The clinical and cost effectivementss of cognitive behavioural therapy plus treatment as usual for the treatment of depression in advanced cancer (CanTalk):study protocol for a radomised controlled trial

BACKGROUND: The prevalence of depressive disorder in adults with advanced cancer is around 20 %. Although cognitive behavioural therapy (CBT) is recommended for depression and may be beneficial in depressed people with cancer, its use for depression in those with advanced disease for whom cure is not likely has not been explored. METHODS: People aged 18 years and above with advanced cancer attending General Practitioner (GP), oncology or hospice outpatients from centres across England will be screened to establish a DSM-IV diagnosis of depression. Self-referral is also accepted. Eligible consenters will be randomised to a single blind, multicentre, randomised controlled trial of the addition to treatment as usual (TAU) of up to 12 one-hour weekly sessions of manualised CBT versus TAU alone. Sessions are delivered in primary care through Increasing Access to Psychological Care (IAPT) service, and the manual includes a focus on issues for people approaching the end of life. The main outcome is the Beck Depression Inventory-II (BDI-II). Subsidiary measures include the Patient Health Questionnaire, quality of life measure EQ-5D, Satisfaction with care, Eastern Cooperative Oncology Group-Performance Status and a modified Client Service Receipt Inventory. At 90 % power, we require 240 participants to enter the trial. Data will be analysed using multi-level (hierarchical) models for data collected at baseline, 6, 12, 18 and 24 weeks. Cost effectiveness analysis will incorporate costs related to the intervention to compare overall healthcare costs and QALYs between the treatment arms. We will conduct qualitative interviews after final follow-up on patient and therapist perspectives of the therapy. DISCUSSION: This trial will provide data on the clinical and cost effectiveness of CBT for people with advanced cancer and depression. We shall gain an understanding of the feasibility of delivering care to this group through IAPT. Our findings will provide evidence for policy-makers, commissioners and clinicians in cancer and palliative care, and in the community. TRIAL REGISTRATION: Controlled Trials ISRCTN07622709 , registered 15 July 2011

Manualised cognitive behavioural therapy in treating depression in advanced cancer:The CanTalk RCT

BACKGROUND: With a prevalence of up to 16.5%, depression is one of the commonest mental disorders in people with advanced cancer. Depression reduces the quality of life (QoL) of patients and those close to them. The National Institute for Health and Care Excellence (NICE) guidelines recommend treating depression using antidepressants and/or psychological treatments, such as cognitive-behavioural therapy (CBT). Although CBT has been shown to be effective for people with cancer, it is unclear whether or not this is the case for people with advanced cancer and depression. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of treatment as usual (TAU) plus manualised CBT, delivered by high-level Improving Access to Psychological Therapy (IAPT) practitioners, versus TAU for people with advanced cancer and depression, measured at baseline, 6, 12, 18 and 24 weeks. DESIGN: Parallel-group, single-blind, randomised trial, stratified by whether or not an antidepressant was prescribed, comparing TAU with CBT plus TAU. SETTING: Recruitment took place in oncology, hospice and primary care settings. CBT was delivered in IAPT centres or/and over the telephone. PARTICIPANTS: Patients (N = 230; n = 115 in each arm) with advanced cancer and depression. Inclusion criteria were a diagnosis of cancer not amenable to cure, a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnosis of depressive disorder using the Mini-International Neuropsychiatric Interview, a sufficient understanding of English and eligibility for treatment in an IAPT centre. Exclusion criteria were an estimated survival of < 4 months, being at high risk of suicide and receiving, or having received in the last 2 months, a psychological intervention recommended by NICE for treating depression. INTERVENTIONS: (1) Up to 12 sessions of manualised individual CBT plus TAU delivered within 16 weeks and (2) TAU. OUTCOME MEASURES: The primary outcome was the Beck Depression Inventory, version 2 (BDI-II) score at 6, 12, 18 and 24 weeks. Secondary outcomes included scores on the Patient Health Questionnaire-9, the Eastern Cooperative Oncology Group Performance Status, satisfaction with care, EuroQol-5 Dimensions and the Client Services Receipt Inventory, at 12 and 24 weeks. RESULTS: A total of 80% of treatments (185/230) were analysed: CBT (plus TAU) (n = 93) and TAU (n = 92) for the BDI-II score at all time points using multilevel modelling. CBT was not clinically effective [treatment effect -0.84, 95% confidence interval (CI) -2.76 to 1.08; p = 0.39], nor was there any benefit for other measures. A subgroup analysis of those widowed, divorced or separated showed a significant effect of CBT on the BDI-II (treatment effect -7.21, 95% CI -11.15 to -3.28; p < 0.001). Economic analysis revealed that CBT has higher costs but produces more quality-adjusted life-years (QALYs) than TAU. The mean service costs for participants (not including the costs of the interventions) were similar across the two groups. There were no differences in EQ-5D median scores at baseline, nor was there any advantage of CBT over TAU at 12 weeks or 24 weeks. There was no statistically significant improvement in QALYs at 24 weeks. LIMITATIONS: Although all participants satisfied a diagnosis of depression, for some, this was of less than moderate severity at baseline, which could have attenuated treatment effects. Only 64% (74/115) took up CBT, comparable to the general uptake through IAPT. CONCLUSIONS: Cognitive-behavioural therapy (delivered through IAPT) does not achieve any clinical benefit in advanced cancer patients with depression. The benefit of CBT for people widowed, divorced or separated is consistent with other studies. Alternative treatment options for people with advanced cancer warrant evaluation. Screening and referring those widowed, divorced or separated to IAPT for CBT may be beneficial. Whether or not improvements in this subgroup are due to non-specific therapeutic effects needs investigation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07622709. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 19. See the NIHR Journals Library website for further project information

Biliary epithelium and liver B cells exposed to bacteria activate intrahepatic MAIT cells through MR1

Background & AimsMucosal-Associated Invariant T (MAIT) cells are innate-like T cells characterised by the invariant TCR-chain, Vα7.2-Jα33, and are restricted by MR1, which presents bacterial vitamin B metabolites. They are important for antibacterial immunity at mucosal sites; however, detailed characteristics of liver-infiltrating MAIT (LI-MAIT) and their role in biliary immune surveillance remain unexplored.MethodsThe phenotype and intrahepatic localisation of human LI-MAIT cells was examined in diseased and normal livers. MAIT cell activation in response to E. coli-exposed macrophages, biliary epithelial cells (BEC) and liver B cells was assessed with/without anti-MR1.ResultsIntrahepatic MAIT cells predominantly localised to bile ducts in the portal tracts. Consistent with this distribution, they expressed biliary tropic chemokine receptors CCR6, CXCR6, and integrin αEβ7. LI-MAIT cells were also present in the hepatic sinusoids and possessed tissue-homing chemokine receptor CXCR3 and integrins LFA-1 and VLA-4, suggesting their recruitment via hepatic sinusoids. LI-MAIT cells were enriched in the parenchyma of acute liver failure livers compared to chronic diseased livers. LI-MAIT cells had an activated, effector memory phenotype, expressed α4β7 and receptors for IL-12, IL-18, and IL-23. Importantly, in response to E. coli-exposed macrophages, liver B cells and BEC, MAIT cells upregulated IFN-γ and CD40 Ligand and degranulated in an MR1-dependent, cytokine-independent manner. In addition, diseased liver MAIT cells expressed T-bet and RORγt and the cytokines IFN-γ, TNF-α, and IL-17.ConclusionsOur findings provide the first evidence of an immune surveillance effector response for MAIT cells towards BEC in human liver; thus they could be manipulated for treatment of biliary disease in the future

Adaptation to ER Stress Is Mediated by Differential Stabilities of Pro-Survival and Pro-Apoptotic mRNAs and Proteins

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates a signaling cascade known as the unfolded protein response (UPR). Although activation of the UPR is well described, there is little sense of how the response, which initiates both apoptotic and adaptive pathways, can selectively allow for adaptation. Here we describe the reconstitution of an adaptive ER stress response in a cell culture system. Monitoring the activation and maintenance of representative UPR gene expression pathways that facilitate either adaptation or apoptosis, we demonstrate that mild ER stress activates all UPR sensors. However, survival is favored during mild stress as a consequence of the intrinsic instabilities of mRNAs and proteins that promote apoptosis compared to those that facilitate protein folding and adaptation. As a consequence, the expression of apoptotic proteins is short-lived as cells adapt to stress. We provide evidence that the selective persistence of ER chaperone expression is also applicable to at least one instance of genetic ER stress. This work provides new insight into how a stress response pathway can be structured to allow cells to avert death as they adapt. It underscores the contribution of posttranscriptional and posttranslational mechanisms in influencing this outcome

Improving the use of crop models for risk assessment and climate change adaptation

Crop models are used for an increasingly broad range of applications, with a commensurate proliferation of methods. Careful framing of research questions and development of targeted and appropriate methods are therefore increasingly important. In conjunction with the other authors in this special issue, we have developed a set of criteria for use of crop models in assessments of impacts, adaptation and risk. Our analysis drew on the other papers in this special issue, and on our experience in the UK Climate Change Risk Assessment 2017 and the MACSUR, AgMIP and ISIMIP projects. The criteria were used to assess how improvements could be made to the framing of climate change risks, and to outline the good practice and new developments that are needed to improve risk assessment. Key areas of good practice include: i. the development, running and documentation of crop models, with attention given to issues of spatial scale and complexity; ii. the methods used to form crop-climate ensembles, which can be based on model skill and/or spread; iii. the methods used to assess adaptation, which need broadening to account for technological development and to reflect the full range options available. The analysis highlights the limitations of focussing only on projections of future impacts and adaptation options using pre-determined time slices. Whilst this long-standing approach may remain an essential component of risk assessments, we identify three further key components: 1. Working with stakeholders to identify the timing of risks. What are the key vulnerabilities of food systems and what does crop-climate modelling tell us about when those systems are at risk? 2. Use of multiple methods that critically assess the use of climate model output and avoid any presumption that analyses should begin and end with gridded output. 3. Increasing transparency and inter-comparability in risk assessments. Whilst studies frequently produce ranges that quantify uncertainty, the assumptions underlying these ranges are not always clear. We suggest that the contingency of results upon assumptions is made explicit via a common uncertainty reporting format; and/or that studies are assessed against a set of criteria, such as those presented in this paper

Effectiveness of cognitive-behavioural therapy for depression in advanced cancer:CanTalk randomised controlled trial

BACKGROUND: Depression is one of the most common mental disorders in people with advanced cancer. Although cognitive-behavioural therapy (CBT) has been shown to be effective for depression in people with cancer, it is unclear whether this is the case for people with advanced cancer and depression. // AIMS: We sought to determine whether CBT is more clinically effective than treatment as usual (TAU) for treating depression in people with advanced cancer (trial registration number ISRCTN07622709). // METHOD: A multi-centre, parallel-group single-blind randomised controlled trial comparing TAU with CBT (plus TAU). Participants (n = 230) with advanced cancer and depression were randomly allocated to (a) up to 12 sessions of individual CBT or (b) TAU. The primary outcome measure was the Beck Depression Inventory-II (BDI-II). Secondary outcome measures included the Patient Health Questionnaire-9, the Eastern Cooperative Oncology Group Performance Status, and Satisfaction with Care. // RESULTS: Multilevel modelling, including complier-average intention-to-treat analysis, found no benefit of CBT. CBT delivery was proficient, but there was no treatment effect (-0.84, 95% CI -2.76 to 1.08) or effects for secondary measures. Exploratory subgroup analysis suggested an effect of CBT on the BDI-II in those widowed, divorced or separated (-7.21, 95% CI -11.15 to -3.28). // CONCLUSIONS: UK National Institute for Health and Care Excellence (NICE) guidelines recommend CBT for treating depression. Delivery of CBT through the Improving Access to Psychological Therapies (IAPT) programme has been advocated for long-term conditions such as cancer. Although it is feasible to deliver CBT through IAPT proficiently to people with advanced cancer, this is not clinically effective. CBT for people widowed, divorced or separated needs further exploration. Alternate models of CBT delivery may yield different results. // DECLARATION OF INTEREST: M.S. is a member of the Health Technology Assessment General Board