Protocol for the EACH trial: a multicentre phase II study evaluating the safety and antitumour activity of the combination of avelumab, an anti-PD-L1 agent, and cetuximab, as any line treatment for patients with recurrent/metastatic head and neck squamous cell cancer (HNSCC) in the UK.

INTRODUCTION: Head and neck cancer is the eighth most common cancer in the UK. Current standard of care treatment for patients with recurrent/metastatic squamous cell head and neck carcinoma (HNSCC) is platinum-based chemotherapy combined with the anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, cetuximab. However, most patients will have poor median overall survival (OS) of 6-9 months despite treatment. HNSCC tumours exhibit an immune landscape poised to respond to immunotherapeutic approaches, with most tumours expressing the immunosuppressive receptor programmed death-ligand 1 (PD-L1). We undertook the current study to determine the safety and efficacy of avelumab, a monoclonal antibody targeting the interaction between PD-L1 and its receptor on cytotoxic T-cells, in combination with cetuximab. METHODS AND ANALYSIS: This is a multi-centre, single-arm dose de-escalation phase II safety and efficacy study of avelumab combined with cetuximab; the study was to progress to a randomised phase II trial, however, the study will now complete after the safety run-in component. Up to 16 participants with histologically/cytologically recurrent/metastatic squamous cell carcinoma (including HNSCC) who have not received cetuximab previously will be recruited. All patients will receive 10 mg/kg avelumab and cetuximab (500, 400 or 300 mg/m2 depending on the cohort open at time of registration) on days 1 and 15 of 4-week cycles for up to 1 year, (avelumab not given cycle 1 day 1). A modified continual reassessment method will be used to determine dose de-escalation. The primary objective is to establish the safety of the combination and to determine the optimum dose of cetuximab. Secondary objectives include assessing evidence of antitumour activity by evaluating response rates and disease control rates at 6 and 12 months as well as progression-free and OS. ETHICS AND DISSEMINATION: Approval granted by City and East REC (18/LO/0021). Findings will be published in peer-reviewed journals and disseminated at conferences. TRIAL REGISTRATION NUMBER: NCT03494322.

A 35-year longitudinal assessment of cognition and midlife depression symptoms: the Vietnam Era Twin Study of Aging.

OBJECTIVE: To determine whether early adult cognitive ability is a risk factor for depressive symptoms in midlife and how genetic and environmental influences explain the association and to examine cross-sectional relationships between depressive symptoms and specific cognitive abilities at midlife. DESIGN: A 35-year longitudinal and cross-sectional twin study of cognitive aging. SETTING: Large multicenter study in the United States. PARTICIPANTS: One thousand two hundred thirty-seven male twins aged 51 to 60 years. MEASUREMENTS: At the age of 20 years and midlife, participants completed the same version of a general cognitive ability test (Armed Forces Qualification Test [AFQT]). Midlife testing included an extensive neurocognitive protocol assessing processing speed, verbal memory, visual-spatial memory, working memory, executive function, and visual-spatial ability. Participants completed the Center for Epidemiologic Studies Depression Scale before cognitive testing and provided health and life style information during a medical history interview. RESULTS: Lower age 20 AFQT scores predicted higher levels of depressive symptoms at age 55 years (r = -0.16,p <0.001). In bivariate twin modeling, 77% of the correlation between early cognitive ability and midlife depressive symptoms was due to shared genetic influences. Controlling for current age, age 20 AFQT, and nonindependence ofobservations, depressive symptoms were associated with worse midlife AFQT scores and poorer performance in all cognitive domains except verbal memory. CONCLUSION: Results suggest that low cognitive ability is a risk factor for depressive symptoms; this association is partly due to shared genetic influences. Crosssectional analyses indicate that the association between depressive symptoms and performance is not linked to specific cognitive domains.

Psychiatry resident education in palliative care: opportunities, desired training, and outcomes of a targeted educational intervention.

OBJECTIVES: To assess the educational offerings provided to psychiatry residents in palliative care as well as their concomitant interest in learning more about this subspecialty. To measure the pre- and post-levels of competence, concern, and knowledge exhibited by psychiatry residents when completing a formalized clinical rotation in hospice and palliative care, with additional comparisons to family and internal medicine residents completing the same clinical rotation. METHODS: Fifty-two Psychiatry Program Directors and 98 psychiatry residents completed an online survey assessing the current course offerings and level of interest in palliative care. Thirty psychiatry residents were additionally evaluated before and after completion of a clinical rotation in hospice and palliative care. RESULTS: Few programs offered any formalized training in palliative care, although nearly all psychiatry residents reported interest in this area. A clinical rotation in palliative care significantly increased psychiatry residents' competence and knowledge while simultaneously decreasing their concerns about practice in this area; most were at levels comparable to family and internal medicine residents completing the same rotation. Psychiatry residents' knowledge of pain assessment, pain management, and generalized non-pain management were also enhanced during the rotation. CONCLUSIONS: Results indicate that training opportunities in palliative care are lacking for psychiatry residents in the United States although residents report strong interest in this area. This study finds psychiatry residents can benefit as much as other disciplines from receiving palliative care training. The need to offer such training within psychiatry residencies is highlighted and the welcoming of psychiatrists into palliative care is suggested.