Childhood experiences and sleep problems: A cross-sectional study on the indirect relationship mediated by stress, resilience and anxiety.

BACKGROUND: Childhood experiences either adverse (ACE) or benevolent (BCE) can indirectly impact sleep quality in adult life, which in turn are modulated by the interplay of a variety of factors such as depression, anxiety, resilience and mental health problems. METHODS: A cross-sectional observational study was conducted across the UK and the Middle Eastern countries during the COVID-pandemic on 405 participants. An online survey used a combination of questionnaires to assess ACE and BCEs. The following tools were then used to assess the contribution of resilience, stress, depression and anxiety respectively: Brief Resilience Scale (BRS), Perceived Stress Scale (PSS-10), Patient Health Questionnaire-2 (PHQ-2) and General Anxiety Disorder-2 (GAD-2) scale on childhood experiences. The extent of sleep disturbances experienced over a period of seven days was assessed using the PROMIS Sleep Disturbance Short-Form Tool. A serial-parallel mediation model was used to evaluate the impact of the mediators on childhood experiences and sleep quality. RESULTS: Over 50% of the cohort were from Middle Eastern countries. Four or more BCEs were experienced by 94.3% of the cohort. In contrast, 67.9% of participants experienced at least one ACE before the age of 18 years, with moderate levels of stress, mild depression and anxiety were reported in 3.7%, 13% and 20% of participants respectively. Whilst 25.4% of participants reported having had four or more ACEs, with higher reports in the middle easter countries (32%). ACEs were found to correlate with sleep disturbance whilst BCEs showed an inverse correlation. The relationship between ACE and sleep disturbances was shown to be mediated by stress, and anxiety, but not by resilience or depression. Resilience and stress, and resilience and anxiety serially mediated the interaction between ACE and sleep disturbance. With regards to BCE, an inverse association with sleep disturbance was recorded with similar mediators of stress and anxiety observed. CONCLUSION: This study confirms the negative effects of ACEs, and the positive effects of BCEs on sleep in adulthood which are both mediated predominantly by psychological resilience, anxiety and stress. Strategies aimed at improving psychological resilience as well as addressing stress and anxiety may help improve sleep quality.

Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH).

Malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHKα). Due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [18F]fluoromethyl-[1,2-2H4]choline ([18F]D4-FCH). [18F]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a 1H/2D isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [18F]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [18F]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [18F]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. Treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12-16 weeks despite predominantly stable radiological appearances. The sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival.

Cognitive Dysfunction in Patients Treated with Androgen Deprivation Therapy: A Multimodality Functional Imaging Study to Evaluate Neuroinflammation.

Background: Androgen deprivation therapy (ADT) for prostate cancer is implicated as a possible cause of cognitive impairment (CI). CI in dementia and Alzheimer's disease is associated with neuroinflammation. In this study, we investigated a potential role of neuroinflammation in ADT-related CI. Methods: Patients with prostate cancer on ADT for ≥3 months were categorized as having ADT-emergent CI or normal cognition (NC) based on self-report at interview. Neuroinflammation was evaluated using positron emission tomography (PET) with the translocator protein (TSPO) radioligand [11C]-PBR28. [11C]-PBR28 uptake in various brain regions was quantified as standardized uptake value (SUVR, normalized to cerebellum) and related to blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) choice-reaction time task (CRT) activation maps. Results: Eleven patients underwent PET: four with reported CI (rCI), six with reported NC (rNC), and one status unrecorded. PET did not reveal any between-group differences in SUVR regionally or globally. There was no difference between groups on brain activation to the CRT. Regardless of the reported cognitive status, there was strong correlation between PET-TSPO signal and CRT activation in the hippocampus, amygdala, and medial cortex. Conclusions: We found no difference in neuroinflammation measured by PET-TSPO between patients with rCI and rNC. However, we speculate that the strong correlation between TSPO uptake and BOLD-fMRI activation in brain regions involved in memory and known to have high androgen-receptor expression mediating plasticity (hippocampus and amygdala) might reflect inflammatory effects of ADT with compensatory upregulated/increased synaptic functions. Further studies of this imaging readout are warranted to investigate ADT-related CI.

Focal therapy versus radical prostatectomy and external beam radiotherapy as primary treatment options for non-metastatic prostate cancer: results of a cost-effectiveness analysis.

AIMS: Focal therapy treats individual areas of tumour in non-metastatic prostate cancer in patients unsuitable for active surveillance. The aim of this work was to evaluate the cost-effectiveness of focal therapy versus prostatectomy and external beam radiotherapy (EBRT). MATERIALS AND METHODS: A Markov cohort health state transition model with four health states (stable disease, local recurrence, metastatic disease and death) was created, evaluating costs and utilities over a 10-year time horizon for patients diagnosed with non-metastatic prostate cancer. National Health Service (NHS) for England perspective was used, based on direct healthcare costs. Clinical transition probabilities were derived from prostate cancer registries in patients undergoing radical prostatectomy, EBRT and focal therapy using cryotherapy (Boston Scientific) or high-intensity focused ultrasound (HIFU) (Sonablate). Propensity score matching was used to ensure that at-risk populations were comparable. Variables included age, prostate-specific antigen (PSA), International Society of Urological Pathology (ISUP) grade group, maximum cancer core length (mm), T-stage and year of treatment. RESULTS: Focal therapy was associated with a lower overall cost and higher quality-adjusted life year (QALY) gains than either prostatectomy or EBRT, dominating both treatment strategies. Positive incremental net monetary benefit (NMB) values confirm focal therapy as cost-effective versus the alternatives at a willingness to pay (WTP) threshold of £30,000/QALY. One-way deterministic sensitivity analyses revealed consistent results. LIMITATIONS: Data used to calculate the transition probabilities were derived from a limited number of hospitals meaning that other potential treatment options were excluded. Limited data were available on later outcomes and none on quality of life data, therefore, literature-based estimates were used. CONCLUSIONS: Cost-effectiveness modelling demonstrates use of focal therapy (cryotherapy or HIFU) is associated with greater QALY gains at a lower overall cost than either radical prostatectomy or EBRT, representing good value for money in the NHS.

Focal therapy can be used for the primary treatment of individual areas of cancer in those patients with prostate cancer whose disease has not spread (localized or non-metastatic prostate cancer) and whose disease is unsuitable for active monitoring. Focal therapy in these patients results in similar control of the cancer to more invasive therapies, such as surgical removal of the prostate and radiotherapy, with the benefit of fewer sexual, urinary and rectal side effects. This work considered whether using focal therapy (either freezing the cancer cells using cryotherapy or using high-intensity focused ultrasound [HIFU] to destroy cancer cells) was good value for money in the National Health Service (NHS) compared with surgery or radiotherapy. An economic model was developed which considered the relative impact of treatment with focal therapies, surgery or radiotherapy within the NHS in England. Previously collected information from people undergoing treatment for their prostate cancer, together with published literature and clinical opinion, was used within the model to predict the treatment pathway, costs incurred and the results of treatment in terms of patient benefits (effectiveness and quality of life). The model showed that focal therapy using either cryotherapy or HIFU was associated with a lower overall cost and higher patient benefit than either surgery or radiotherapy, indicating that focal therapy represents good value for money in the NHS.

Sleep Profiles in Eating Disorders: A Scientometric Study on 50 Years of Clinical Research.

Sleep and diet are essential for maintaining physical and mental health. These two factors are closely intertwined and affect each other in both timing and quality. Eating disorders, including anorexia nervosa and bulimia nervosa, are often accompanied by different sleep problems. In modern society, an increasing number of studies are being conducted on the relationship between eating disorders and sleep. To gain a more comprehensive understanding of this field and highlight influential papers as well as the main research domains in this area, a scientometric approach was used to review 727 publications from 1971 to 2023. All documents were retrieved from Scopus through the following string "TITLE-ABS (("sleep" OR "insomnia") AND ("anorexia nervosa" OR "bulimia nervosa" OR "binge eating" OR "eating disorder*") AND NOT "obes*") AND (LIMIT-TO (LANGUAGE, "English"))". A document co-citation analysis was applied to map the relationship between relevant articles and their cited references as well as the gaps in the literature. Nine publications on sleep and eating disorders were frequently cited, with an article by Vetrugno and colleagues on nocturnal eating being the most impactful in the network. The results also indicated a total of seven major thematic research clusters. The qualitative inspection of clusters strongly highlights the reciprocal influence of disordered eating and sleeping patterns. Researchers have modelled this reciprocal influence by taking into account the role played by pharmacological (e.g., zolpidem, topiramate), hormonal (e.g., ghrelin), and psychological (e.g., anxiety, depression) factors, pharmacological triggers, and treatments for eating disorders and sleep problems. The use of scientometric perspectives provides valuable insights into the field related to sleep and eating disorders, which can guide future research directions and foster a more comprehensive understanding of this important area.

Exploring the Relationship between Disordered Sleep and Mood in Male Anorexia Nervosa: An Actigraphy Study.

Eating disorders (EDs), including anorexia nervosa (AN), are severe psychological disorders that affect individuals' eating behaviours and body perception. Previous research has shown that people with EDs often report poorer sleep. Some literature has suggested that it is mood dysregulation that mediates the link between EDs and sleep. However, the majority of previous studies only focused on females, while male ED patients have been overlooked. Therefore, the present study aimed to investigate the relationships between EDs, mood, and sleep among male ED patients. Using a mixture of actigraphy recordings and self-reported questionnaires, the current study analysed a total 33 adult male participants diagnosed with AN. The participants first wore an actigraphy device for seven continuous days, following which their ED severity and mood were assessed by the Eating Disorder Examination Questionnaire (EDE-Q) and Depression Anxiety Stress Scale (DASS), respectively. The descriptive actigraphy results suggested that, similar to females, males with AN also showed disturbed sleep, including insomnia, sleep fragmentation, low sleep efficiency, and increased napping sessions. However, when ED severity was correlated against actigraphy data and mood, no significant relationships were found between them. Thus, it was suggested that future studies may investigate discrete ED symptoms instead of global ED severity interacting with sleep and mood. Overall, this study represents an initial step in the investigation of EDs and sleep and mood dysregulation among an under-represented sample.

Understanding Sleep Disturbances in Prostate Cancer-A Scientometric Analysis of Sleep Assessment, Aetiology, and Its Impact on Quality of Life.

Prostate cancer is the most commonly diagnosed cancer in the United Kingdom. While androgen-deprivation therapy is the most common treatment for prostate cancer, patients undergoing this treatment typically experience side effects in terms of sleep disturbances. However, the relation between prostate cancer and sleep and the way in which sleep interventions may benefit oncological patients is underinvestigated in the literature. The current study aims to review in a data-driven approach the existing literature on the field of prostate cancer and sleep to identify impactful documents and major thematic domains. To do so, a sample of 1547 documents was downloaded from Scopus, and a document co-citation analysis was conducted on CiteSpace software. In the literature, 12 main research domains were identified as well as 26 impactful documents. Research domains were examined regarding the link between prostate cancer and sleep, by taking into account variations in hormonal levels. A major gap in the literature was identified in the lack of use of objective assessment of sleep quality in patients with prostate cancer.

Parental Experiences of Melatonin Administration to Manage Sleep Disturbances in Autistic Children and Adolescent in the UK.

BACKGROUND: Autistic children and adolescents are 40-80% more likely to experience sleep disturbances than their neurotypical peers. In the United Kingdom, melatonin is licensed for short-term usage in adults at age 55 years and above; however, it is often prescribed to autistic children and adolescents to help manage their sleep. The current study sought to understand parental experiences and their motivation of using melatonin to manage sleep disturbances of their autistic children. METHODS: The sample included 26 parents who took part in online focus groups answering questions regarding their experiences of using melatonin as a sleep treatment for their children diagnosed with autism between 4 and 18 years old. RESULTS: Four main themes were identified: (i) parental perception of melatonin used as 'a naturally produced hormone'; (ii) perceived benefits of using melatonin to improve their child's sleep; (iii) administration of melatonin: dosage amount, timing and pulverising; and (iv) expectation and apprehension over melatonin use. CONCLUSION: Some parents reported success with the use of melatonin, and others reported the effects being limited or diminishing in time. Suggestions for healthcare professionals and families regarding melatonin usage in the UK are made with respect to setting clear guidelines for usage, whilst ensuring expectations are set and managed appropriately.

Healthcare systems data in the context of clinical trials - A comparison of cardiovascular data from a clinical trial dataset with routinely collected data.

BACKGROUND: Routinely-collected healthcare systems data (HSD) are proposed to improve the efficiency of clinical trials. A comparison was undertaken between cardiovascular (CVS) data from a clinical trial database with two HSD resources. METHODS: Protocol-defined and clinically reviewed CVS events (heart failure (HF), acute coronary syndrome (ACS), thromboembolic stroke, venous and arterial thromboembolism) were identified within the trial data. Data (using pre-specified codes) was obtained from NHS Hospital Episode Statistics (HES) and National Institute for Cardiovascular Outcomes Research (NICOR) HF and myocardial ischaemia audits for trial participants recruited in England between 2010 and 2018 who had provided consent. The primary comparison was trial data versus HES inpatient (APC) main diagnosis (Box-1). Correlations are presented with descriptive statistics and Venn diagrams. Reasons for non-correlation were explored. RESULTS: From 1200 eligible participants, 71 protocol-defined clinically reviewed CVS events were recorded in the trial database. 45 resulted in a hospital admission and therefore could have been recorded by either HES APC/ NICOR. Of these, 27/45 (60%) were recorded by HES inpatient (Box-1) with an additional 30 potential events also identified. HF and ACS were potentially recorded in all 3 datasets; trial data recorded 18, HES APC 29 and NICOR 24 events respectively. 12/18 (67%) of the HF/ACS events in the trial dataset were recorded by NICOR. CONCLUSION: Concordance between datasets was lower than anticipated and the HSD used could not straightforwardly replace current trial practices, nor directly identify protocol-defined CVS events. Further work is required to improve the quality of HSD and consider event definitions when designing clinical trials incorporating HSD.

Short Report: Lack of Diurnal Variation in Salivary Cortisol Is Linked to Sleep Disturbances and Heightened Anxiety in Adolescents with Williams Syndrome.

OBJECTIVE: The aim of the current study was to examine the potential relationship between sleep patterns, cortisol levels, and anxiety profiles in adolescents with Williams Syndrome (WS) compared to typically developing adolescents. METHOD: Thirteen adolescents with WS and thirteen TD adolescents (age range 12-18 years) were recruited. Participants were provided with a "testing kit", containing instructions for collecting data through a sleep diary, MotionWare actigraphy, the Childhood Sleep Habits Questionnaire (CSHQ), and the Spence Children's Anxiety Scale, and a salivary cortisol collection kit. RESULTS: Adolescents in the WS group did not show diurnal variation in salivary cortisol. Significantly higher scores were reported for two CSHQ subsections, night wakings and parasomnias, in the WS group. Regarding the actigraphy, only significantly longer sleep latency was observed in the WS group. In comparison to the TD group, the WS group had significantly higher anxiety. As expected, the TD group showed typical diurnal variation in cortisol, whereas the WS group showed a flattened cortisol profile throughout the day. CONCLUSIONS: From the developmental perspective, this study provides new data supporting the conclusion that sleep problems are not transient but continue to persist into adolescence in WS. Future studies ought to consider examining the role of cortisol and its interplay with anxiety levels and sleep problems across the lifespan in individuals with WS.

Eligibility for 177Lu-PSMA Therapy Depends on the Choice of Companion Diagnostic Tracer: A Comparison of 68Ga-PSMA-11 and 99mTc-MIP-1404 in Metastatic Castration-Resistant Prostate Cancer.

177Lu-prostate-specific membrane antigen-617 (177Lu-PSMA-617) is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC), with evidence of improved survival over standard care. The VISION trial inclusion criteria required a metastatic lesion-to-liver ratio of greater than 1 on 68Ga-PSMA-11 PET scans. We aimed to determine whether an equivalent ratio is suitable for a SPECT tracer, 99mTc-MIP-1404, and to compare lesion and lesion-to-normal-organ ratios between the 2 radiotracers. Methods: Two cohorts of patients with mCRPC matched for age, prostate-specific antigen level, and total Gleason score, with either 99mTc-MIP-1404 SPECT/CT (n = 25) or 68Ga-PSMA-11 PET/CT (n = 25) scans, were included for analysis. Up to 3 lesions in each site (prostate/prostate bed, lymph nodes, bone and soft-tissue metastases) as well as normal liver, parotid gland, spleen, and mediastinal blood-pool SUVmax were measured. Results: 99mTc-MIP-1404 SPECT lesion SUVmax was not significantly different from 68Ga-PSMA-11 PET (median, 18.2 vs. 17.3; P = 0.93). However, 99mTc-MIP-1404 liver SUVmax was higher (median, 8.5 vs. 5.8; P = 0.002) and lesion-to-liver ratios were lower (median, 2.7 vs. 3.5; P = 0.009). There was no significant difference in parotid gland or splenic SUVmax or lesion-to-parotid gland ratios between the 2 tracers although there was a small difference in lesion-to-spleen ratios (P = 0.034). Conclusion: There are differences in biodistribution and, in particular, liver activity, between 68Ga-PSMA-11 and 99mTc-MIP-1404. Therefore, if 99mTc-MIP-1404 is used to assess eligibility for 177Lu-PSMA-617 therapy, a lower adjusted lesion-to-liver ratio should be used.

Telehealth delivery of adapted CBT-I for insomnia in chronic pain patients: a single arm feasibility study.

Objectives: A large proportion of individuals with chronic pain experience insomnia-related symptoms which can be persistent in nature, and negatively impact one's quality of life. This single arm trial aimed to investigate the feasibility and preliminary efficacy of CBT-I, adapted for people with chronic musculoskeletal pain, delivered via telehealth. Methods: We conducted a single arm feasibility trial in which 10 adult women (M age = 50.76 years, SD = 8.03 years) with self-reported insomnia and a diagnosed chronic musculoskeletal chronic pain received six CBT-I individual treatment sessions over 6-10 weeks. Treatment was delivered via telehealth. Participants completed weekly sleep diaries, and self-reported measures of insomnia, pain, anxiety and depression pre-treatment, post-treatment, and one-month follow-up. Results: The trial yielded, high levels of compliance with intervention protocols, and affirmative feedback on satisfaction which demonstrated feasibility. The enrolment rate into the study was 37% (27 participants screened, 10 participants enrolled). The intervention was associated with statistically and clinically meaningful improvements in self-reported insomnia severity. There were statistically significant improvements in sleep efficiency, wake after sleep onset, sleep onset latency, anxiety and depression. Conclusion: Adapted CBT-I delivered via telehealth may be a feasible, acceptable, and efficacious therapeutic approach for individuals with co-existent sleep and chronic pain. Future trials should adopt a randomized design against usual care.

Evaluating Patterns and Factors Related to Sleep Disturbances in Prostate Cancer Patients.

Prostate cancer patients may experience disturbed sleep as a result of their diagnosis or treatment. This study sought to evaluate disturbed sleep and excessive daytime sleepiness in newly diagnosed patients and those receiving androgen deprivation therapy (ADT). This study was conducted with 74 patients. Subjective data using the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) and actigraphy data on ADT/ADT-naïve patients were collected. The prevalence of poor sleep quality, determined from PSQI and ESS scores, was 50% and 16.7% respectively. Those on ADT (n = 20) had poorer sleep quality as determined by significantly higher PSQI scores (70 vs. 40% scoring > 5) and were more likely to have poor sleep quality, sleep latency, and sleep efficiency than ADT-naïve patients (n = 40). Actigraphy data showed that ADT patients slept significantly longer (7.7 vs. 6.8 h), experienced a higher Fragmentation Index (48.3 vs. 37.4%), and had longer daytime nap duration (64.1 vs. 45.2 min) than ADT-naïve patients. The use of objective measures such as actigraphy in the clinical arena is recommended and may be used as a valuable tool for research into sleep assessment in prostate cancer patients.

A Systematic Review of Patients' Values, Preferences, and Expectations for the Treatment of Metastatic Prostate Cancer.

CONTEXT: Advances in systemic agents have increased overall survival for men diagnosed with metastatic prostate cancer. Additional cytoreductive prostate treatments and metastasis-directed therapies are under evaluation. These confer toxicity but may offer incremental survival benefits. Thus, an understanding of patients' values and treatment preferences is important for counselling, decision-making, and guideline development. OBJECTIVE: To perform a systematic review of patients' values, preferences, and expectations regarding treatment of metastatic prostate cancer. EVIDENCE ACQUISITION: The MEDLINE, Embase, and CINAHL databases were systematically searched for qualitative and preference elucidation studies reporting on patients' preferences for treatment of metastatic prostate cancer. Certainty of evidence was assessed using Grading of Recommendation, Assessment, Development and Evaluation (GRADE) or GRADE Confidence in the Evidence from Reviews of Qualitative Research (CERQual). The protocol was registered on PROSPERO as CRD42020201420. EVIDENCE SYNTHESIS: A total of 1491 participants from 15 studies met the prespecified eligibility for inclusion. The study designs included were discrete choice experiments (n = 5), mixed methods (n = 3), and qualitative methods (n = 7). Disease states reported per study were: metastatic castration-resistant prostate cancer in nine studies (60.0%), metastatic hormone-sensitive prostate cancer in two studies (13.3%), and a mixed cohort in four studies (26.6%). In quantitative preference elicitation studies, patients consistently valued treatment effectiveness and delay in time to symptoms as the two top-ranked treatment attributes (low or very low certainty). Patients were willing to trade off treatment-related toxicity for potential oncological benefits (low certainty). In qualitative studies, thematic analysis revealed cancer progression and/or survival, pain, and fatigue as key components in treatment decisions (low or very low certainty). Patients continue to value oncological benefits in making decisions on treatments under qualitative assessment. CONCLUSIONS: There is limited understanding of how patients make treatment and trade-off decisions following a diagnosis of metastatic prostate cancer. For appropriate investment in emerging cytoreductive local tumour and metastasis-directed therapies, we should seek to better understand how this cohort weighs the oncological benefits against the risks. PATIENT SUMMARY: We looked at how men with advanced (metastatic) prostate cancer make treatment decisions. We found that little is known about patients' preferences for current and proposed new treatments. Further studies are required to understand how patients make decisions to help guide the integration of new treatments into the standard of care.

Metastatic prostate cancer men's attitudes towards treatment of the local tumour and metastasis evaluative research (IP5-MATTER): protocol for a prospective, multicentre discrete choice experiment study.

INTRODUCTION: Systemic therapy with androgen deprivation therapy (ADT) and intensification with agents such as docetaxel, abiraterone acetate and enzalutamide has resulted in improved overall survival in men with de novo synchronous metastatic hormone-sensitive prostate cancer (mHSPC). Novel local cytoreductive treatments and metastasis-directed therapy are now being evaluated. Such interventions may provide added survival benefit or delay the requirement for further systemic agents and associated toxicity but can confer additional harm. Understanding men's preferences for treatment options in this disease state is crucial for patients, clinicians, carers and future healthcare service providers. METHODS: Using a prospective, multicentre discrete choice experiment (DCE), we aim to determine the attributes associated with treatment that are most important to men with mHSPC. Furthermore, we plan to determine men's preferences for, and trade-offs between, the attributes (survival and side effects) of different treatment options including systemic therapy, local cytoreductive approaches (external beam radiotherapy, cytoreductive radical prostatectomy or minimally invasive ablative therapy) and metastases-directed therapies (metastasectomy or stereotactic ablative body radiotherapy). All men with newly diagnosed mHSPC within 4 months of commencing ADT and WHO performance status 0-2 are eligible. Men who have previously consented to a cytoreductive treatment or have developed castrate-resistant disease will be excluded. This study includes a qualitative analysis component, with patients (n=15) and healthcare professionals (n=5), to identify and define the key attributes associated with treatment options that would warrant trade-off evaluation in a DCE. The main phase component planned recruitment is 300 patients over 1 year, commencing in January 2021, with planned study completion in March 2022. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Health Research Authority East of England, Cambridgeshire and Hertfordshire Research Ethics Committee (Reference: 20/EE/0194). Project information will be reported on the publicly available Imperial College London website and the Heath Economics Research Unit (HERU website including the HERU Blog). We will use the social media accounts of IP5-MATTER, Imperial Prostate London, HERU and the individual researchers to disseminate key findings following publication. Findings from the study will be presented at national/international conferences and peer-reviewed journals. Authorship policy will follow the recommendations of the International Committee of Medical Journal Editors. TRIAL REGISTRATION NUMBER: NCT04590976.

Conventional radical versus focal treatment for localised prostate cancer: a propensity score weighted comparison of 6-year tumour control.

BACKGROUND: For localised prostate cancer, focal therapy offers an organ-sparing alternative to radical treatments (radiotherapy or prostatectomy). Currently, there is no randomised comparative effectiveness data evaluating cancer control of both strategies. METHODS: Following the eligibility criteria PSA < 20 ng/mL, Gleason score ≤ 7 and T-stage ≤ T2c, we included 830 radical (440 radiotherapy, 390 prostatectomy) and 530 focal therapy (cryotherapy, high-intensity focused ultrasound or high-dose-rate brachytherapy) patients treated between 2005 and 2018 from multicentre registries in the Netherlands and the UK. A propensity score weighted (PSW) analysis was performed to compare failure-free survival (FFS), with failure defined as salvage treatment, metastatic disease, systemic treatment (androgen deprivation therapy or chemotherapy), or progression to watchful waiting. The secondary outcome was overall survival (OS). Median (IQR) follow-up in each cohort was 55 (28-83) and 62 (42-83) months, respectively. RESULTS: At baseline, radical patients had higher PSA (10.3 versus 7.9) and higher-grade disease (31% ISUP 3 versus 11%) compared to focal patients. After PSW, all covariates were balanced (SMD < 0.1). 6-year weighted FFS was higher after radical therapy (80.3%, 95% CI 73.9-87.3) than after focal therapy (72.8%, 95% CI 66.8-79.8) although not statistically significant (p = 0.1). 6-year weighted OS was significantly lower after radical therapy (93.4%, 95% CI 90.1-95.2 versus 97.5%, 95% CI 94-99.9; p = 0.02). When compared in a three-way analysis, focal and LRP patients had a higher risk of treatment failure than EBRT patients (p < 0.001), but EBRT patients had a higher risk of mortality than focal patients (p = 0.008). CONCLUSIONS: Within the limitations of a cohort-based analysis in which residual confounders are likely to exist, we found no clinically relevant difference in cancer control conferred by focal therapy compared to radical therapy at 6 years.

Additional Treatments to the Local tumour for metastatic prostate cancer-Assessment of Novel Treatment Algorithms (IP2-ATLANTA): protocol for a multicentre, phase II randomised controlled trial.

INTRODUCTION: Survival in men diagnosed with de novo synchronous metastatic prostate cancer has increased following the use of upfront systemic treatment, using chemotherapy and other novel androgen receptor targeted agents, in addition to standard androgen deprivation therapy (ADT). Local cytoreductive and metastasis-directed interventions are hypothesised to confer additional survival benefit. In this setting, IP2-ATLANTA will explore progression-free survival (PFS) outcomes with the addition of sequential multimodal local and metastasis-directed treatments compared with standard care alone. METHODS: A phase II, prospective, multicentre, three-arm randomised controlled trial incorporating an embedded feasibility pilot. All men with new histologically diagnosed, hormone-sensitive, metastatic prostate cancer, within 4 months of commencing ADT and of performance status 0 to 2 are eligible. Patients will be randomised to Control (standard of care (SOC)) OR Intervention 1 (minimally invasive ablative therapy to prostate±pelvic lymph node dissection (PLND)) OR Intervention 2 (cytoreductive radical prostatectomy±PLND OR prostate radiotherapy±pelvic lymph node radiotherapy (PLNRT)). Metastatic burden will be prespecified using the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) definition. Men with low burden disease in intervention arms are eligible for metastasis-directed therapy, in the form of stereotactic ablative body radiotherapy (SABR) or surgery. Standard systemic therapy will be administered in all arms with ADT±upfront systemic chemotherapy or androgen receptor agents. Patients will be followed-up for a minimum of 2 years. PRIMARY OUTCOME: PFS. Secondary outcomes include predictive factors for PFS and overall survival; urinary, sexual and rectal side effects. Embedded feasibility sample size is 80, with 918 patients required in the main phase II component. Study recruitment commenced in April 2019, with planned follow-up completed by April 2024. ETHICS AND DISSEMINATION: Approved by the Health Research Authority (HRA) Research Ethics Committee Wales-5 (19/WA0005). Study results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03763253; ISCRTN58401737.

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme.

BACKGROUND: Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. METHODS: PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 µg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive. FINDINGS: Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4-7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80-1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86-1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001). INTERPRETATION: Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer. FUNDING: Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London.

Evaluating the prevalence and predictive factors of vasomotor and psychological symptoms in prostate cancer patients receiving hormonal therapy: Results from a single institution experience.

BACKGROUND & PURPOSE: The impact of vasomotor symptoms (VMS) occurring in prostate cancer (PC) patients whilst on androgen deprivation therapy (ADT) has not been extensively researched. This longitudinal study sought to assess the VMS and identify any predictive factors. MATERIAL & METHODS: Data from 250 PC patients on ADT were prospectively evaluated between January 10 and August 13 using a physician-directed questionnaire, to assess the impact of VMS. Parameters including height, weight, body surface area (BSA), body mass index (BMI), duration/type of ADT, co-morbidities and ethnicity were recorded. RESULTS: Fifty (20%) men reported no toxicity, whilst 171 (68.4%), and 29 (11.6%) reported mild to moderate and severe symptoms, respectively. Drenching sweats and hot flashes were common, and coexisted with sleep disturbances and fatigue. Patients with severe toxicity were younger (73 vs. 77 yrs; p = 0.04), had higher BMI (28 vs. 26; p = 0.02), and higher BSA (1.99 vs. 1.90; p = 0.04), when compared with those experiencing no toxicity. On multivariate analysis, younger age was predictive of sweats and hot flushes, whilst Afro-Caribbean men were twice as likely to experience sweats (OR 2.03, p = 0.05). CONCLUSIONS: The short-term side-effect profile of ADT for prostate cancer was favourable, though debilitating VMS can occur in a significant minority of cases. Younger age and higher BMI predicted for severe toxicity but not the duration of ADT.

Erythema nodosum as a result of estrogen patch therapy for prostate cancer: a case report.

INTRODUCTION: Erythema nodosum is often associated with a distressing symptomatology, including painful subcutaneous nodules, polyarthropathy, and significant fatigue. Whilst it is a well-documented side-effect of estrogen therapy in females, we describe what we believe to be the first report in the literature of erythema nodosum as a result of estrogen therapy in a male. CASE PRESENTATION: A 64-year-old Afro-Caribbean man with locally advanced carcinoma of the prostate agreed to participate in a randomized controlled trial comparing estrogen patches with luteinizing hormone-releasing hormone analogs to achieve androgen deprivation, and was allocated to the group receiving estrogen patches. One month later he presented with tender lesions on his shins and painful swelling of his ankles, wrists, and left shoulder. This was followed by progressive severe fatigue that required hospital admission, where he was diagnosed with erythema nodosum by a rheumatologist. Two months after discontinuing the estrogen patches the erythema nodosum, and associated symptoms, had fully resolved, and to date he remains well with no further recurrence. CONCLUSION: Trial results may establish transdermal estrogen as an alternative to luteinizing hormone-releasing hormone analogs in the management of prostate cancer, and has already been established as a therapy for male to female transsexuals. It is essential to record the toxicity profile of transdermal estrogen in men to ensure accurate safety information. This case report highlights a previously undocumented toxicity of estrogen therapy in men, of which oncologists, urologists, and endocrinologists need to be aware. Rheumatologists and dermatologists should add estrogen therapy to their differential diagnosis of men presenting with erythema nodosum.