Validation of epidermal AMBRA1 and loricrin (AMBLor) as a prognostic biomarker for nonulcerated American Joint Committee on Cancer stage I/II cutaneous melanoma.

BACKGROUND: Combined expression of the autophagy-regulatory protein AMBRA1 (activating molecule in Beclin1-regulated autophagy) and the terminal differentiation marker loricrin in the peritumoral epidermis of stage I melanomas can identify tumour subsets at low risk of -metastasis. OBJECTIVES: To validate the combined expression of peritumoral AMBRA1 and loricrin (AMBLor) as a prognostic biomarker able to identify both stage I and II melanomas at low risk of tumour recurrence. METHODS: Automated immunohistochemistry was used to analyse peritumoral AMBRA1 and loricrin expression in geographically distinct discovery (n = 540) and validation (n = 300) cohorts of nonulcerated American Joint Committee on Cancer (AJCC) stage I and II melanomas. AMBLor status was correlated with clinical outcomes in the discovery and validation cohorts separately and combined. RESULTS: Analysis of AMBLor in the discovery cohort revealed a recurrence-free survival (RFS) rate of 95.5% in the AMBLor low-risk group vs. 81.7% in the AMBLor at-risk group (multivariate log-rank, P < 0.001) and a negative predictive value (NPV) of 96.0%. In the validation cohort, AMBLor analysis revealed a RFS rate of 97.6% in the AMBLor low-risk group vs. 78.3% in the at-risk group (multivariate log-rank, P < 0.001) and a NPV of 97.6%. In a multivariate model considering AMBLor, Breslow thickness, age and sex, analysis of the combined discovery and validation cohorts showed that the estimated effect of AMBLor was statistically significant, with a hazard ratio of 3.469 (95% confidence interval 1.403-8.580, P = 0.007) and an overall NPV of 96.5%. CONCLUSIONS: These data provide further evidence validating AMBLor as a prognostic biomarker to identify nonulcerated AJCC stage I and II melanoma tumours at low risk of disease recurrence.

Coping with uncertainty in everyday situations (CUES©) to address intolerance of uncertainty in autistic children: an intervention feasibility trial.

BACKGROUND: Anxiety related to uncertainty is common in autism. Coping with Uncertainty in Everyday Situations (CUES©) is a parent-mediated group intervention aiming to increase autistic children's tolerance to uncertain situations. A pilot study was conducted to test its feasibility and acceptability. METHODS: Parents of 50 autistic children were randomised to receive CUES© or enhanced services as usual. RESULTS: All children met the clinical threshold for at least one anxiety disorder. Of the 26 participants randomised to CUES©, 72% attended 4-8 sessions. Parents and therapists reported they found CUES© useful and acceptable. CONCLUSIONS: Families were willing to be recruited and randomised, the format/content was feasible to deliver, and the outcome measures were acceptable. CUES© should be evaluated in a clinical and cost effectiveness randomised controlled trial.

Health professional and patient views of a novel prognostic test for melanoma: A theoretically informed qualitative study.

OBJECTIVES: Cutaneous melanoma rates are steadily increasing. Up to 20% of patients diagnosed with AJCC Stage I/II melanomas will develop metastatic disease. To date there are no consistently reliable means to accurately identify truly high versus low-risk patient subpopulations. There is hence an urgent need for more accurate prediction of prognosis to determine appropriate clinical management. Validation of a novel prognostic test based on the immunohistochemical expression of two protein biomarkers in the epidermal microenvironment of primary melanomas was undertaken; loss of these biomarkers had previously been shown to be associated with a higher risk of recurrence or metastasis. A parallel qualitative study exploring secondary care health professional and patient views of the test was undertaken and this paper reports the perceived barriers and enablers to its implementation into the melanoma care pathway. METHODS: Qualitative methods were employed drawing upon the Theoretical Domains Framework (TDF) in the exploration and analysis. An inductive-deductive analysis was performed, with all data coded using a thematic then TDF framework. FINDINGS: 20 dermatologists, plastic surgeons, cancer nurse specialists, oncologists and histopathologists participated. Nine TDF domains were relevant to all health professional groups and the 'Skills' and 'Beliefs about Capabilities' domains were relevant only to histopathologists. 'Optimism' and 'Beliefs about consequences' were strong enablers particularly for clinicians. 'Environmental context and resources' (impact on pathology services) and 'Knowledge' (the need for robust evidence about the test reliability) were the main perceived barriers. 19 patients and one carer were interviewed. For the patients eight domains were relevant. ('Knowledge', 'Emotions', 'Beliefs about consequences', 'Social Role and identity', 'Behavioural regulation', 'Memory, attention and decision processes', 'Reinforcement' and 'Skills'). The consequences of the implementation of the test were reassurance about future risk, changes to the follow-up pathway on which there were mixed views, and the need to ensure they maintained self-surveillance (Beliefs about consequences). The test was acceptable to all patient interviewees but the resultant changes to management would need to be supported by mechanisms for fast-track back into the clinic, further information on self-surveillance and clear management plans at the time the result is conveyed (Behavioural regulation). CONCLUSIONS: Health professionals and patients perceived positive consequences-for patients and for health services-of adopting the test. However, its implementation would require exploration of the resource implications for pathology services, psychological support for patients with a high-risk test result and mechanisms to reassure and support patients should the test lead to reduced frequency or duration of follow-up. Exploring implementation at an early stage with health professionals presented challenges related to the provision of specific details of the test and its validation.

Caregiver perspectives on the impact of uncertainty on the everyday lives of autistic children and their families.

LAY ABSTRACT: Anxiety is common in autistic children. Research shows that this may be related to intolerance of uncertainty, which is a tendency to react negatively to uncertain situations. Understanding when, why and how autistic children respond to uncertainty is important in the development of anxiety programmes. We asked 53 (including 3 dyads) parents of autistic children about the types of uncertain situations that cause difficulties for their child and how uncertainty impacts on daily life for them and their families. We found that uncertain situations made autistic children and their families feel sad, worried, frustrated and angry through the themes: child's reactions to uncertainty, trying to reduce uncertainty, the impact of difficulties with uncertainty, the impact of uncertainty on parenting and the impact on parents. There are lots of situations that are anxiety provoking for autistic children because of uncertainty, such as school. Programmes to reduce anxiety and increase autistic children's ability to cope with everyday uncertain situations could improve quality of life for autistic children and their families.

Optimal surveillance strategies for patients with stage 1 cutaneous melanoma post primary tumour excision: three systematic reviews and an economic model.

BACKGROUND: Malignant melanoma is the fifth most common cancer in the UK, with rates continuing to rise, resulting in considerable burden to patients and the NHS. OBJECTIVES: The objectives were to evaluate the effectiveness and cost-effectiveness of current and alternative follow-up strategies for stage IA and IB melanoma. REVIEW METHODS: Three systematic reviews were conducted. (1) The effectiveness of surveillance strategies. Outcomes were detection of new primaries, recurrences, metastases and survival. Risk of bias was assessed using the Cochrane Collaboration's Risk-of-Bias 2.0 tool. (2) Prediction models to stratify by risk of recurrence, metastases and survival. Model performance was assessed by study-reported measures of discrimination (e.g. D-statistic, Harrel's c-statistic), calibration (e.g. the Hosmer-Lemeshow 'goodness-of-fit' test) or overall performance (e.g. Brier score, R2). Risk of bias was assessed using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). (3) Diagnostic test accuracy of fine-needle biopsy and ultrasonography. Outcomes were detection of new primaries, recurrences, metastases and overall survival. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Review data and data from elsewhere were used to model the cost-effectiveness of alternative surveillance strategies and the value of further research. RESULTS: (1) The surveillance review included one randomised controlled trial. There was no evidence of a difference in new primary or recurrence detected (risk ratio 0.75, 95% confidence interval 0.43 to 1.31). Risk of bias was considered to be of some concern. Certainty of the evidence was low. (2) Eleven risk prediction models were identified. Discrimination measures were reported for six models, with the area under the operating curve ranging from 0.59 to 0.88. Three models reported calibration measures, with coefficients of ≥ 0.88. Overall performance was reported by two models. In one, the Brier score was slightly better than the American Joint Committee on Cancer scheme score. The other reported an R2 of 0.47 (95% confidence interval 0.45 to 0.49). All studies were judged to have a high risk of bias. (3) The diagnostic test accuracy review identified two studies. One study considered fine-needle biopsy and the other considered ultrasonography. The sensitivity and specificity for fine-needle biopsy were 0.94 (95% confidence interval 0.90 to 0.97) and 0.95 (95% confidence interval 0.90 to 0.97), respectively. For ultrasonography, sensitivity and specificity were 1.00 (95% confidence interval 0.03 to 1.00) and 0.99 (95% confidence interval 0.96 to 0.99), respectively. For the reference standards and flow and timing domains, the risk of bias was rated as being high for both studies. The cost-effectiveness results suggest that, over a lifetime, less intensive surveillance than recommended by the National Institute for Health and Care Excellence might be worthwhile. There was considerable uncertainty. Improving the diagnostic performance of cancer nurse specialists and introducing a risk prediction tool could be promising. Further research on transition probabilities between different stages of melanoma and on improving diagnostic accuracy would be of most value. LIMITATIONS: Overall, few data of limited quality were available, and these related to earlier versions of the American Joint Committee on Cancer staging. Consequently, there was considerable uncertainty in the economic evaluation. CONCLUSIONS: Despite adoption of rigorous methods, too few data are available to justify changes to the National Institute for Health and Care Excellence recommendations on surveillance. However, alternative strategies warrant further research, specifically on improving estimates of incidence, progression of recurrent disease; diagnostic accuracy and health-related quality of life; developing and evaluating risk stratification tools; and understanding patient preferences. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018086784. 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 25, No. 64. See the NIHR Journals Library website for further project information.

Malignant melanoma is the deadliest of skin cancers; in the UK, > 2500 people die from it every year. Initially, the cancer is removed surgically, which cures it for most people, but, for some, the cancer returns. For this reason, after a melanoma is removed, patients are followed up to see if the melanoma reoccurs or if new melanomas have developed. It is felt that early cancer detection improves the chance of future treatment working. A key question is how best to follow up patients after initial melanoma surgery. This study concentrates on the earliest stage of melanoma (American Joint Committee on Cancer stage I), which accounts for more than 7 out of 10 of all melanoma diagnoses. The study also investigates if new ways of follow-up could be at least as good as current practice and a better use of NHS money. We systematically reviewed studies comparing different ways of organising follow-up, and then methods to identify those patients at high risk of developing a further melanoma and how good different tests are at detecting this cancer. We then compared different possible follow-up strategies. For each strategy, we considered its impact on quality and length of life, and how well it used NHS resources. We found little evidence to support a change in how follow-up should be organised currently. There were some ways of organising follow-up that might be better than current care, but further research is needed. We found that new research on whether or not follow-up should be performed by a cancer nurse specialist, rather than a dermatologist or surgeon, would be worthwhile. We also found that more research could be worthwhile on how frequently melanoma recurs and spreads, as well as how accurately a diagnosis of further cancer is made and how to identify those most at risk of further melanoma spread.

HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1.

Oropharyngeal squamous cell carcinoma (OPSCC) is an increasing world health problem with a more favorable prognosis for patients with human papillomavirus (HPV)-positive tumors compared to those with HPV-negative OPSCC. How HPV confers a less aggressive phenotype, however, remains undefined. We demonstrated that HPV-positive OPSCC cells display reduced macroautophagy/autophagy activity, mediated by the ability of HPV-E7 to interact with AMBRA1, to compete with its binding to BECN1 and to trigger its calpain-dependent degradation. Moreover, we have shown that AMBRA1 downregulation and pharmacological inhibition of autophagy sensitized HPV-negative OPSCC cells to the cytotoxic effects of cisplatin. Importantly, semi-quantitative immunohistochemical analysis in primary OPSCCs confirmed that AMBRA1 expression is reduced in HPV-positive compared to HPV-negative tumors. Collectively, these data identify AMBRA1 as a key target of HPV to impair autophagy and propose the targeting of autophagy as a viable therapeutic strategy to improve treatment response of HPV-negative OPSCC.Abbreviations: AMBRA1: autophagy and beclin 1 regulator 1; CDDP: cisplatin (CDDP); FFPE: formalin-fixed paraffin-embedded (FFPE); HNC: head and neck cancers (HNC); HPV: human papillomavirus (HPV); hrHPV: high risk human papillomavirus (hrHPV); OCSCC: oral cavity squamous carcinomas (OCSSC); OPSCC: oropharyngeal squamous cell carcinoma (OPSCC); OS: overall survival (OS); qPCR: quantitative polymerase chain reaction; RB1: RB transcriptional corepressor 1; ROC: receiver operating characteristic curve (ROC).

Coping with Uncertainty in Everyday Situations (CUES©) to address intolerance of uncertainty in autistic children: study protocol for an intervention feasibility trial.

BACKGROUND: Anxiety is a common diagnosis in children with autism spectrum disorder (ASD). One key mechanism underlying anxiety is intolerance of uncertainty, which is a tendency to react negatively on an emotional, cognitive, and behavioural level to uncertain situations and events. We developed the first intervention programme specifically targeting intolerance of uncertainty in children with ASD: Coping with Uncertainty in Everyday Situations (CUES). CUES is a parent group intervention providing parents of children with ASD with strategies to increase tolerance to uncertainty for their children in everyday situations. The principal aims of the current study are: 1) evaluate the acceptability and feasibility of delivering CUES to parents who have a child with ASD and anxiety; and 2) inform the design of a fully powered trial. METHOD: This is a feasibility and acceptability single-blind pilot randomised controlled trial comparing CUES (intervention) to a brief psychoeducation, emotional literacy, and relaxation programme (enhanced services as usual). Participants will be assessed at baseline and followed-up immediately post-treatment, and at 12 and 26 weeks post-treatment. Parents who have a child with ASD and anxiety (aged 6-16 years) will be invited to take part in the study and written parental informed consent and child assent will be obtained. Participants will be recruited from the National Health Service mental health teams in the UK. Sixty participants will be randomised to either intervention or enhanced services as usual in a 1:1 ratio. DISCUSSION: The present study will provide evidence on the acceptability of the CUES intervention to parents and children, and the feasibility of recruitment and delivery to inform the design and sample size for a full-scale randomised controlled trial. Qualitative data will be obtained to understand how feasible CUES is for families, and the experiences of participants regarding their experiences of the intervention. TRIAL REGISTRATION: ISRCTN, ISRCTN10139240 . Registered on 14 May 2018.

Using Virtual Reality Environments to Augment Cognitive Behavioral Therapy for Fears and Phobias in Autistic Adults.

Fears and phobias are common in people on the autism spectrum and can impact on their ability to undertake usual daily activities. Graded exposure to the anxiety-provoking stimulus is a recognized method of treatment for fears/phobias in the nonautistic population but may pose specific difficulties for autistic people. For example, real-life exposure can be too anxiety-provoking to allow treatment to take place, and imaginal exposure can be problematic. To address this, we developed an intervention that combines cognitive behavioral therapy (CBT) with immersive virtual reality (VR) exposure to reduce anxiety. Following successful trials of this intervention with young people on the autism spectrum, we report a pilot study using the same intervention with autistic adults. Eight adults (aged 18-57 years) received one psychoeducation session and then four 20-minute sessions of graded exposure with a therapist in an immersive VR room (known as the Blue Room). Each participant completed all sessions showing that the intervention is feasible and acceptable. Outcomes were monitored at 6 weeks and 6 months postintervention. Five of the eight participants were classified as intervention responders and at 6 months after the end of intervention were experiencing real-life functional improvements. These preliminary findings show that VR-graded exposure alongside CBT may be an effective treatment for autistic people with phobias. LAY SUMMARY: Why was this study done?Anxiety is common in autistic adults. For some people, fears and phobias regarding everyday objects and situations occur frequently affecting everyday life. The main method to treat fears and phobias for people without autism is gradual exposure to the situation that causes anxiety. However, this method may be challenging for people on the autism spectrum. We wanted to test a new method of treatment that uses cognitive behavioral therapy (CBT) delivered with gradual exposure in a fully immersive virtual reality (VR) environment.What was the purpose of this study?We have already delivered this treatment successfully with autistic children. We wanted to test if this treatment would work for autistic adults. Changing traditional psychological treatments, such as CBT, to make it more suitable for autistic people is recommended by the National Institute for Health and Care Excellence.What did the researchers do?We recruited eight autistic adults (aged 18-57 years) with a fear/phobia and their supporter (parent/friend/support worker). Each adult had one session with a therapist to learn anxiety management techniques. They then had four 20-minute sessions of graded exposure with a therapist in an immersive VR room (known as the Blue Room). Each participant had a computer-generated scene designed for their specific anxiety-provoking situation. After four sessions, the participant tried real-life exposure with their supporter. We measured progress at 6 weeks and 6 months after the last VR session.What were the results of this study?Each participant completed all four sessions. This shows that the intervention was possible to deliver and acceptable to autistic people and therapists. Participants completed assessments at 6 weeks and 6 months after the VR sessions. Five of the eight participants were "responders" to the intervention. This means that 6 months after the last VR session, they still had real-life day-to-day improvements in relation to their phobia.What do these findings add to what was already known?We had not delivered this intervention to autistic adults previously. The findings show that this VR intervention has the potential to be an effective treatment for anxiety in autistic adults.What are the potential weaknesses in the study?This is a small study and future work will be a larger trial of this treatment-comparing results from people who get the intervention with people who do not. We would also want to have an outcome assessor who did not know whether people had received the intervention or not.How will these findings help autistic adults now or in the future?This new intervention has the potential to help autistic adults manage their anxiety in stressful situations and therefore may improve their quality of life.

A Randomised Controlled Feasibility Trial of Immersive Virtual Reality Treatment with Cognitive Behaviour Therapy for Specific Phobias in Young People with Autism Spectrum Disorder.

We examined the feasibility and acceptability of using an immersive virtual reality environment (VRE) alongside cognitive behaviour therapy (CBT) for young people with autism experiencing specific phobia. Thirty-two participants were randomised to treatment or control. Treatment involved one session introducing CBT techniques and four VRE sessions, delivered by local clinical therapists. Change in target behaviour was independently rated. Two weeks after treatment, four treatment participants (25%) and no control participants were responders; at 6 months after treatment, six (38%) treatment and no control participants were responders. At 6 months post-treatment, symptoms had worsened for one treatment and five control (untreated) participants. Brief VRE exposure with CBT is feasible and acceptable to deliver through child clinical services and is effective for some participants.