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In a randomized trial, 450 patients with venous leg ulcers were assigned to early endovenous ablation within 2 weeks after randomization or to deferred ablation after ulcer healing. The time to ulcer healing was shorter with early ablation than with deferred ablation.

Background High mammographic density is associated with both risk of cancers being missed at mammography, and increased risk of developing breast cancer. Stratification of breast cancer prevention and screening requires mammographic density measures predictive of cancer. This study compares five mammographic density measures to determine the association with subsequent diagnosis of breast cancer and the presence of breast cancer at screening. Methods Women participating in the “Predicting Risk Of Cancer At Screening” (PROCAS) study, a study of cancer risk, completed questionnaires to provide personal information to enable computation of the Tyrer-Cuzick risk score. Mammographic density was assessed by visual analogue scale (VAS), thresholding (Cumulus) and fully-automated methods (Densitas, Quantra, Volpara) in contralateral breasts of 366 women with unilateral breast cancer (cases) detected at screening on entry to the study (Cumulus 311/366) and in 338 women with cancer detected subsequently. Three controls per case were matched using age, body mass index category, hormone replacement therapy use and menopausal status. Odds ratios (OR) between the highest and lowest quintile, based on the density distribution in controls, for each density measure were estimated by conditional logistic regression, adjusting for classic risk factors. Results The strongest predictor of screen-detected cancer at study entry was VAS, OR 4.37 (95% CI 2.72–7.03) in the highest vs lowest quintile of percent density after adjustment for classical risk factors. Volpara, Densitas and Cumulus gave ORs for the highest vs lowest quintile of 2.42 (95% CI 1.56–3.78), 2.17 (95% CI 1.41–3.33) and 2.12 (95% CI 1.30–3.45), respectively. Quantra was not significantly associated with breast cancer (OR 1.02, 95% CI 0.67–1.54). Similar results were found for subsequent cancers, with ORs of 4.48 (95% CI 2.79–7.18), 2.87 (95% CI 1.77–4.64) and 2.34 (95% CI 1.50–3.68) in highest vs lowest quintiles of VAS, Volpara and Densitas, respectively. Quantra gave an OR in the highest vs lowest quintile of 1.32 (95% CI 0.85–2.05). Conclusions Visual density assessment demonstrated a strong relationship with cancer, despite known inter-observer variability; however, it is impractical for population-based screening. Percentage density measured by Volpara and Densitas also had a strong association with breast cancer risk, amongst the automated measures evaluated, providing practical automated methods for risk stratification.

IntroductionMulti-cancer early detection (MCED) blood tests look for cancer signals in cell-free deoxyribonucleic acid. These tests have the potential to detect cancers at an earlier (asymptomatic) stage, improving cancer outcomes. Any screening method needs careful consideration of the psychological harms prior to implementation. The aim of this research is to explore the psychological impact of having a cancer signal detected following an MCED blood test.Methods and analysisThe project is embedded in the NHS-Galleri trial (ISRCTN91431511; NCT05611632), a large clinical trial in eight Cancer Alliances in England. In the trial, over 140 000 members of the general population aged 50–77 have been randomised 1:1 to either the intervention (blood tested with MCED test) or control (blood stored) arm. The proposed project focuses on participants in the intervention arm, who have a cancer signal detected. All participants who have a cancer signal detected (expected to be around 700 assuming a 1% test positive rate) will be sent a questionnaire at three timepoints: soon after receiving their result, 6 months and approximately 12 months later. The primary outcome is anxiety, assessed using the short-form 6-item Spielberger State Trait Anxiety Inventory. We will also assess the psychological consequences of screening (using the Psychological Consequences of Screening Questionnaire), reassurance/concern about the test result, understanding of results and help/health-seeking behaviour. A subsample of 40 participants (20 with a cancer diagnosis and 20 for whom no cancer was found) will be invited to take part in a one-to-one semistructured interview.Ethics and disseminationEthical approval for this work has been granted by the Wales Research Ethics Committee as part of the NHS-Galleri trial (Ref 21/WA/0141). Consent to be sent questionnaires is collected as part of the main trial. A separate consent form will be required for interview. Results will be disseminated via peer-reviewed publication and conference presentations.

Although breast density is a powerful factor for predicting the risk of developing breast cancer, unfortunately current methods of measuring mammographic density are not entirely satisfactory. This Review analyzes the different factors affecting breast density and how to consider them so that the accuracy of individual risk assessments can be improved. High mammographic density is associated with an increased risk of breast cancer, and of all known breast cancer risk factors has the greatest attributable fraction. Mammographic density is estimated to account for 16% of all breast cancers, but can be altered by endogenous and exogenous hormonal factors, and generally declines with age. Confounding factors such as age, parity, menopausal status and BMI make the interpretation of mammographic density particularly challenging. Furthermore, none of the established means of measuring mammographic density are entirely satisfactory because they are time consuming or subjective. It is hoped that by adding information regarding mammographic density to existing models of breast cancer risk assessment, the accuracy of individual risk assessments can be improved. Although mammographic density has clearly been shown to be a powerful factor for predicting the risk of developing breast cancer, its potential role in assessing hormonal preventive regimens and helping to tailor screening algorithms cannot be fully realized until we have more-precise, simple and reproducible density measures. Key Points Mammographic density appears as white areas on a mammogram and it comprises fibroglandular tissue, stroma and epithelium within the breast The current ways of measuring mammographic density are time consuming and subjective Mammographic density is one of the most important indicators of breast cancer risk; the greater the mammographic density the greater the breast cancer risk Mammographic density can be altered by endogenous and exogenous hormonal factors, and generally declines with age Models to predict a woman's risk of breast cancer from her mammographic density and other risk factors are currently being developed Mammographic density has considerable potential in risk stratification and in monitoring the effects of interventions in risk alteration, but further work on measuring density and risk prediction is required

IntroductionThe number of robotic-assisted hip replacement procedures has expanded globally with the intended aim of improving outcomes. Intraoperative robotic-arm systems add additional costs to total hip replacement (THR) surgery but may improve surgical precision and could contribute to diminished pain and improved function. Additionally, these systems may reduce the need for expensive revision surgery. Surgery with conventional instruments may be just as successful, quick and affordable. There is timely demand for a robust evaluation of this technology.Methods and analysisThe Robotic Arthroplasty Clinical and cost Effectiveness Randomised controlled trial for Hips (RACER-Hip) is a multicentre (minimum of six UK sites), participant–assessor blinded, randomised controlled trial. 378 participants with hip osteoarthritis requiring THR will be randomised (1:1) to receive robotic-assisted THR, or THR using conventional surgical instruments. The primary outcome is the Forgotten Joint Score at 12 months post-randomisation; a patient-reported outcome measure assessing participants’ awareness of their joint when undertaking daily activities. Secondary outcomes will be collected post-operatively (pain, blood loss and opioid usage) and at 3, 6, 12, 24 months, then 5 and 10 years postrandomisation (including function, pain, health-related quality of life, reoperations and satisfaction). Allocation concealment will be accomplished using a computer-based randomisation procedure on the day of surgery. Blinding methods include the use of sham incisions for marker clusters and blinded operation notes. The primary analysis will adhere to the intention-to-treat principle. Results will adhere to Consolidated Standards of Reporting Trials statements.Ethics and disseminationThe trial was approved by an ethics committee (Solihull Research Ethics Committee, 30 June 2021, IRAS: 295831). Participants will provide informed consent before agreeing to participate. Results will be disseminated using peer-reviewed journal publications, presentations at international conferences and through the use of social media. We will develop plans to disseminate to patients and public with our patient partners.Trial registration numberISRCTN13374625.

ObjectiveTourniquet use in total knee replacement (TKR) is believed to improve the bone-cement interface by reducing bleeding, potentially prolonging implant survival. This study aimed to compare the risk of revision for primary cemented TKR performed with or without a tourniquet.DesignWe analysed data from the National Joint Registry (NJR) for all primary cemented TKRs performed in England and Wales between April 2003 and December 2003. Kaplan-Meier plots and Cox regression were used to assess the influence of tourniquet use, age at time of surgery, sex and American Society of Anaesthesiologists (ASA) classification on risk of revision for all-causes.ResultsData were available for 16 974 cases of primary cemented TKR, of which 16 132 had surgery with a tourniquet and 842 had surgery without a tourniquet. At 10 years, 3.8% had undergone revision (95% CI 2.6% to 5.5%) in the no-tourniquet group and 3.1% in the tourniquet group (95% CI 2.8% to 3.4%). After adjusting for age at primary surgery, gender and primary ASA score, the HR for all-cause revision for cemented TKR without a tourniquet was 0.82 (95% CI 0.57 to 1.18).ConclusionsWe did not find evidence that using a tourniquet for primary cemented TKR offers a clinically important or statistically significant reduction in the risk of all-cause revision up to 13 years after surgery. Surgeons should consider this evidence when deciding whether to use a tourniquet for cemented TKR.

Recent advancement in the immunological understanding of genesis of hepatocellular carcinoma (HCC) has implicated a decline in anti-tumour immunity on the background of chronic inflammatory state of liver parenchyma. The development of HCC involves a network of immunological activity in the tumour microenvironment involving continuous interaction between tumour and stromal cells. The reduction in anti-tumour immunity is secondary to changes in various immune cells and cytokines, and the tumour microenvironment plays a critical role in modulating the process of liver fibrosis, hepatocarcinogenesis, epithelial-mesenchymal transition (EMT), tumor invasion and metastasis. Thus, it is considered as one of primary factor behind the despicable tumour behavior and observed poor survival; along with increased risk of recurrence following treatment in HCC. The primary intent of the present review is to facilitate the understanding of the complex network of immunological interactions of various immune cells, cytokines and tumour cells associated with the development and progression of HCC.

A majority of hepatocellular carcinoma (HCC) develops in the setting of persistent chronic inflammation as immunological mechanisms have been shown to play a vital role in the initiation, growth and progression of tumours. The index review has been intended to highlight ongoing immunological changes in the hepatic parenchyma responsible for the genesis and progression of HCC. The in-situ vaccine effect of radiofrequency (RF) is through generation tumour-associated antigens (TAAs), following necrosis and apoptosis of tumour cells, which not only re-activates the antitumour immune response but can also act in synergism with checkpoint inhibitors to generate a superlative effect with intent to treat primary cancer and distant metastasis. An improved understanding of oncogenic responses of immune cells and their integration into signaling pathways of the tumour microenvironment will help in modulating the antitumour immune response. Finally, we analyzed contemporary literature and summarised the recent advances made in the field of targeted immunotherapy involving checkpoint inhibitors along with RF application with the intent to reinstate antitumour immunity and outline future directives in very early and early stages of HCC.

Background Behavioural problems are common in early childhood, and can result in enduring costs to the individual and society, including an increased risk of mental and physical illness, criminality, educational failure and drug and alcohol misuse. Most previous research has examined the impact of interventions targeting older children when difficulties are more established and harder to change, and have rarely included fathers. We are conducting a trial of a psychological intervention delivered to families with very young children, engaging both parents where possible. Methods This study is a two-arm, parallel group, researcher-blind, randomized controlled trial, to test the clinical effectiveness and cost-effectiveness of a parenting intervention, Video Feedback Intervention to Promote Positive Parenting and Sensitive Discipline (VIPP-SD) for parents of young children (12–36 months) at risk of behavioural difficulties. VIPP-SD is an evidence-based parenting intervention developed at Leiden University in the Netherlands which uses a video-feedback approach to support parents, particularly by enhancing parental sensitivity and sensitive discipline in caring for children. The trial will involve 300 families, who will be randomly allocated into either an intervention group, who will receive the video-feedback intervention (n = 150), or a control group, who will receive treatment as usual (n = 150). The trial will evaluate whether VIPP-SD, compared to treatment as usual, leads to lower levels of behavioural problems in young children who are at high risk of developing these difficulties. Assessments will be conducted at baseline, and 5 and 24 months post-randomization. The primary outcome measure is a modified version of the Preschool Parental Account of Child Symptoms (Pre-PACS), a structured clinical interview of behavioural symptoms. Secondary outcomes include caregiver-reported behavioural difficulties, parenting behaviours, parental sensitivity, parental mood and anxiety and parental relationship adjustment. An economic evaluation will also be carried out to assess the cost-effectiveness of the intervention compared to treatment as usual. Discussion If shown to be effective, the intervention could be delivered widely to parents and caregivers of young children at risk of behavioural problems as part of community based services. Trial registration ISRCTN Registry: ISRCTN58327365 . Registered 19 March 2015.

IntroductionTourniquets are routinely used during total knee replacement (TKR) surgery. They could increase the risk of thromboembolic events including cerebral emboli, cognitive decline, pain and other adverse events (AEs). A randomised controlled trial to assess whether tourniquet use might safely be avoided is therefore warranted but it is unclear whether such a trial would be feasible.MethodsIn a single-site feasibility study and pilot randomised controlled trial, adults having a TKR were randomised to surgery with an inflated tourniquet versus a non-inflated tourniquet. Participants underwent brain MRI preoperatively and within 2 days postoperatively. We assessed cognition using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Oxford Cognitive Screen (OCS) and thigh pain using a Visual Analogue Scale at baseline and days 1 and 2, and 1 week postsurgery. AEs related to surgery were recorded up to 12 months.ResultsWe randomised 53 participants (27 tourniquet inflated and 26 tourniquet not inflated). Fifty-one participants received care per-protocol (96%) and 48 (91%) were followed up at 12 months. One new ischaemic brain lesion was detected. Of the cognitive tests, MoCA was easy to summarise, sensitive to change with lower ceiling effects compared with OCS and MMSE. There was a trend towards more thigh pain (mean 49.6 SD 30.4 vs 36.2 SD 28 at day 1) and more AEs related to surgery (21 vs 9) in participants with an inflated tourniquet compared with those with a tourniquet not inflated.ConclusionA full trial is feasible, but using MRI as a primary outcome is unlikely to be appropriate or feasible. Suitable primary outcomes would be cognition measured using MoCA, pain and AEs, all of which warrant investigation in a large multicentre trial.Trial registration numberISRCTN20873088.