Clinical and cost effectiveness of endoscopic bipolar radiofrequency ablation for the treatment of malignant biliary obstruction: a systematic review.

Background: Early evidence suggests that using radiofrequency ablation as an adjunct to standard care (i.e. endoscopic retrograde cholangiopancreatography with stenting) may improve outcomes in patients with malignant biliary obstruction. Objectives: To assess the clinical effectiveness, cost-effectiveness and potential risks of endoscopic bipolar radiofrequency ablation for malignant biliary obstruction, and the value of future research. Data sources: Seven bibliographic databases, three websites and seven trials registers were searched from 2008 until 21 January 2021. Review methods: The study inclusion criteria were as follows: patients with biliary obstruction caused by any form of unresectable malignancy; the intervention was reported as an endoscopic biliary radiofrequency ablation to ablate malignant tissue that obstructs the bile or pancreatic ducts, either to fit a stent (primary radiofrequency ablation) or to clear an obstructed stent (secondary radiofrequency ablation); the primary outcomes were survival, quality of life or procedure-related adverse events; and the study design was a controlled study, an observational study or a case report. Risk of bias was assessed using Cochrane tools. The primary analysis was meta-analysis of the hazard ratio of mortality. Subgroup analyses were planned according to the type of probe, the type of stent (i.e. metal or plastic) and cancer type. A de novo Markov model was developed to model cost and quality-of-life outcomes associated with radiofrequency ablation in patients with primary advanced bile duct cancer. Insufficient data were available for pancreatic cancer and secondary bile duct cancer. An NHS and Personal Social Services perspective was adopted for the analysis. A probabilistic analysis was conducted to estimate the incremental cost-effectiveness ratio for radiofrequency ablation and the probability that radiofrequency ablation was cost-effective at different thresholds. The population expected value of perfect information was estimated in total and for the effectiveness parameters. Results: Sixty-eight studies (1742 patients) were included in the systematic review. Four studies (336 participants) were combined in a meta-analysis, which showed that the pooled hazard ratio for mortality following primary radiofrequency ablation compared with a stent-only control was 0.34 (95% confidence interval 0.21 to 0.55). Little evidence relating to the impact on quality of life was found. There was no evidence to suggest an increased risk of cholangitis or pancreatitis, but radiofrequency ablation may be associated with an increase in cholecystitis. The results of the cost-effectiveness analysis were that the costs of radiofrequency ablation was £2659 and radiofrequency ablation produced 0.18 quality-adjusted life-years, which was more than no radiofrequency ablation on average. With an incremental cost-effectiveness ratio of £14,392 per quality-adjusted life-year, radiofrequency ablation was likely to be cost-effective at a threshold of £20,000 per quality-adjusted life-year across most scenario analyses, with moderate uncertainty. The source of the vast majority of decision uncertainty lay in the effect of radiofrequency ablation on stent patency. Limitations: Only 6 of 18 comparative studies contributed to the survival meta-analysis, and few data were found concerning secondary radiofrequency ablation. The economic model and cost-effectiveness meta-analysis required simplification because of data limitations. Inconsistencies in standard reporting and study design were noted. Conclusions: Primary radiofrequency ablation increases survival and is likely to be cost-effective. The evidence for the impact of secondary radiofrequency ablation on survival and of quality of life is limited. There was a lack of robust clinical effectiveness data and, therefore, more information is needed for this indication. Future work: Future work investigating radiofrequency ablation must collect quality-of-life data. High-quality randomised controlled trials in secondary radiofrequency ablation are needed, with appropriate outcomes recorded. Study registration: This study is registered as PROSPERO CRD42020170233. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 7. See the NIHR Journals Library website for further project information.

The bile and pancreatic ducts transport fluids to the intestines to help people digest their food properly. Some types of cancer can cause these ducts to become totally or partially blocked. We wanted to know if endoscopic radiofrequency ablation is safe and works well to treat people who have one of these blockages that cannot be removed by surgery. Radiofrequency ablation burns away a blockage by hitting it with radio waves. Endoscopic means that the radio waves are directed to the blockage using a thin, tube-like wire with a camera at the end. During radiofrequency ablation, a person might have a small tube called a stent put into their bile or pancreatic duct to keep it open or to replace an already blocked stent.

We searched for research studies that looked at (1) whether or not radiofrequency ablation was able to remove blockages from the ducts, (2) if radiofrequency ablation allowed people to live longer, (3) if patients had a better quality of life after radiofrequency ablation, (4) if radiofrequency ablation caused any side effects and (5) how much it costs to treat people with radiofrequency ablation.

We found that treatment with radiofrequency ablation before giving a person a stent helped them to live a little longer with their cancer. We did not find any evidence that radiofrequency ablation increased pain or swelling in the bile duct or pancreatic duct. Radiofrequency ablation might cause more swelling in the gall bladder than having a stent without radiofrequency ablation, but there was not enough research available for us to be certain of this.

Radiofrequency ablation before inserting a stent could be a safe option to add to treatment of bile and pancreatic duct blockages caused by cancer. There is limited research evidence and so we are unable to recommend radiofrequency ablation as a treatment for standard clinical practice.

Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial.

Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (NFKBIE) and 24% (SF3B1). Mutations beyond Sanger resolution (<12% VAF) were observed in all genes, with KRAS mutations principally composed of these low VAF variants. Firstly, employing orthogonal approaches to confirm <12% VAF TP53 mutations, we assessed the clinical impact of TP53 clonal architecture. Whilst ≥ 12% VAF TP53mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between <12% VAF TP53 mutations and either wild type or ≥12% VAF TP53mut cases. Secondly, we identified biallelic BIRC3 lesions (mutation and deletion) as an independent marker of inferior PFS and OS. Finally, we observed that mutated MAPK-ERK genes were independent markers of poor OS in multivariate survival analysis. In conclusion, our study supports using targeted resequencing of expanded gene panels to elucidate the prognostic impact of gene mutations.

Characterization of Somatically-Acquired Copy Number Alterations in Chronic Lymphocytic Leukaemia Using Shallow Whole Genome Sequencing.

Shallow whole genome sequencing (sWGS) is a simple, robust, and cost-effective technique recently optimized for the identification of copy number aberrations (CNAs) in tumor samples. This multiplexed methodology sequences 50 bp from one end of the DNA molecule, generating ˜0.1× coverage, and utilizes the observed sequence depth across the genome to infer copy number. It is amenable to low quantities of input DNA, sequencing costs are modest, processing is compatible with low-output instruments, and downstream analysis is simplified by the use of freely available bioinformatics tools and a data analysis package written especially for the analysis of sWGS data. It is the aim of this chapter to introduce the fundamental concepts of sWGS and to provide an overview of the steps involved in a successful sWGS experiment.

Supporting Looked After Children and Care Leavers In Decreasing Drugs, and alcohol (SOLID): protocol for a pilot feasibility randomised controlled trial of interventions to decrease risky substance use (drugs and alcohol) and improve mental health of looked after children and care leavers aged 12-20 years.

BACKGROUND: Looked after children (LAC) and care leavers are young people who have been placed under the legal care of local authorities, in many instances due to a history of abuse and/or neglect. These young people have a significantly increased risk of substance use and mental disorder compared to their peers. The aim of the SOLID study is to assess the feasibility and acceptability of a definitive three-arm multi-centre randomised controlled trial (RCT) that compares the effectiveness of two interventions that aim to reduce risky drug and alcohol use and improve mental health among LAC aged 12 to 20 years with usual care. METHODS: All LAC aged 12 to 20 years residing in four local authorities in North East England will be screened by their social worker for risky drug and alcohol use using the CRAFFT (Car, Relax, Alone, Forget, Friends and Trouble) screening tool. Those who score ≥2 will be invited to take part in the trial after further eligibility checks. Informed consent will be taken and baseline data collected. Participants will then be randomised into either (i) Motivational Enhancement Therapy, (ii) Social Behaviour and Network Therapy, or (iii) control-usual care. Follow-up data will be collected 12 months post-baseline. The baseline and follow-up questionnaires will measure self-reported drug and alcohol use, mental health and well-being and health-related quality of life. The follow-up will also collect data on placement stability and self-reported sexual, antisocial and criminal behaviour. Participants will also be asked about the use of health and social services. A detailed process evaluation, using both qualitative and quantitative methods, will be conducted and involve LAC, their carers, social workers and drug and alcohol practitioners. DISCUSSION: Despite having an increased likelihood of risky substance misuse, there is a lack of evidence outlining specific interventions to decrease drug and alcohol use targeting LAC. This feasibility study will provide the information needed to develop a definitive trial. LAC will benefit from the results of this study and the further development of the interventions. TRIAL REGISTRATION: ISRCTN80786829.

Examining the implementation of NICE guidance: cross-sectional survey of the use of NICE interventional procedures guidance by NHS Trusts.

BACKGROUND: In the UK, NHS hospitals receive large amounts of evidence-based recommendations for care delivery from the National Institute for Health and Care Excellence (NICE) and other organisations. Little is known about how NHS organisations implement such guidance and best practice for doing so. This study was therefore designed to examine the dissemination, decision-making, and monitoring processes for NICE interventional procedures (IP) guidance and to investigate the barriers and enablers to the implementation of such guidance. METHODS: A cross-sectional survey questionnaire was developed and distributed to individuals responsible for managing the processes around NICE guidance in all 181 acute NHS hospitals in England, Scotland, Wales and Northern Ireland. A review of acute NHS hospital policies for implementing NICE guidance was also undertaken using information available in the public domain and from organisations' websites. RESULTS: The response rate to the survey was 75 % with 135 completed surveys received. Additionally, policies from 25 % of acute NHS hospitals were identified and analysed. NHS acute hospitals typically had detailed processes in place to implement NICE guidance, although organisations recognised barriers to implementation including organisational process barriers, clinical engagement and poor targeting with a large number of guidance issued. Examples of enablers to, and good practice for, implementation of guidance were found, most notably the value of shared learning experiences between NHS hospitals. Implications for NICE were also identified. These included making improvements to the layout of guidance, signposting on the website and making better use of their shared learning platform. CONCLUSIONS: Most organisations have robust processes in place to deal with implementing guidance. However, resource limitations and the scope of guidance received by organisations create barriers relating to organisational processes, clinician engagement and financing of new procedures. Guidance implementation can be facilitated through encouragement of shared learning by organisations such as NICE and open knowledge transfer between organisations.

CONSUMER PREFERENCES FOR SCANNING MODALITY TO DIAGNOSE FOCAL LIVER LESIONS.

OBJECTIVES: Differences in the process of using liver imaging technologies might be important to patients. This study aimed to investigate preferences for scanning modalities used in diagnosing focal liver lesions. METHODS: A discrete choice experiment was administered to 504 adults aged 25 ≥years. Respondents made repeated choices between two hypothetical scans, described according to waiting time for scan and results, procedure type, the chance of minor side-effects, and whether further scanning procedures were likely to be required. Choice data were analyzed using mixed-logit models with respondent characteristics used to explain preference heterogeneity. RESULTS: Respondents preferred shorter waiting times, the procedure to be undertaken with a handheld scanner on a couch instead of within a body scanner, no side-effects, and no follow­up scans (p≤.01). The average respondent was willing to wait an additional 2 weeks for the scan if it resulted in avoiding side-effects, 1.5 weeks to avoid further procedures or to be told the results immediately, and 1 week to have the scan performed on a couch with a handheld scanner. However, substantial heterogeneity was observed in the strength of preference for desirable imaging characteristics. CONCLUSIONS: An average individual belonging to a general population sub­group most likely to require imaging to characterize focal liver lesions in the United Kingdom would prefer contrast­enhanced ultrasound over magnetic resonance imaging or computed tomography. Insights into the patient perspective around differential characteristics of imaging modalities have the potential to be used to guide recommendations around the use of these technologie

A review of the economic tools for assessing new medical devices.

Whereas the economic evaluation of pharmaceuticals is an established practice within international health technology assessment (HTA) and is often produced with the support of comprehensive methodological guidance, the equivalent procedure for medical devices is less developed. Medical devices, including diagnostic products, are a rapidly growing market in healthcare, with over 10,000 medical technology patent applications filed in Europe in 2012-nearly double the number filed for pharmaceuticals. This increase in the market place, in combination with the limited, or constricting, budgets that healthcare decision makers face, has led to a greater level of examination with respect to the economic evaluation of medical devices. However, methodological questions that arise due to the unique characteristics of medical devices have yet to be addressed fully. This review of journal publications and HTA guidance identified these characteristics and the challenges they may subsequently pose from an economic evaluation perspective. These unique features of devices can be grouped into four categories: (1) data quality issues; (2) learning curve; (3) measuring long-term outcomes from diagnostic devices; and (4) wider impact from organisational change. We review the current evaluation toolbox available to researchers and explore potential future approaches to improve the economic evaluation of medical devices.

Heterogeneity in patient diagnostic pathways: an example from contrast-enhanced ultrasound diagnostic scans for focal liver lesions.

BACKGROUND: The UK's National Institute for Health and Care Excellence (NICE) has recommended contrast-enhanced ultrasound (CEUS) for the characterisation of focal liver lesions where the results of standard unenhanced ultrasound are inconclusive. A further recommendation is for CEUS to replace other imaging modalities. However, little is currently known about the diagnostic pathways in the National Health Service (NHS) followed by patients with potential liver lesions. The aim of this study was to identify the diagnostic pathways for a number of representative hospital trusts and record the clinicians' views on patient experiences of these processes through a series of semi-structured interviews with UK clinicians (radiologists and sonographers) (N = 7). This study was undertaken in the broader context of a larger research project where the overarching research question is focused on patient preferences for CEUS and other imaging modalities, and how these impact on patient quality of life (QOL). RESULTS: The results from the semi-structured interviews with UK clinicians revealed that there is a great deal of heterogeneity in diagnostic pathways followed by patients with potential liver lesions which differ both within and between hospitals. In terms of the patient experience, the clinicians believed that a combination of the more patient-friendly ultrasound process, and the fact that scan results are given to patients in 80-90% of cases on the day, as well as the problems inherent to other scan modalities (claustrophobia, anxiety) would lead to patients preferring ultrasound compared with other imaging modalities (CT or MR). However, current clinical practice means that patient choice is virtually non-existent. CONCLUSIONS: The significant variation in diagnostic pathways across the NHS will require further standardisation through local agreements if contrast-enhanced ultrasound is to replace other imaging modalities in characterising focal liver lesions in line with NICE Diagnostics Guidance. The gradual development of patient choice of modalities may necessitate a change of practice in radiology processes.