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Lancet (London, England) May 2024Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for...
Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.
BACKGROUND
Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear.
METHODS
RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.
FINDINGS
Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths.
INTERPRETATION
Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population.
FUNDING
Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
PubMed: 38763154
DOI: 10.1016/S0140-6736(24)00548-8 -
BioRxiv : the Preprint Server For... May 2024Clinical research emphasizes the implementation of rigorous and reproducible study designs that rely on between-group matching or controlling for sources of biological...
Clinical research emphasizes the implementation of rigorous and reproducible study designs that rely on between-group matching or controlling for sources of biological variation such as subject's sex and age. However, corrections for body size (i.e. height and weight) are mostly lacking in clinical neuroimaging designs. This study investigates the importance of body size parameters in their relationship with spinal cord (SC) and brain magnetic resonance imaging (MRI) metrics. Data were derived from a cosmopolitan population of 267 healthy human adults (age 30.1±6.6 years old, 125 females). We show that body height correlated strongly or moderately with brain gray matter (GM) volume, cortical GM volume, total cerebellar volume, brainstem volume, and cross-sectional area (CSA) of cervical SC white matter (CSA-WM; 0.44≤r≤0.62). In comparison, age correlated weakly with cortical GM volume, precentral GM volume, and cortical thickness (-0.21≥r≥-0.27). Body weight correlated weakly with magnetization transfer ratio in the SC WM, dorsal columns, and lateral corticospinal tracts (-0.20≥r≥-0.23). Body weight further correlated weakly with the mean diffusivity derived from diffusion tensor imaging (DTI) in SC WM (r=-0.20) and dorsal columns (-0.21), but only in males. CSA-WM correlated strongly or moderately with brain volumes (0.39≤r≤0.64), and weakly with precentral gyrus thickness and DTI-based fractional anisotropy in SC dorsal columns and SC lateral corticospinal tracts (-0.22≥r≥-0.25). Linear mixture of sex and age explained 26±10% of data variance in brain volumetry and SC CSA. The amount of explained variance increased at 33±11% when body height was added into the mixture model. Age itself explained only 2±2% of such variance. In conclusion, body size is a significant biological variable. Along with sex and age, body size should therefore be included as a mandatory variable in the design of clinical neuroimaging studies examining SC and brain structure.
PubMed: 38746371
DOI: 10.1101/2024.04.29.591421 -
PloS One 2024This is the first study to assess longitudinal changes in anthropometric, physiological, and physical qualities of international women's rugby league players. Thirteen...
This is the first study to assess longitudinal changes in anthropometric, physiological, and physical qualities of international women's rugby league players. Thirteen forwards and 11 backs were tested three times over a 10-month period. Assessments included: standing height and body mass, body composition measured by dual x-ray absorptiometry (DXA), a blood panel, resting metabolic rate (RMR) assessed by indirect calorimetry, aerobic capacity (i.e.,[Formula: see text]) evaluated by an incremental treadmill test, and isometric force production measured by a force plate. During the pre-season phase, lean mass increased significantly by ~2% for backs (testing point 1: 47 kg; testing point 2: 48 kg) and forwards (testing point 1: 50 kg; testing point 2: 51 kg) (p = ≤ 0.05). Backs significantly increased their [Formula: see text] by 22% from testing point 1 (40 ml kg-1 min-1) to testing point 3 (49 ml kg-1 min-1) (p = ≤ 0.04). The [Formula: see text] of forwards increased by 10% from testing point 1 (41 ml kg-1 min-1) to testing point 3 (45 ml kg-1 min-1), however this change was not significant (p = ≥ 0.05). Body mass (values represent the range of means across the three testing points) (backs: 68 kg; forwards: 77-78 kg), fat mass percentage (backs: 25-26%; forwards: 30-31%), resting metabolic rate (backs: 7 MJ day-1; forwards: 7 MJ day-1), isometric mid-thigh pull (backs: 2106-2180 N; forwards: 2155-2241 N), isometric bench press (backs: 799-822 N; forwards: 999-1024 N), isometric prone row (backs: 625-628 N; forwards: 667-678 N) and bloods (backs: ferritin 21-29 ug/L, haemoglobin 137-140 g/L, iron 17-21 umol/L, transferrin 3 g/L, transferring saturation 23-28%; forwards: ferritin 31-33 ug/L, haemoglobin 141-145 g/L, iron 20-23 umol/L, transferrin 3 g/L, transferrin saturation 26-31%) did not change (p = ≥ 0.05). This study provides novel longitudinal data which can be used to better prepare women rugby league players for the unique demands of their sport, underpinning female athlete health.
Topics: Humans; Female; Adult; Body Composition; Football; Longitudinal Studies; Basal Metabolism; Young Adult; Anthropometry; Athletes; Absorptiometry, Photon; Exercise Test; Body Mass Index; Rugby
PubMed: 38743656
DOI: 10.1371/journal.pone.0298709 -
Therapeutic Advances in Medical Oncology 2024Despite advances in the treatment of early triple-negative breast cancer (TNBC), patients with residual invasive disease after neoadjuvant therapy have a high risk of...
TROPION-Breast03: a randomized phase III global trial of datopotamab deruxtecan ± durvalumab in patients with triple-negative breast cancer and residual invasive disease at surgical resection after neoadjuvant therapy.
BACKGROUND
Despite advances in the treatment of early triple-negative breast cancer (TNBC), patients with residual invasive disease after neoadjuvant therapy have a high risk of disease recurrence and worse survival outcomes than those who have pathological complete response (pCR). Improving outcomes in early TNBC remains an unmet need requiring new adjuvant treatment approaches. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 immunoglobulin G1 (IgG1) monoclonal antibody attached a plasma-stable, cleavable linker to a potent topoisomerase I inhibitor payload, with activity observed in advanced TNBC.
OBJECTIVES
TROPION-Breast03 is an ongoing phase III study evaluating the efficacy and safety of Dato-DXd alone or combined with durvalumab standard-of-care therapy as adjuvant treatment in patients with stage I-III TNBC with residual invasive disease at surgical resection following neoadjuvant treatment.
METHODS AND DESIGN
Eligible patients, aged ⩾18 years, will be randomized in a 2:1:2 ratio to receive Dato-DXd [6 mg/kg intravenously (IV) every 3 weeks (Q3W); eight cycles] and durvalumab (1120 mg IV Q3W; nine cycles), Dato-DXd monotherapy (6 mg/kg IV Q3W), or investigator's choice of therapy (ICT; capecitabine, pembrolizumab, or capecitabine and pembrolizumab). The primary endpoint is invasive disease-free survival (iDFS) for Dato-DXd and durvalumab ICT. Key secondary endpoints include safety, distant disease-free survival, and overall survival for Dato-DXd and durvalumab ICT and iDFS for Dato-DXd monotherapy ICT.
ETHICS
TROPION-Breast03 will be approved by the independent ethics committees or institutional review boards at each study site. All study participants will provide written informed consent.
DISCUSSION
TROPION-Breast03 will help define the potential role of Dato-DXd in the treatment of patients with early-stage TNBC who do not have pCR after neoadjuvant therapy.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT05629585 (registration date: 29 November 2022).
PubMed: 38686016
DOI: 10.1177/17588359241248336 -
Journal of Affective Disorders Jul 2024The transdiagnostic approach to psychopathology has emerged as an alternative to traditional taxonomic approaches. The Multidimensional Emotional Disorders Inventory...
The assessment of transdiagnostic dimensions of emotional disorders: Validation of the Multidimensional Emotional Disorders Inventory (MEDI) in adolescents with subthreshold anxiety and depression.
BACKGROUND
The transdiagnostic approach to psychopathology has emerged as an alternative to traditional taxonomic approaches. The Multidimensional Emotional Disorders Inventory (MEDI) is a specifically designed self-report to measure the transdiagnostic dimensions proposed by Brown and Barlow (2009). This study aims to analyse the psychometric properties of the MEDI scores in adolescents with subthreshold anxiety and depression.
METHOD
The sample consisted of a total of 476 students. The mean age was 13.77 years (SD = 1.43) (range 10 to 18 years), 73.9 % were females. Several questionnaires assessing positive affect, negative affect, mental health difficulties, and quality of life were used.
RESULTS
The original 9-factor structure of the MEDI was confirmed with good fit indices. Satisfactory levels of internal consistency were observed in most of the MEDI scores using McDonald's Omega, ranging from 0.58 to 0.87. The MEDI dimensions were associated with psychopathology, positive affect, negative affect, and quality of life.
LIMITATIONS
Reliance on self-reported data, a cross-sectional design limiting temporal assessment, and a 73.9 % female gender imbalance.
CONCLUSION
The MEDI scores showed adequate psychometric properties among adolescents with subclinical emotional symptoms. The results found might have potential clinical implications for conceptualization, assessment, intervention, and prevention of emotional disorders at both clinical and research levels.
Topics: Humans; Adolescent; Female; Male; Psychometrics; Child; Quality of Life; Depression; Anxiety; Reproducibility of Results; Anxiety Disorders; Surveys and Questionnaires; Cross-Sectional Studies; Self Report; Psychiatric Status Rating Scales; Depressive Disorder
PubMed: 38685278
DOI: 10.1016/j.jad.2024.04.081 -
Applied and Environmental Microbiology Apr 2024Given the multitude of extracellular enzymes at their disposal, many of which are designed to degrade nature's polymers (lignin, cutin, cellulose, etc.), fungi are adept...
Given the multitude of extracellular enzymes at their disposal, many of which are designed to degrade nature's polymers (lignin, cutin, cellulose, etc.), fungi are adept at targeting synthetic polyesters with similar chemical composition. Microbial-influenced deterioration of xenobiotic polymeric surfaces is an area of interest for material scientists as these are important for the conservation of the underlying structural materials. Here, we describe the isolation and characterization of the 5307AH () cutinase, Plcut1. is basidiomycete yeast with the ability to disperse Impranil-DLN (Impranil), a colloidal polyester polyurethane, in agar plates. To test whether the fungal factor involved in this clearing was a secreted enzyme, we screened the ability of culture supernatants to disperse Impranil. Using size exclusion chromatography (SEC), we isolated fractions that contained Impranil-clearing activity. These fractions harbored a single ~22 kD band, which was excised and subjected to peptide sequencing. Homology searches using the peptide sequences identified, revealed that the protein Papla1 543643 (Plcut1) displays similarities to serine esterase and cutinase family of proteins. Biochemical assays using recombinant Plcut1 confirmed that this enzyme has the capability to hydrolyze Impranil, soluble esterase substrates, and apple cutin. Finally, we confirmed the presence of the Plcut1 in culture supernatants using a custom antibody that specifically recognizes this protein. The work shown here supports a major role for the Plcut1 in the fungal degradation of natural polyesters and xenobiotic polymer surfaces.IMPORTANCEFungi play a vital role in the execution of a broad range of biological processes that drive ecosystem function through production of a diverse arsenal of enzymes. However, the universal reactivity of these enzymes is a current problem for the built environment and the undesired degradation of polymeric materials in protective coatings. Here, we report the identification and characterization of a hydrolase from 5307AH, an aircraft-derived fungal isolate found colonizing a biodeteriorated polymer-coated surface. We show that secretes a cutinase capable of hydrolyzing soluble esters as well as ester-based compounds forming solid surface coatings. These findings indicate that this fungus plays a significant role in biodeterioration through the production of a cutinase adept at degrading ester-based polymers, some of which form the backbone of protective surface coatings. The work shown here provides insights into the mechanisms employed by fungi to degrade xenobiotic polymers.
PubMed: 38624219
DOI: 10.1128/aem.01694-23 -
JAMA Network Open Mar 2024Reducing acute care use is an important strategy for improving value. Patients with cancer are at risk for unplanned emergency department (ED) visits and hospital stays...
IMPORTANCE
Reducing acute care use is an important strategy for improving value. Patients with cancer are at risk for unplanned emergency department (ED) visits and hospital stays (HS). Clinical trial patients have homogeneous treatment; despite this, structural barriers to care may independently impact acute care use.
OBJECTIVE
To examine whether ED visits and HS within 12 months of trial enrollment are more common among Medicare enrollees who live in areas of socioeconomic deprivation or have Medicaid insurance.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study included patients with cancer who were 65 years or older and treated in SWOG Cancer Research Network trials from 1999 to 2018 using data linked to Medicare claims. Data were collected from 1999 to 2019 and analyzed from 2022 to 2024.
MAIN OUTCOMES AND MEASURES
Outcomes were ED visits, HS, and costs in the first year following enrollment. Neighborhood socioeconomic deprivation was measured using patients' zip code linked to the Area Deprivation Index (ADI), measured on a 0 to 100 scale for increasing deprivation and categorized into tertiles (T1 to T3). Type of insurance was classified as Medicare with or without commercial insurance vs dual Medicare and Medicaid. Demographic, clinical, and prognostic factors were captured from trial records. Multivariable regression was used, and the association of ADI and insurance with each outcome was considered separately.
RESULTS
In total, 3027 trial participants were analyzed. The median (range) age was 71 (65-98) years, 1280 (32.3%) were female, 221 (7.3%) were Black patients, 2717 (89.8%) were White patients, 90 (3.0%) had Medicare and Medicaid insurance, and 660 (22.3%) were in the areas of highest deprivation (ADI-T3). In all, 1094 patients (36.1%) had an ED visit and 983 patients (32.4%) had an HS. In multivariable generalized estimating equation, patients living in areas categorized as ADI-T3 were more likely to have an ED visit (OR, 1.34; 95% CI, 1.10-1.62; P = .004). A similar but nonsignificant pattern was observed for HS (OR, 1.36; 95% CI, 0.96-1.93; P = .08). Patients from areas with the highest deprivation had a 62% increase in risk of either an ED visit or HS (OR, 1.62; 95% CI, 1.25-2.09; P < .001). Patients with Medicare and Medicaid were 96% more likely to have an ED visit (OR, 1.96; 95% CI, 1.56-2.46; P < .001).
CONCLUSIONS AND RELEVANCE
In this cohort of older patients enrolled in clinical trials, neighborhood deprivation and economic disadvantage were associated with an increase in ED visits and HS. Efforts are needed to ensure adequate resources to prevent unplanned use of acute care in socioeconomically vulnerable populations.
Topics: United States; Humans; Aged; Female; Aged, 80 and over; Male; Medicare; Cohort Studies; Medicaid; Neoplasms; Socioeconomic Factors; Delivery of Health Care
PubMed: 38546646
DOI: 10.1001/jamanetworkopen.2024.4008 -
BMC Medicine Mar 2024Black men have higher prostate-specific antigen (PSA) levels and higher prostate cancer incidence and mortality than White men, while Asian men tend to have lower...
BACKGROUND
Black men have higher prostate-specific antigen (PSA) levels and higher prostate cancer incidence and mortality than White men, while Asian men tend to have lower prostate cancer incidence and mortality than White men. Much of the evidence comes from the USA, and information from UK populations is limited.
METHODS
This retrospective cohort study used data on patients registered at general practices in England contributing to the Clinical Practice Research Datalink (CPRD) Aurum dataset. Those eligible were men aged 40 and over with a record of ethnicity and a PSA test result recorded between 2010 and 2017 with no prior cancer diagnosis. The aim was to assess the incidence of prostate cancer following a raised PSA test result in men from different ethnic groups. Additionally, incidence of advanced prostate cancer was investigated. Cancer incidence was estimated from multi-level logistic regression models adjusting for potential confounding factors.
RESULTS
730,515 men with a PSA test were included (88.9% White). Black men and men with mixed ethnicity had higher PSA values, particularly for those aged above 60 years. In the year following a raised PSA result (using age-specific thresholds), Black men had the highest prostate cancer incidence at 24.7% (95% CI 23.3%, 26.2%); Asian men had the lowest at 13.4% (12.2%, 14.7%); incidence for White men was 19.8% (19.4%, 20.2%). The peak incidence of prostate cancer for all groups was in men aged 70-79. Incidence of prostate cancer diagnosed at an advanced stage was similar between Black and White men.
CONCLUSIONS
More prostate cancer was diagnosed in Black men with a raised PSA result, but rates of advanced prostate cancer were not higher in this group. In this large primary care-based cohort, the incidence of prostate cancer in men with elevated PSA levels increases with increasing age, even when using age-adjusted thresholds, with Black men significantly more likely to be diagnosed compared to White or Asian men. The incidence of advanced stage prostate cancer at diagnosis was similar for Black and White men with a raised PSA result, but lower for Asian men.
Topics: Male; Humans; Adult; Middle Aged; Cohort Studies; Prostate-Specific Antigen; Ethnicity; Retrospective Studies; Prostatic Neoplasms; Primary Health Care; United Kingdom; White
PubMed: 38424555
DOI: 10.1186/s12916-024-03283-5 -
International Journal of Population... 2023Using routinely collected clinical data for observational research is an increasingly important method for data collection, especially when rare outcomes are being...
BACKGROUND
Using routinely collected clinical data for observational research is an increasingly important method for data collection, especially when rare outcomes are being explored. The POOL study was commissioned to evaluate the safety of waterbirth in the UK using routine maternity and neonatal clinical data. This paper describes the design, rationale, set-up and pilot for this data linkage study using bespoke methods.
METHODS
Clinical maternity information systems hold many data items of value for research purposes, but often lack specific data items required for individual studies. This study used the novel method of amending an existing clinical maternity database for the purpose of collecting additional research data fields. In combination with the extraction of existing data fields, this maximised the potential use of existing routinely collected clinical data for research purposes, whilst reducing NHS staff data collection burden.Wellbeing Software, provider of the Euroking Maternity Information System, added new study specific data fields to their information system, extracted data from participating NHS sites and transferred data for matching with the National Neonatal Research Database to ascertain outcomes for babies admitted to neonatal units. Study set-up processes were put in place for all sites. The data extraction, linkage and cleaning processes were piloted with one pre-selected NHS site.
RESULTS
Twenty-six NHS sites were set-up over 27 months (January 2019 - April 2021). Twenty-four thousand maternity records were extracted from the one NHS site, pertaining to the period January 2015 to March 2019. Data field completeness for maternal and neonatal primary outcomes were mostly acceptable. Neonatal identifiers flowed to the National Neonatal Research Database for successful matching and linkage between maternity and neonatal unit records.
DISCUSSION
Piloting the data extraction and linkage highlighted the need for additional governance arrangements, training at NHS sites and new processes for the study team to ensure data quality and confidentiality are upheld during the study. Amending existing NHS electronic information systems and accessing clinical data at scale, is possible, but continues to be a time consuming and a technically challenging exercise.
Topics: Infant, Newborn; Infant; Humans; Female; Pregnancy; Data Collection; Natural Childbirth; Data Accuracy; Information Systems; United Kingdom
PubMed: 38414546
DOI: 10.23889/ijpds.v8i1.2072