KEYNOTE-716: Phase III study of adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma.

Patients with high-risk stage II melanoma are at significant risk for recurrence after surgical resection. Adjuvant treatment options to lower the risk for distant metastases are limited. Although adjuvant IFN-α2b is associated with improved relapse-free survival in patients with high-risk melanoma, toxicity and limited overall survival benefits limit its use. Adjuvant treatment with the PD-1 inhibitor pembrolizumab significantly improved recurrence-free survival, compared with placebo, in patients with resected stage III melanoma in the Phase III KEYNOTE-054 trial; efficacy in patients with stage II disease has not been established. This article describes the design and rationale of KEYNOTE-716 (NCT03553836), a two-part, randomized, placebo-controlled, multicenter Phase III study of adjuvant pembrolizumab in patients with surgically resected high-risk stage II melanoma. Clinical trial registry & ID: ClinicalTrials.gov, NCT0355383

REFINE (reduced frequency ImmuNE checkpoint inhibition in cancers): A multi-arm phase II basket trial testing reduced intensity immunotherapy across different cancers

Background Immune checkpoint inhibitors (ICI) have revolutionised treating advanced cancers. ICI are administered intravenously every 2–6 weeks for up to 2 years, until cancer progression/unacceptable toxicity. Physiological efficacy is observed at lower doses than those used as standard of care (SOC). Pharmacodynamic studies indicate sustained target occupancy, despite a pharmacological half-life of 2–3 weeks. Reducing frequency of administration may be possible without compromising outcomes. The REFINE trial aims to limit individual patient exposure to ICI whilst maintaining efficacy, with potential benefits in quality of life and reduced drug treatment/attendance costs. Methods/Design REFINE is a randomised phase II, multi-arm, multi-stage (MAMS) adaptive basket trial investigating extended interval administration of ICIs. Eligible patients are those responding to conventionally dosed ICI at 12 weeks. In stage I, patients (n = 160 per tumour-specific cohort) will be randomly allocated (1:1) to receive maintenance ICI at SOC vs extended dose interval. REFINE is currently recruiting UK patients with locally advanced or metastatic renal cell carcinoma (RCC) who have tolerated and responded to initial nivolumab/ipilimumab, randomised to receive maintenance nivolumab SOC (480 mg 4 weekly) vs extended interval (480 mg 8 weekly). Additional tumour cohorts are planned. Subject to satisfactory outcomes (progression-free survival) stage II will investigate up to 5 different treatment intervals. Secondary outcome measures include overall survival, quality-of-life, treatment-related toxicity, mean incremental pathway costs and quality-adjusted life-years per patient. REFINE is funded by the Jon Moulton Charity Trust and Medical Research Council, sponsored by University College London (UCL), and coordinated by the MRC CTU at UCL

Facilitating the transition of young people with long-term conditions through health services from childhood to adulthood: the Transition research programme

Background: As young people with long-term conditions move from childhood to adulthood, their health may deteriorate and their social participation may reduce. ‘Transition’ is the ‘process’ that addresses the medical, psychosocial and educational needs of young people during this time. ‘Transfer’ is the ‘event’ when medical care moves from children’s to adults’ services. In a typical NHS Trust serving a population of 270,000, approximately 100 young people with long-term conditions requiring secondary care reach the age of 16 years each year. As transition extends over about 7 years, the number in transition at any time is approximately 700. Objectives: Purpose – to promote the health and well-being of young people with long-term conditions by generating evidence to enable NHS commissioners and providers to facilitate successful health-care transition. Objectives – (1) to work with young people to determine what is important in their transitional health care, (2) to identify the effective and efficient features of transitional health care and (3) to determine how transitional health care should be commissioned and provided. Design, settings and participants: Three work packages addressed each objective. Objective 1. (i) A young people’s advisory group met monthly throughout the programme. (ii) It explored the usefulness of patient-held health information. (iii) A ‘Q-sort’ study examined how young people approached transitional health care. Objective 2. (i) We followed, for 3 years, 374 young people with type 1 diabetes mellitus (150 from five sites in England), autism spectrum disorder (118 from four sites in England) or cerebral palsy (106 from 18 sites in England and Northern Ireland). We assessed whether or not nine proposed beneficial features (PBFs) of transitional health care predicted better outcomes. (ii) We interviewed a subset of 13 young people about their transition. (iii) We undertook a discrete choice experiment and examined the efficiency of illustrative models of transition. Objective 3. (i) We interviewed staff and observed meetings in three trusts to identify the facilitators of and barriers to introducing developmentally appropriate health care (DAH). We developed a toolkit to assist the introduction of DAH. (ii) We undertook a literature review, interviews and site visits to identify the facilitators of and barriers to commissioning transitional health care. (iii) We synthesised learning on ‘what’ and ‘how’ to commission, drawing on meetings with commissioners. Main outcome measures: Participation in life situations, mental well-being, satisfaction with services and condition-specific outcomes. Strengths: This was a longitudinal study with a large sample; the conditions chosen were representative; non-participation and attrition appeared unlikely to introduce bias; the research on commissioning was novel; and a young person’s group was involved. Limitations: There is uncertainty about whether or not the regions and trusts in the longitudinal study were representative; however, we recruited from 27 trusts widely spread over England and Northern Ireland, which varied greatly in the number and variety of the PBFs they offered. The quality of delivery of each PBF was not assessed. Owing to the nature of the data, only exploratory rather than strict economic modelling was undertaken. Results and conclusions: (1) Commissioners and providers regarded transition as the responsibility of children’s services. This is inappropriate, given that transition extends to approximately the age of 24 years. Our findings indicate an important role for commissioners of adults’ services to commission transitional health care, in addition to commissioners of children’s services with whom responsibility for transitional health care currently lies. (2) DAH is a crucial aspect of transitional health care. Our findings indicate the importance of health services being commissioned to ensure that providers deliver DAH across all health-care services, and that this will be facilitated by commitment from senior provider and commissioner leaders. (3) Good practice led by enthusiasts rarely generalised to other specialties or to adults’ services. This indicates the importance of NHS Trusts adopting a trust-wide approach to implementation of transitional health care. (4) Adults’ and children’s services were often not joined up. This indicates the importance of adults’ clinicians, children’s clinicians and general practitioners planning transition procedures together. (5) Young people adopted one of four broad interaction styles during transition: ‘laid back’, ‘anxious’, ‘wanting autonomy’ or ‘socially oriented’. Identifying a young person’s style would help personalise communication with them. (6) Three PBFs of transitional health care were significantly associated with better outcomes: ‘parental involvement, suiting parent and young person’, ‘promotion of a young person’s confidence in managing their health’ and ‘meeting the adult team before transfer’. (7) Maximal service uptake would be achieved by services encouraging appropriate parental involvement with young people to make decisions about their care. A service involving ‘appropriate parental involvement’ and ‘promotion of confidence in managing one’s health’ may offer good value for money. Future work: How might the programme’s findings be implemented by commissioners and health-care providers? What are the most effective ways for primary health care to assist transition and support young people after transfer

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Old times in Dixie land; a southern matron's memories,

Mode of access: Internet