Behavioural intervention to promote the uptake of planned care in urgent dental care attenders: a feasibility randomised controlled trial.

BACKGROUND: Urgent dental care may be the only place where many people, especially vulnerable groups, access care. This presents an opportunity for delivery of a behavioural intervention promoting planned dental visiting, which may help address one of the factors contributing to a socio-economic gradient in oral health. Although we know that cueing events such as having a cancer diagnosis may create a 'teachable moment' stimulating positive changes in health behaviour, we do not know whether delivering an opportunistic intervention in urgent dental care is feasible and acceptable to patients. METHODS: The feasibility study aimed to recruit 60 patients in a Dental Hospital and dental practices delivering urgent care within and outside working hours. Follow-up was by telephone, e mail and post over 4 months. RESULTS: Although the recruitment window was shortened because of COVID-19, of 47 patients assessed for eligibility, 28 were enrolled (70.1% of screened patients provided consent). A relatively high proportion were from disadvantaged backgrounds (46.4%, 13/28 receiving State benefits). Retention was 82.1% (23/28), which was also the rate of completion of the Oral Health Impact Profile co-primary outcome. The other primary outcome involved linking participant details at recruitment, with centrally-held data on services provided, with 84.6% (22/26) records partly or fully successfully matched. All intervention participants received at least some of the intervention, although we identified aspects of dental nurse training which would improve intervention fidelity. CONCLUSIONS: Despite recruitment being impacted by the pandemic, when the majority of clinical trials experienced reduced rates of recruitment, we found a high recruitment and consenting rate, even though patients were approached opportunistically to be enrolled in the trial and potentially receive an intervention. Retention rates were also high even though a relatively high proportion had a low socio-economic background. Therefore, even though patients may be in pain, and had not anticipated involvement before their urgent care visit, the study indicated that this was a feasible and acceptable setting in which to position an opportunistic intervention. This has the potential to harness the potential of the 'teachable moment' in people's lives, and provide support to help address health inequalities. TRIAL REGISTRATION: ISRCTN 10,853,330 07/10/2019.

IntAct: intra-operative fluorescence angiography to prevent anastomotic leak in rectal cancer surgery: a randomized controlled trial.

AIM: Anastomotic leak (AL) is a major complication of rectal cancer surgery. Despite advances in surgical practice, the rates of AL have remained static, at around 10-15%. The aetiology of AL is multifactorial, but one of the most crucial risk factors, which is mostly under the control of the surgeon, is blood supply to the anastomosis. The MRC/NIHR IntAct study will determine whether assessment of anastomotic perfusion using a fluorescent dye (indocyanine green) and near-infrared laparoscopy can minimize the rate of AL leak compared with conventional white-light laparoscopy. Two mechanistic sub-studies will explore the role of the rectal microbiome in AL and the predictive value of CT angiography/perfusion studies. METHOD: IntAct is a prospective, unblinded, parallel-group, multicentre, European, randomized controlled trial comparing surgery with intra-operative fluorescence angiography (IFA) against standard care (surgery with no IFA). The primary end-point is rate of clinical AL at 90 days following surgery. Secondary end-points include all AL (clinical and radiological), change in planned anastomosis, complications and re-interventions, use of stoma, cost-effectiveness of the intervention and quality of life. Patients should have a diagnosis of adenocarcinoma of the rectum suitable for potentially curative surgery by anterior resection. Over 3 years, 880 patients from 25 European centres will be recruited and followed up for 90 days. DISCUSSION: IntAct will rigorously evaluate the use of IFA in rectal cancer surgery and explore the role of the microbiome in AL and the predictive value of preoperative CT angiography/perfusion scanning.

Cost-effectiveness analysis of PET-CT-guided management for locally advanced head and neck cancer.

BACKGROUND: A recent large United Kingdom (UK) clinical trial demonstrated that positron-emission tomography-computed tomography (PET-CT)-guided administration of neck dissection (ND) in patients with advanced head and neck cancer after primary chemo-radiotherapy treatment produces similar survival outcomes to planned ND (standard care) and is cost-effective over a short-term horizon. Further assessment of long-term outcomes is required to inform a robust adoption decision. Here we present results of a lifetime cost-effectiveness analysis of PET-CT-guided management from a UK secondary care perspective. METHODS: Initial 6-month cost and health outcomes were derived from trial data; subsequent incidence of recurrence and mortality was simulated using a de novo Markov model. Health benefit was measured in quality-adjusted life years (QALYs) and costs reported in 2015 British pounds. Model parameters were derived from trial data and published literature. Sensitivity analyses were conducted to assess the impact of uncertainty and broader National Health Service (NHS) and personal social services (PSS) costs on the results. RESULTS: PET-CT management produced an average per-person lifetime cost saving of £1485 and an additional 0.13 QALYs. At a £20,000 willingness-to-pay per additional QALY threshold, there was a 75% probability that PET-CT was cost-effective, and the results remained cost-effective over the majority of sensitivity analyses. When adopting a broader NHS and PSS perspective, PET-CT management produced an average saving of £700 and had an 81% probability of being cost-effective. CONCLUSIONS: This analysis indicates that PET-CT-guided management is cost-effective in the long-term and supports the case for wide-scale adoption.

Costs of cancer care for use in economic evaluation: a UK analysis of patient-level routine health system data.

BACKGROUND: The rising financial burden of cancer on health-care systems worldwide has led to the increased demand for evidence-based research on which to base reimbursement decisions. Economic evaluations are an integral component of this necessary research. Ascertainment of reliable health-care cost and quality-of-life estimates to inform such studies has historically been challenging, but recent advances in informatics in the United Kingdom provide new opportunities. METHODS: The costs of hospital care for breast, colorectal and prostate cancer disease-free survivors were calculated over 15 months from initial diagnosis of cancer using routinely collected data within a UK National Health Service (NHS) Hospital Trust. Costs were linked at patient level to patient-reported outcomes and registry-derived sociodemographic factors. Predictors of cost and the relationship between costs and patient-reported utility were examined. RESULTS: The study population included 223 breast cancer patients, 145 colorectal and 104 prostate cancer patients. The mean 15-month cumulative health-care costs were £12 595 (95% CI £11 517-£13 722), £12 643 (£11 282-£14 102) and £3722 (£3263-£4208), per-patient respectively. The majority of costs occurred within the first 6 months from diagnosis. Clinical stage was the most important predictor of costs for all cancer types. EQ-5D score was predictive of costs in colorectal cancer but not in breast or prostate cancer. CONCLUSION: It is now possible to evaluate health-care cost using routine NHS data sets. Such methods can be utilised in future retrospective and prospective studies to efficiently collect economic data.

The cost-effectiveness of primary care referral to a UK commercial weight loss programme.

Primary care referral to commercial weight loss programmes that follow best practice is included in current UK guidance on the management of adult obesity. This study investigated whether such a programme was cost-effective compared with usual care. A decision-analytical Markov model was developed to estimate the lifetime costs and benefits of the referral programme compared with usual care and enable a cost-utility analysis. The model cohort transited between body mass index classifications and type 2 diabetes, stroke and myocardial infarction (MI) with risk, cost and effect parameter values taken from published literature. The cost per incremental quality-adjusted life year (QALY) was calculated. Extensive deterministic and scenario sensitivity analyses and probabilistic sensitivity analyses (PSA) were conducted. At 12 months, the incremental cost-effectiveness ratio was £6906, indicating that programme referral was cost-effective. Over a lifetime, referral to the commercial programme was dominant as it led to a cost saving of £924 and conferred incremental benefit (0.22 QALY) over usual care. Model simulations estimated lower lifetime rates of type 2 diabetes, stroke and MI as a result of the weight loss achieved. The results were robust to extensive sensitivity analyses. The PSA indicated that programme referral had a 68% chance of being cost-effective at a willingness to pay per incremental QALY threshold of £20,000. Referral to the programme dominated usual care, being both cheaper and more effective. These results compare favourably with economic evaluations of other obesity interventions and add to a growing evidence base on the cost-effectiveness of commercial weight loss providers and practices.

The effectiveness and cost-effectiveness of acupressure for the control and management of chemotherapy-related acute and delayed nausea: Assessment of Nausea in Chemotherapy Research (ANCHoR), a randomised controlled trial.

BACKGROUND: Chemotherapy-induced nausea and vomiting remain difficult symptoms to manage in clinical practice. As standard antiemetic drugs do not fully eliminate these symptoms, it is important to explore the adjuvant role of non-pharmacological and complementary therapies in antiemetic management approaches. Acupressure is one such treatment showing highly suggestive evidence so far of a positive effect, meriting further investigation. OBJECTIVES: The primary objective was to assess the effectiveness and cost-effectiveness of self-acupressure using wristbands compared with sham acupressure wristbands and standard care alone in the management of chemotherapy-induced nausea. Secondary objectives included assessment of the effectiveness and cost-effectiveness of the wristbands in relation to vomiting and quality of life and exploration of any age, gender and emetogenic risk effects. DESIGN: Randomised three-arm sham-controlled trial (Assessment of Nausea in Chemotherapy Research or ANCHoR) with an economic evaluation. Arms include the wristband arm, the sham wristband arm and the standard care only arm. Randomisation consisted of minimisation with a random element balancing for gender, age (16-24, > 24-50, >50 years) and three levels of emetogenic chemotherapy (low, moderate and high). Qualitative interviews were incorporated to shed more light on the quantitative findings. SETTING: Outpatient chemotherapy clinics in three regions in the UK involving 14 different cancer units/centres. PARTICIPANTS: Chemotherapy-naive cancer patients receiving chemotherapy of low, moderate and high emetogenic risk. INTERVENTION: The intervention was acupressure wristbands pressing the P6 point (anterior surface of the forearm). MAIN OUTCOME MEASURES: The Rhodes Index for Nausea/Vomiting, the Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool and the Functional Assessment of Cancer Therapy - General (FACT-G). At baseline participants completed measures of anxiety/depression, nausea/vomiting expectation and expectations from using the wristbands. RESULTS: In total, 500 patients were randomised in the study arms (166 standard care, 166 sham acupressure and 168 acupressure) and data were available for 361 participants for the primary outcome. The primary outcome analysis (nausea in cycle 1) revealed no statistically significant differences between the three arms, although the median nausea experience in patients using wristbands (both real and sham ones) was somewhat lower than that in the antiemetics only group (median nausea experience scores for the four cycles: standard care arm 1.43, 1.71, 1.14, 1.14; sham acupressure arm 0.57, 0.71, 0.71, 0.43; acupressure arm 1.00, 0.93, 0.43, 0). A gender effect was evident (p= 0.002), with women responding more favourably to the use of sham acupressure wristbands than men (odds ratio 0.35 for men and 2.02 for women in the sham acupressure group; 1.27 for men and 1.17 for women in the acupressure group). This suggests a placebo effect. No significant differences were detected in relation to vomiting outcomes, anxiety and quality of life. Some transient adverse effects were reported, including tightness in the area of the wristbands, feeling uncomfortable when wearing them and minor swelling in the wristband area (n= 6).There were no statistically significant cost differences associated with the use of real acupressure bands (£70.66 for the acupressure group, £111.13 for the standard care group and £161.92 for the sham acupressure group). In total, 26 subjects took part in qualitative interviews. The qualitative data suggested that participants perceived the wristbands (both real and sham) as effective and helpful in managing their nausea during chemotherapy. CONCLUSIONS: There were no statistically significant differences between the three arms in terms of nausea, vomiting and quality of life, although apparent resource use was less in both the real acupressure arm and the sham acupressure arm compared with standard care only; therefore; no clear conclusions can be drawn about the use of acupressure wristbands in the management of chemotherapy-related nausea and vomiting. However, the study provided encouraging evidence in relation to an improved nausea experience and some indications of possible cost savings to warrant further consideration of acupressure both in practice and in further clinical trials. TRIAL REGISTRATION: ISRCTN87604299. SOURCE OF FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 26. See the HTA programme website for further project information.

Selecting breast cancer patients for chemotherapy: the opening of the UK OPTIMA trial.

The mortality from breast cancer has improved steadily over the past two decades, in part because of the increased use of more effective adjuvant therapies. Thousands of women are routinely treated with intensive chemotherapy, which can be unpleasant, is expensive and is occasionally hazardous. Oncologists have long known that some of these women may not need treatment, either because they have a low risk of relapse or because they have tumour biology that makes them less sensitive to chemotherapy and more suitable for early adjuvant endocrine therapy. There is an urgent need to improve patient selection so that chemotherapy is restricted to those patients who will benefit from it. Here we review the emerging technologies that are available for improving patient selection for chemotherapy. We describe the OPTIMA trial, which has just opened to recruitment in the UK, is the latest addition to trials in this area, and is the first to focus on the relative cost-effectiveness of alternate predictive assays.

A systematic review and economic evaluation of the use of tumour necrosis factor-alpha (TNF-α) inhibitors, adalimumab and infliximab, for Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a severe, lifelong disease characterised by inflammation of the gastrointestinal mucosa. The impact on patients and society is high as ill health can be lifelong and can negatively affect patients' quality of life. Costs to the NHS are high, particularly for patients needing hospitalisation. Conventional treatment pathways are complex. More recently, a group of drugs called tumour necrosis factor (TNF) inhibitors (anti-TNF-α agents) have been evaluated for their effectiveness in CD. One of these, infliximab, is currently recommended by the National Institute for Health and Clinical Excellence (NICE; 2002) for patients with severe, active CD where patients are refractory to or intolerant of conventional treatment. OBJECTIVES: To investigate whether there is evidence for greater clinical effectiveness or cost-effectiveness for either adalimumab or infliximab. DATA SOURCES: Cochrane Library (Cochrane Central Register of Controlled Trials) 2007 Issue 2; MEDLINE (Ovid) 2000 to May/June 2007; MEDLINE In-Process & Other Non-Indexed Citations (Ovid) 4 June and 26 June 2007; EMBASE (Ovid) 2000 to May/June 2007. The European Medicines Agency, the US Food and Drug Administration and other relevant websites. REVIEW METHODS: Standard systematic review methods were used for study identification and selection, data extraction and quality assessment. Only randomised controlled trials (RCTs) comparing adalimumab or infliximab with standard treatment (placebo), RCTs comparing adalimumab with infliximab, or RCTs comparing different dosing regimens of either adalimumab or infliximab in adults and children with moderate-to-severe active CD intolerant or resistant to conventional treatment were eligible for inclusion. A systematic review of published studies on the cost and cost-effectiveness of adalimumab and infliximab was undertaken. The economic models of cost-effectiveness submitted by the manufacturers of both drugs were critically appraised and, where appropriate, rerun using parameter inputs based on the evidence identified by the authors of the technology asessment report. A de novo Markov state transition model was constructed to calculate the incremental cost-effectiveness ratio for adalimumab and infliximab therapy compared with standard care. RESULTS: Based on 11 trials, there was evidence from both induction and maintenance trials that both adalimumab and infliximab therapy were beneficial compared with placebo (standard care) for adults with moderate-to-severe CD and, for infliximab, for adults with fistulising CD; results were statistically significant for some time points. Between 6% and 24% (adalimumab), and 21% and 44% (infliximab) more patients achieved remission with anti-TNF-α antibodies than with placebo in the induction trials. Between 24% and 29% (adalimumab), and 14% and 24% (infliximab) more patients achieved remission with anti-TNF-α antibodies in the two large maintenance trials at reported follow-up. In fistulising CD, between 29% and 42% (induction trial) and 23% (maintenance trial) more patients achieved a > 50% reduction in fistulas with infliximab than with placebo at reported follow-up. There was no direct evidence to show that 'responders' were more likely to benefit from treatment than 'non-responders' in the longer term. Few differences were found between treatment and standard care arms for selected adverse events, though high proportions of scheduled crossovers resulted in a lack of a true placebo group in most of the maintenance trials. No published studies on the cost-effectiveness of adalimumab were identified. The four independently funded studies identified for infliximab suggested high cost-effectiveness ratios [all above £50,000/quality-adjusted life-year (QALY) for non-fistulising disease and all above £100,000/QALY for fistulising disease]. A budget impact assessment suggested that total cost to the NHS in England and Wales for induction in severe disease only could range between £17M and £92M and for maintenance for 1 year between £140M and £200M. LIMITATIONS: Regarding clinical effectiveness, there were concerns about the trial design and lack of clarity, which may have affected interpretation of results. None of the trials matched exactly the licence indications or NICE guidance, which specify the use of these drugs in patients with 'severe' disease. All trials were multicentre, and applicability to UK populations, particularly in terms of standard care being provided and in terms of patients having failed or having become intolerant to conventional treatment, was uncertain. The published economic models relied heavily on little information and data from small samples. CONCLUSIONS: Anti-TNF therapy with adalimumab or infliximab may have a beneficial effect compared with standard care on outcome measures for induction and maintenance. The findings were that for induction, both adalimumab and infliximab are cost-effective (dominant relative to standard care) in the management of severe CD, and adalimumab (but not infliximab) is cost-effective for moderate CD, according to limits generally accepted by NICE. On the basis of the analysis presented here, neither drug is likely to be cost-effective as maintenance therapy for moderate or severe disease. Perhaps, most importantly, the analysis reflected the fact that a substantial number of patients would achieve remission under standard care and that the incidence of relapse among those in remission was such that maintenance therapy would have to show greater effectiveness than at present and/or be much less costly than it currently is in order to reach the levels of generally accepted cost-effectiveness. Any future trials need to be designed to meet the particular challenges of measuring and quantifying benefit in this patient group. FUNDING: The research was funded by the HTA programme on behalf of NICE.

Imatinib as adjuvant treatment following resection of KIT-positive gastrointestinal stromal tumours.

This is a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of adjuvant imatinib post resection of KIT-positive gastrointestinal stromal tumours (GISTs) compared with resection only in patients at significant risk of relapse. The ERG report is based on the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The bulk of the clinical evidence submitted was in the form of one randomised controlled trial (RCT), the Z9001 trial, funded by the manufacturer, which compared resection + adjuvant imatinib for 1 year to resection only. Results were immature, with median recurrence-free survival (RFS) not yet having been reached at the time of analysis. The trial did provide evidence of a delay in disease recurrence [1-year RFS rate of 98% in the imatinib arm vs 83% in the placebo arm [hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.22 to 0.53, p < 0.0001)] but no evidence of an overall survival benefit. There was no long-term evidence around the rate of imatinib resistance over time with different treatment strategies (± adjuvant treatment). The relevant patient group for this appraisal is those at significant risk of relapse. These form a subgroup of the Z9001 trial, and all information regarding this group was designated 'Commercial-in-Confidence' (CIC). Median observation time for RFS was also CIC. The manufacturer constructed a Markov model comprising 10 health states designed to estimate costs and effects of treatment over a lifetime time horizon. The manufacturer's estimate of the base-case incremental cost-effectiveness ratio (ICER) was 22,937 pounds/quality-adjusted life-year (subsequently amended by the manufacturer to 23,601 pounds). While the structure of the model reasonably reflected the natural history of the disease, the ERG had numerous concerns regarding the selection of, and assumptions around, input parameters (utilities, monthly probabilities of recurrence and death). Furthermore, the model was set up in such a way that any delay in recurrence translated directly into a survival benefit, an assumption that has no evidence base. A further assumption not supported by evidence was that any treatment benefit gained in the first year is carried on for a further 2 years at the same rate. Appropriate probabilistic sensitivity analysis was undertaken on the base case only, but not on scenario analyses, or choice of model used to estimate long-term survival data. The model was not amenable to changes in input values, thus limiting any additional analyses by the ERG to test assumptions. Due to the large number of uncertainties and assumptions, the estimated ICERs should be regarded as highly uncertain. The guidance issued by NICE in June 2010 as a result of the STA does not recommend imatinib as adjuvant treatment after resection of gastrointestinal stromal tumours, although individuals currently receiving adjuvant imatinib should have the option to continue treatment until they and their clinician consider it appropriate to stop.

A self-administered questionnaire for basal osteoarthritis of the thumb.

Basal osteoarthritis of the thumb is a common condition for which numerous operations have been proposed without any particular one having been shown to be superior. One of the problems in evaluating the results of surgery is that there is no validated outcome score specifically for the condition. The purpose of this study was to construct a self-administered questionnaire (the Nelson score) to assess the outcome following surgery for this condition and to test its properties. Correlating the questionnaire score with physical findings on clinical examination showed external validity and test-retest reliability was high. Simultaneous administration of the score with the DASH score, both before and after surgery, showed it to be more sensitive to change (P=0.056). In addition, it is shorter than the DASH score, which may make it more acceptable to patients.

Orally active indole N-oxide PDE4 inhibitors.

This communication describes the synthesis and in vitro and in vivo evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. Several of the compounds presented possess low nanomolar IC50's for PDE4 inhibition and excellent in vivo activity for inhibition of TNF-alpha levels in LPS challenged mice (mouse endotoxemia model). Emesis studies (dog) and efficacy in a SCW arthritis model for the most potent PDE4 inhibitors are presented.

Comments on the use of a dichromophoric circular dichroism assay for the identification of beta-turns in peptides.

Use of the dichromophoric CD assay for beta-turn formation in peptide sequences has been investigated. The assay involves the observation of Cotton effects in CD spectra, originating from the approach of N- and C-terminal aromatic chromophores in tetrapeptides. The approach of the chromophores was believed to be brought about by a beta-turn in the peptide structure. Our investigations were paralleled by NMR studies which revealed the presence of a previously unreported hydrogen bond in the beta-turn conformers, which appears to play a role in the generation of the observed Cotton effects. This suggests caution in the use of the CD technique alone as an assay for beta-turn conformers in peptides.