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Figure S2 documents PD-1, TIGIT and PD-1/TIGIT co-expression on whole peripheral CD8+ T cells from HLA-A2 melanoma patients, before and after PD-1 therapy.

Purpose: Bevacizumab improves survival for patients with metastatic colorectal cancer with chemotherapy, but no proven predictive markers exist. The VEGF-A splice form, VEGF165b, anti-angiogenic in animal models, binds bevacizumab. We tested the hypothesis that prolonged progression-free survival (PFS) would occur only in patients with low relative VEGF165b levels treated with bevacizumab.Experimental Design: Blinded tumor samples from the phase III trial of FOLFOX4 ± bevacizumab were assessed for VEGF165b and VEGFtotal by immunohistochemistry and scored relative to normal tissue. A predictive index (PI) was derived from the ratio of VEGF165b:VEGFtotal for 44 samples from patients treated with FOLFOX + bevacizumab (arm A) and 53 samples from patients treated with FOLFOX4 (arm B), and PFS, and overall survival (OS) analyzed on the basis of PI relative to median ratio.Results: Unadjusted analysis of PFS showed significantly better outcome for individuals with VEGF165b:VEGFtotal ratio scores below median treated with FOLFOX4 + bevacizumab compared with FOLFOX4 alone (median, 8.0 vs. 5.2 months; P < 0.02), but no effect of bevacizumab on PFS in patients with VEGF165b:VEGFtotal ratio >median (5.9 vs. 6.3 months). These findings held after adjustment for other clinical and demographic features. OS was increased in arm A (median, 13.6 months) compared with arm B (10.6 months) in the low VEGF165b group, but this did not reach statistical significance. There was no difference in the high VEGF165b:VEGFtotal group between FOLFOX + bevacizumab (10.8 months) and FOLFOX alone (11.3months).Conclusion: Low VEGF165b:VEGFtotal ratio may be a predictive marker for bevacizumab in metastatic colorectal cancer, and individuals with high relative levels may not benefit. Clin Cancer Res; 18(22); 6384–91. ©2012 AACR.

Legends of supplemental figures S1, S2, S3 and S4

Therapeutic strategies using anti–PD-1–blocking antibodies reported unparalleled effectiveness for melanoma immunotherapy, but deciphering immune responses modulated by anti–PD-1 treatment remains a crucial issue. Here, we analyzed the composition and functions of the large Melan-A–specific T-cell repertoire in the peripheral blood of 9 melanoma patients before and after 2 months of treatment with anti–PD-1. We observed amplification of Melan-A–specific Vß subfamilies undetectable before therapy (thereafter called emerging Vß subfamilies) in responding patients, with a predominant expansion in patients with a complete response. These emerging Vß subfamilies displayed a higher functional avidity for their cognate antigen than Vß subfamilies not amplified upon anti–PD-1 therapy and could be identified by a sustained coexpression of PD-1 and TIGIT receptors. Thus, in addition to the emergence of neoantigen-specific T cells previously documented upon anti–PD-1 therapy, our work describes the emergence of high-avidity Melan-A–specific clonotypes as a surrogate marker of treatment efficacy. Cancer Res; 77(24); 7083–93. ©2017 AACR.

PDF file - 37K, Comparison of study cases and overall patient population

PDF file - 260K, Scoring of immunohistochemically stained samples

The topic of this dissertation is corpus analysis: the use of computational techniques to search through large collections of real-world texts (called corpora) to discover facts about language use which hold throughout the collection. I examine how corpus analysis can be used as an empirical methodology within philosophy of language to confirm semantic analyses of philosophically important expressions. I begin by discussing the philosophical importance of analyzing the ordinary meaning of people's language use, as through that we can come to understand how they categorize the world around them. Specifically, I am concerned with philosophical semantics: the study of the meaning of expressions for which different theories of their meaning will have different philosophical upshots. After discussing the kind of meaning relevant to this subject area (namely operative concepts: the concepts that actually determine how we apply expressions to cases), I rationally reconstruct and analyze existing methods of confirmation in philosophical semantics, including intuitive methods and questionnaire methods from experimental philosophy. I then critique these methods in terms of the strength of evidence they can offer.Next, I introduce corpus analysis, and explain how it can be used as a method of confirmation in philosophical semantics. I pay special attention to the question of how corpus analysis can be used to discover the 'deep', semantic, representational features of text relevant for confirming semantic analyses, and offer several techniques to perform this task.I argue that corpus analysis has many benefits over existing methods of confirmation in philosophical semantics, given that it studies (i) actual, rather than imagined, instances of language use, and (ii) the language use of the actual communities whose meanings we are interested in, rather than just that of philosophers.The dissertation concludes with a case study of the use of corpus analysis to confirm a theory of the reference conditions of definite descriptions over a rival theory with different philosophical upshots. This is the first corpus study in philosophical semantics to make use of an annotated corpus, which is a technique with lot of promise within this field.

Background: Targeted therapy is used to treat patients with a BRAF-mutated metastatic melanoma and is continued until disease progression or severe toxicity. No robust data on the management of patients achieving a complete remission (CR) are available. Main Objective: To determine the relapse rate in the first year after targeted therapy discontinuation in patients in CR. Secondary Objectives: To determine the relapse rates throughout the follow-up and to identify prognostic factors for relapse at 1 year. Methods: A retrospective, monocentric observational study was conducted in patients with advanced melanoma included in the RIC-Mel database who discontinued targeted therapy after achieving a CR confirmed by CT scan and PET/CT scan. Results: Twenty-nine patients were included. Seventeen (58.6%) patients were treated with BRAF inhibitor (BRAFi) alone and 12 (41.4%) with a BRAFi combined with a MEK inhibitor (BRAFi + MEKi). The median treatment duration was 9.7 months. The relapse rates after discontinuation were 69% at 12 months (BRAFi: 70.6%; BRAFi + MEKi: 66.7%) and 76% at 36 months (BRAFi: 76.5%; BRAFi + MEKi: 75%). A non-significant trend towards a higher risk of relapse was found in women (p = 0.1; RR 3.36; 95% CI 0.77–17.07), in patients with an LDH level greater than the upper limits of normal (p = 0.58; RR 2.43; 95% CI 0.10–56.71), and when more than two metastatic sites were involved (p = 0.19; RR 4.6; 95% CI 0.46–46.51). After relapse, targeted therapy was resumed in 17 patients (7 with BRAFi; 10 with BRAFi + MEKi) with a response rate of 53%. Conclusions: This real-life study provided long-term data in patients who discontinued targeted therapy after CR. Most patients experienced a relapse in the first year after targeted therapy discontinuation, of whom 50% were in the first 3 months. After targeted therapy resumption, 53% of relapsing patients achieved an objective response. Patients should be followed during the first year after treatment discontinuation. In addition, patients with less than 3 metastatic sites, a baseline LDH level with normal ranges, men, and patients responding rapidly to treatment would be more likely to maintain a CR after treatment discontinuation.

Metastasectomy for selected patients with melanoma was associated with improved survival in the era before effective systemic therapy. Emerging evidence shows that these benefits persist even in this era of BRAF-targeted therapy and immune checkpoint inhibitor immunotherapy. This study aimed to evaluate the outcomes of salvage metastasectomy after failure of systemic therapy. Stage 3 or 4 melanoma patients with extracranial disease progression after at least 4 weeks of systemic treatment between 2009 and 2020 were identified and categorized as resected to no evidence of disease (NED), non-progressive residual disease (NPRD), or progressive residual disease (PRD). Systemic therapy was stratified into BRAF-targeted therapy, immune checkpoint inhibitor immunotherapy, or both. The end points of overall survival (OS), progression-free survival (PFS), and locoregional disease control (LRC) were assessed using Kaplan-Meier curves. Uni- and multivariable Cox regression procedures were used to examine factors associated with OS, PFS and LRC. The study enrolled 190 patients. Among all the patients, the 5-year OS from metastatectomy was 52%, the 3-year PFS was 21%, and the 5-year LRC was 61%. After resection to NED, NPRD, and PRD, the 5-year OS values were 69%, 62% and 8%, respectively. Fewer lines of preoperative therapy, use of preoperative immunotherapy, and resection to NED were predictors of improved OS. After resection to NED, NPRD, and PRD, the 3-year PFS values were 23%, 24% and 10%, and the 5-year LRC values were 61%, 72% and 34%, respectively. Salvage metastasectomy was associated with durable survival and disease control, particularly after resection to NED, preoperative immunotherapy, and fewer lines of preoperative systemic therapy

Background Nursing home residents are typically older adults with high levels of chronic illness and impairment. As such, they are particularly susceptible to severe complications and mortality from COVID-19. Since all nursing home residents are at increased risk, nursing home care staff need to know what residents would want to happen should they become infected with COVID-19. This study aims to develop and evaluate advance care planning (ACP) COVID-centric online training and information resources for nursing home staff and family members of residents, to improve care at the end of life during a COVID-19 outbreak. Based on the findings we will develop implementation guidelines for nursing homes to ensure wider impact and application during the pandemic and beyond. Methods The content of the training and information resources will be based on a rapid review of literature and guidance on ACP in the context of COVID-19 and consultation with the study expert reference group. An integrated communications company will then work alongside the research team to design the online training and information resources. To evaluate the resources, we will employ a multiple case study design where a nursing home (defined as an institutional setting in which nursing care is provided to older adults on-site 24 h a day) will be the unit of analysis or ‘case’. The RE-AIM (reach, effectiveness, adoption, implementation, maintenance) framework will guide the evaluation of implementation of the training and information resources. We will recruit and interview staff and family members from between 6 and 9 nursing homes across Northern Ireland, England and Scotland and gather quantitative data from a feedback survey included in the training and information resources. Discussion The Necessary Discussions study is very timely given the challenging experiences of nursing homes, their staff, residents and their family members during the COVID-19 pandemic. It meets a key need and addresses an important gap in research and practice. The training and information resources will be ‘COVID-centric’, but they will also have a longstanding relevance for future ACP practice in UK care homes. Trial registration ISRCTN registry (ID 18003630) on 19.05.21

To reduce the spread of COVID-19, governments initiated lockdowns, limiting mobility and social interaction of populations. Lockdown is linked to health issues, yet the full impact on health remains unknown, particularly in more vulnerable groups. This study examined the impact on frailty and outcomes in high and low COVID-19 risk older adults. We examined health-related behaviours and support resources participants used during lockdown(s). Lockdown impacts in two countries were compared across four time points to examine impacts of different rules. We recruited 70 participants (aged70 years) in England and Spain. Participants were allocated to higher or lower COVID-19-risk groups based on UK NHS guidelines. They completed assessments for frailty, quality-of-life, loneliness, exercise frequency and social interaction, coping resources and perception of age-friendliness of their environment. The four assessments took place over a 7-month period. Frailty was highest at Time 1 (most severe lockdown restrictions) and significantly higher in the Spanish group. It was lower at Time 3 (lowest restrictions), but did not continue to reduce for the English participants. Perceptions of the age friendliness of the environment matched these changes. Coping resources did not mitigate changes in frailty and outcomes over time, but more frequent physical activity predicted more reduction in frailty. Lockdown had a negative impact on frailty, increasing risk of adverse events for older people, but recovery once lockdowns are eased is evidenced. Further research is required to consider longer term impacts and methods to mitigate effects of lockdown on health.

Background Immune checkpoint inhibitors have improved the management of metastatic melanoma, however, we have witnessed an emergence of adverse cardiac events such as myocarditis. Objectives We first aimed to assess the prevalence of adverse cardiac events in patients treated with anti-PD-1 for metastatic melanoma. Our second objective was to determine the role of troponin monitoring in the diagnosis of these events. Materials & methods We retrospectively analysed the prevalence of patients treated with anti-PD-1 in a real-life setting based on a cohort of 183 patients. We then performed a prospective cohort, in which clinical and biological profiles of patients were collected, along with monthly monitoring of troponin levels. Results The prevalence of adverse cardiac events in the retrospective cohort was 2.2%, with three cases of myocarditis and one of myocardial infarction. In the prospective cohort, 14/52 patients had an abnormal baseline troponin T level. All patients had a history of cardiac or vascular complaints. Six patients showed an increase in troponin T level during follow-up, in two patients associated with clinical symptoms. Conclusion Adverse cardiac events with immunotherapy are both frequent and life-threatening. Troponin T may be of interest to detect early adverse cardiac events before any clinical sign, however, the data supporting this remain to be confirmed.

Degree apprenticeships have recently been introduced in the UK, representing a significant shift in approaches to degree-level study: from traditional models of higher education to workplaces as locations for learning. As the model matures it is important to hear the under-researched perspectives of apprentices who hold dual roles: as students and employees. Using Q methodology, the study aims to identify the different apprentices’ viewpoints of the degree apprenticeship, exploring aspects of belonging, support, challenges and views of the learning experience. Thirty-five second-year computing apprentices at a UK university participated in the study. Centroid factor analysis was conducted to identify different perspectives. Three perspectives of apprentices were revealed: aligned student-workers, busy professionals, and the cast adrift. Aligned student-workers were balancing work and study effectively, finding value in both. Busy professionals were already consolidated as professionals, using this degree apprenticeship to upskill. Finally, the cast adrift, reported a lack of support in the workplace that was affecting their view on the apprenticeship. This exploratory study, resulting in a new research instrument and approach, contributes apprentices’ perspectives to research and practice, as apprenticeship models expand in the UK and beyond. Support for individual apprentices is a shared responsibility, between universities and employers. All three parties, including apprentices, benefit from learning more about apprentices’ situated experiences, their sense of belonging and identity, and their views on the apprenticeship. Policymakers also benefit from insight into the shared responsibilities of successful degree apprenticeships, as these apprenticeships evolve.

Primary scalp melanomas are associated with a higher rate of brain metastasis than primary cutaneous melanomas occurring at other head and neck and body sites, but the reason is unclear. Spread to brain parenchyma via emissary veins draining from the scalp to dural sinuses has been suggested. We sought to examine the locations of metastases from primary scalp and nonscalp head and neck melanomas to determine whether there was anatomical evidence supporting direct venous spread to the brain. Data from patients who developed distant metastases from cutaneous head and neck melanomas (CHNMs) between 2000 and 2018 were analyzed. Anatomical sites of primary scalp melanomas and their respective intracranial metastases were compared. Times to first brain and nonbrain metastases were investigated for scalp and nonscalp primary CHNMs. Of 693 patients with CHNMs, 244 developed brain metastases: 109 (44.7%) had scalp primaries and 135 (55.3%) had nonscalp primaries. There was no significant association between anatomical sites of scalp primary melanomas and brain metastases (Cramer's V = 0.21; Chi-square P = 0.63). Compared with nonscalp CHNMs, scalp melanomas had no greater propensity for the brain as the first distant metastatic site ( P = 0.52) but had a shorter time to both brain metastasis (76.3 vs. 168.5 months; P0.001) and nonbrain metastasis (22.6 vs. 35.8 months; P0.001). No evidence was found to support a direct vascular pathway for metastatic spread of scalp melanomas to the brain. The increased incidence of brain metastases from scalp melanomas is probably driven by aggressive biological mechanisms.

Little guidance is currently available for managing patients with melanocytic tumours of uncertain or low malignant potential (MelTUMPs, including melanocytomas), in particular the optimal excision margins and whether to offer sentinel node biopsy (SNB). The objective of this review was to evaluate excision margins and the prognostic utility of SNB by systematic review of the literature and meta-analysis. PRISMA guidelines were followed. Medline, EMBASE and Cochrane databases were searched to October 2021 for studies of patients with MelTUMPs reporting excision margins and/or SNB-positivity. Meta-analysis was performed on the SNB-positivity rate using a random effects model, followed by sensitivity analyses on subgroups. 111 primary studies reported excision margins and/or SNB data for 1962 patients. Follow-up was available for 1649 patients: 1561 (94.7%) were alive without disease at last review, 53 (3.2%) had developed further disease, 29 (1.8%) had died of metastatic disease (melanoma) and six (0.4%) died of unrelated causes. SNB was performed in 837 patients. The pooled positivity rate on meta-analysis was 32% (95% CI: 23-44%). Clinical outcome could be correlated with excision margin in only 171 patients (60% of those with known follow up) and was therefore not analysed further. Evidence indicating the ideal excision margins for MelTUMPs was lacking. SNB had a high positivity rate despite very low rates of recurrence or melanoma-related death. Consequently, SNB should not be offered routinely for MelTUMPs (including melanocytomas), due to its lack of prognostic utility for this tumour type (high certainty of evidence).