists of surveillance-based follow up. The SORCE trial is designed to investigate whether treatment with adjuvant sorafenib can reduce recurrence rates in this cohort. CASE PRESENTATION: Here we report an idiosyncratic reaction to sorafenib resulting in fatal hepatotoxicity and associated renal failure in a 62 year-old man treated with sorafenib within the SORCE trial. CONCLUSION: This is the first reported case of sorafenib exposure associated fatal toxicity in the adjuvant setting and highlights the unpredictable adverse effects of novel adjuvant therapies.

First case report of pre-mortem biopsy-proven kidney involvement by necrobiotic xanthogranuloma with monoclonal gammopathy.

Necrobiotic xanthogranuloma (NXG) is a rare non-Langerhans cell histiocytosis with characteristic cutaneous features and rare visceral involvement. More than 80% of individuals with this disease have a detectable paraprotein but the precise pathogenesis remains obscure. A 68-year-old man with known cutaneous necrobiotic xanthogranuloma presented with acute kidney injury and imaging suggestive of bilateral perinephric infiltration. Renal biopsy showed a prominent histiocytic infiltration of renal capsule and cortex with necrobiosis and characteristic 'Touton-type' giant cells suggestive of necrobiotic xanthogranuloma involvement. Kidney function returned to normal and cutaneous lesions improved with a combination of corticosteroid, chlorambucil and rituximab. This case represents only the second reported incidence of kidney involvement by necrobiotic xanthogranuloma and the first with acute kidney injury and pre-mortem histopathology. This report adds to a small body of literature on the diagnosis and management of visceral involvement by this rare disease.

Differential Effects of Fingolimod and Natalizumab on B Cell Repertoires in Multiple Sclerosis Patients.

Natalizumab and fingolimod are effective multiple sclerosis (MS) therapies that disrupt lymphocyte migration but have differential effects on B cell maturation and trafficking. We investigated their effects on peripheral blood (PB) and cerebrospinal fluid (CSF) B cell repertoires using next-generation deep sequencing. Paired CSF and PB B cell subsets (naïve, CD27+ memory, and CD27-IgD- double-negative B cells and plasmablasts) were collected by applying flow cytometry at baseline and after 6 months of treatment and their respective heavy-chain variable region repertoires assessed by Illumina MiSeq. Treatment with fingolimod contracted, whereas natalizumab expanded circulating PB B cells. CSF B cell numbers remained stable following fingolimod treatment but decreased with natalizumab therapy. Clonal overlap between CSF and PB B cells was reduced with natalizumab treatment but remained stable with fingolimod therapy. Lineage analyses of pre- and posttreatment CSF B cell repertoires revealed large, clonally expanded B cell clusters in natalizumab-treated MS patients but no intrathecal clonal expansion following fingolimod therapy. Our findings suggest that natalizumab diminishes the exchange of peripheral and intrathecal B cells without impacting intrathecal clonal expansion. In contrast, fingolimod treatment fails to alter blood-brain barrier B cell exchange but diminishes intrathecal clonal expansion. Sphingosine-1 phosphate receptor inhibition may alter intrathecal B cell biology in MS.

Psychiatry as a specialization: influential factors and gender differences among medical students in a low- to middle-income country.

OBJECTIVES: To assess the perception of Ghanaian medical students about factors influencing their career interest in psychiatry and to explore gender differences in these perceptions. METHODS: This is a cross-sectional quantitative survey of 5th and 6th year medical students in four public medical schools in Ghana. Data were analyzed with descriptive and inferential statistics using SPSS version 20. RESULTS: Responses were obtained from 545 medical students (response rate of 52%). Significantly, more male medical students expressed that stigma is an important consideration for them to choose or not to choose a career in psychiatry compared to their female counterparts (42.7% v. 29.7%, respectively). Over two-thirds of the medical students perceived that psychiatrists were at risk of being attacked by their patients, with just a little over a third expressing that risk was an important consideration for them to choose a career in psychiatry. There were no gender differences regarding perceptions about risk. Around 3 to 4 out of 10 medical students will consider careers in psychiatry if offered various incentives with no gender differences in responses provided. CONCLUSION: Our study presents important and novel findings in the Ghanaian context, which can assist health policy planners and medical training institutions in Ghana to formulate policies and programs that will increase the number of psychiatry residents and thereby increase the psychiatrist-to-patient ratio in Ghana.

Primary megakaryocytes reveal a role for transcription factor NF-E2 in integrin alpha IIb beta 3 signaling.

Platelet integrin alphaIIbbeta3 responds to intracellular signals by binding fibrinogen and triggering cytoskeletal reorganization, but the mechanisms of alphaIIbbeta3 signaling remain poorly understood. To better understand this process, we established conditions to study alphaIIbbeta3 signaling in primary murine megakaryocytes. Unlike platelets, these platelet precursors are amenable to genetic manipulation. Cytokine-stimulated bone marrow cultures produced three arbitrary populations of alphaIIbbeta3-expressing cells with increasing size and DNA ploidy: small progenitors, intermediate-size young megakaryocytes, and large mature megakaryocytes. A majority of the large megakaryocytes bound fibrinogen in response to agonists, while almost none of the smaller cells did. Fibrinogen binding to large megakaryocytes was inhibited by Sindbis virus-mediated expression of isolated beta3 integrin cytoplasmic tails. Strikingly, large megakaryocytes from mice deficient in the transcription factor NF-E2 failed to bind fibrinogen in response to agonists, despite normal surface expression of alphaIIbbeta3. Furthermore, while megakaryocytes from wild-type mice spread on immobilized fibrinogen and exhibited filopodia, lamellipodia and Rho-dependent focal adhesions and stress fibers, NF-E2-deficient megakaryocytes adhered poorly. These studies establish that agonist-induced activation of alphaIIbbeta3 is controlled by NF-E2-regulated signaling pathways that mature late in megakaryocyte development and converge at the beta3 cytoplasmic tail. Megakaryocytes provide a physiologically relevant and tractable system for analysis of bidirectional alphaIIbbeta3 signaling.

Dependence of alignment direction on magnitude of strain in esophageal smooth muscle cells.

The response of cells in vitro to mechanical forces has been the subject of much research using devices to exert controlled mechanical stimulation on cultured cells or isolated tissue. In this study, esophageal smooth muscle cells were seeded on flexible polyurethane membranes to form a confluent cell layer. The cells were then subjected to uniform cyclic stretch of varying magnitudes at a frequency of approximately five cycles per minute in a custom made mechatronic bioreactor, providing similar strains experienced in the in vivo mechanical environment of the esophagus. The results show that the orientation response is dependent on the magnitude of cyclic stretch applied. Smooth muscle cells showed parallel alignment to the force direction at low cyclic strains (2%) compared to the hill-valley morphology of static controls. At higher strains (5% and 10% magnitude), the cells exhibited a consistent alignment perpendicular to the strain. To our knowledge, this is the first time that the alignment direction's dependence on strain magnitude has been demonstrated. MTS analysis indicated that cell metabolism was reduced when mechanical strain was applied, and proliferation was inhibited by mechanical strain. Protein expression indicates a decrease in smooth muscle alpha-actin, indicative of changes in cell phenotype, an increase in vimentin, which is associated with increased cell motility, and an increase in desmin, indicating differentiation in stimulated cells.

Vesicular and synaptoplasmic synthesis of acetylcholine.

The synthesis and distribution of acetylcholine has been studied in the isolated synaptosome. Binding or contamination of [(14)C]acetylcholine in the synaptic vesicle fraction represents 1.5 percent of the total amount found in the synaptoplasm (synaptosomal cytoplasm). However, when the [(14)C]acetylcholine is derived solely by synthesis from labeled choline, then the labeled acetylcholine in the synaptic vesicle is 15 percent of the amount of acetylcholine synthesized in the synaptoplasm. The results suggest that the [(14)C]acetylcholine found in the vesicle fraction of synaptosomes incubated with labeled choline is due to vesicular synthesis.

Exploring the use of APTS as a fluorescent reporter dye for continuous glucose sensing.

The anionic fluorescent dye, aminopyrene trisulfonic acid (APTS), was synthesized and used in a solution-based two-component glucose-sensing system comprising the dye and a boronic acid-appended viologen. The fluorescence of the dye was quenched in the presence of the viologen and the fluorescence restored upon glucose addition. An important feature of this fluorophore is that it can be covalently bonded to a polymer through the amine group without a significant effect on optical properties. Two APTS derivatives, functionalized with polymerizable groups, were synthesized and immobilized in hydroxyethyl methacrylate (HEMA)-based hydrogels. The latter were used to continuously monitor glucose. The fluorescence signal modulation, signal stability, reversibility, reproducibility, and pH sensitivity of the hydrogels were evaluated. The APTS dyes described herein are insensitive to pH changes within the physiological range, both in solution and when immobilized in a hydrogel. When APTS is used in conjunction with boronic acid-appended viologens to sense glucose, the system displays some pH sensitivity because of the presence of the boronic acid.

Protocol: Using N-of-1 tests to identify responders to melatonin for sleep disturbance in Parkinson's disease.

BACKGROUND: 40% of Parkinson's Disease (PD) sufferers experience insomnia, impacting health and quality of life for patients and family members, especially carers. There is little evidence that current treatments are effective. OBJECTIVES: To determine the effectiveness of melatonin in reducing insomnia in 44 individuals with PD using N-of-1 trials. To aggregate group data to arrive at population estimates of effectiveness (measured by improvements in PDSS-2) and safety (measured by adverse events) of melatonin in improving insomnia in PD. To assess the feasibility of offering N-of-1 trials for insomnia in PD. METHODOLOGY: Participants will receive either immediate-release melatonin or placebo in random order in 3 paired two-week treatment periods (12 weeks total). Based on their response in a two-week run-in period on 3 mg daily, they will trial either 3 mg or 6 mg. Patients will keep daily sleep diaries and wear a MotionWatch throughout. After the trial patients will discuss their individual report with their doctor, which provides direct feedback about effectiveness and safety of melatonin for them. STATISTICAL METHODS: We will analyse N-of-1 tests 1) individually: effects of melatonin on PDSS-2 and safety will be reported; and 2) aggregated across individual N-of-1 studies, combined using a Bayesian multilevel random effects model, which will account for repeated measures on individuals over time, and will return posterior estimates of overall treatment effect, and effect in each individual. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12617001103358.

The phospholipase A inhibitor, aristolochic acid, disrupts cortical microtubule arrays and root growth in Arabidopsis.

The role of phospholipase A(2) in Arabidopsis root growth and microtubule organisation was investigated using a specific inhibitor, aristolochic acid. At 0.5-1.5 microm concentrations, this inhibitor reduced root elongation and caused radial swelling of the root tip. The normally transverse cortical microtubules in root tip cells became progressively more disorganised with increasing concentrations of the inhibitor. Microtubule disorganisation also occurred in leaf epidermal cells of Allium porrum. We propose that phospholipase A(2) is involved in microtubule organisation and anisotropic growth in a manner similar to that reported previously for phospholipase D, thus broadening the significance of phospholipid signalling in microtubule organisation in plants.

Recent Advances in the Etiology and Treatment of Burning Mouth Syndrome.

Burning mouth syndrome (BMS) is a debilitating condition that has a striking female predilection. Although the oral mucosa is normal in appearance, patients with BMS experience oral burning that most commonly localizes to the lips and tongue. BMS is a diagnosis of exclusion, and all underlying pathoses associated with allodynia must be ruled out prior to rendering the diagnosis. The etiopathogenesis of BMS remains poorly understood, and thus patient management is challenging. Data indicate that oral and systemic factors both contribute to the development and persistence of the condition. Of particular interest, emerging work identifies structural and functional deficits within the nervous system that may lead to a more mechanistic understanding of BMS pathology. In addition, several novel findings suggest that circadian rhythm dysfunction may be a previously unappreciated yet clinically significant driver of disease. Circadian rhythm controls pain perception, mood, and sleep and plays a key role in the regulation of the hypothalamic-pituitary-adrenal axis. Since these are altered in patients with BMS, this may be reflective of underlying circadian dysfunction. While evidence-based treatment strategies for BMS are lacking, current treatment approaches consist of local and systemic medications, such as clonazepam, alpha lipoic acid, capsaicin, low-level laser therapy, gabapentin, and amitriptylin. In addition, the use of cognitive behavioral therapy is reported. This review provides an overview of the recent literature related to the etiology and treatment of BMS and identifies current challenges facing researchers and clinicians alike.

Exploring electrophysiological correlates of social cognition in subclinical schizotypy.

Impairments in social cognition and associated abnormalities in brain function are well documented in psychotic disorders. They may represent neurodevelopmental vulnerabilities and may therefore be present in less severe or even subclinical conditions of the schizophrenia spectrum, such as schizotypy. Schizotypy has features highly suggestive of social cognitive impairments, but little is known about possible related abnormalities of brain function. This exploratory pilot study examines electrophysiological event-related potentials (ERPs) implicated in schizophrenia, in 23 undergraduates with a range of subclinical schizotypal characteristics. ERPs were recorded in response to emotional face stimuli in an experimental paradigm designed to assess very early stages of social stimulus processing. Three ERPs were assessed, P100, N170 and P300. P100 and P300 were found to be related to multiple schizotypal features, but N170 was not. The results support occurrence of social cognitive impairments linked to abnormal brain function across the schizophrenia spectrum. Copyright © 2018 John Wiley & Sons, Ltd.

Use of community genetic screening to prevent HFE-associated hereditary haemochromatosis.

HFE-associated hereditary haemochromatosis is a recessive, iron-overload disorder that affects about one in 200 north Europeans and that can be easily prevented. However, genetic screening for this disease is controversial, and so we assessed whether such screening was suitable for communities. Cheek-brush screening for the Cys282Tyr HFE mutation was offered to individuals in the workplace. Outcomes were assessed by questionnaires before and after testing. 11,307 individuals were screened. We recorded no increase in anxiety in individuals who were homozygous for the Cys282Tyr mutation or non-homozygous. Self-reported tiredness before testing was significantly higher in homozygous participants than in non-homozygous participants (chi2 test, p=0.029). Of the 47 homozygous individuals identified, 46 have taken steps to treat or prevent iron accumulation. Population genetic screening for HFE-associated hereditary haemochromatosis can be practicable and acceptable.