Clinical applications of PD-L1 bioassays for cancer immunotherapy

Abstract Programmed death ligand 1 (PD-L1) has emerged as a biomarker that can help to predict responses to immunotherapies targeted against PD-L1 and its receptor (PD-1). Companion tests for evaluating PD-L1 expression as a biomarker of response have been developed for many cancer immunotherapy agents. These assays use a variety of detection platforms at different levels (protein, mRNA), employ diverse biopsy and surgical samples, and have disparate positivity cutoff points and scoring systems, all of which complicate the standardization of clinical decision-making. This review summarizes the current understanding and ongoing investigations regarding PD-L1 expression as a potential biomarker for clinical outcomes of anti-PD-1/PD-L1 immunotherapy

Key stakeholder perceptions about consent to participate in acute illness research: a rapid, systematic review to inform epi/pandemic research preparedness

Background A rigorous research response is required to inform clinical and public health decision-making during an epi/pandemic. However, the ethical conduct of such research, which often involves critically ill patients, may be complicated by the diminished capacity to consent and an imperative to initiate trial therapies within short time frames. Alternative approaches to taking prospective informed consent may therefore be used. We aimed to rapidly review evidence on key stakeholder (patients, their proxy decision-makers, clinicians and regulators) views concerning the acceptability of various approaches for obtaining consent relevant to pandemic-related acute illness research. Methods We conducted a rapid evidence review, using the Internet, database and hand-searching for English language empirical publications from 1996 to 2014 on stakeholder opinions of consent models (prospective informed, third-party, deferred, or waived) used in acute illness research. We excluded research on consent to treatment, screening, or other such procedures, non-emergency research and secondary studies. Papers were categorised, and data summarised using narrative synthesis. Results We screened 689 citations, reviewed 104 full-text articles and included 52. Just one paper related specifically to pandemic research. In other emergency research contexts potential research participants, clinicians and research staff found third-party, deferred, and waived consent to be acceptable as a means to feasibly conduct such research. Acceptability to potential participants was motivated by altruism, trust in the medical community, and perceived value in medical research and decreased as the perceived risks associated with participation increased. Discrepancies were observed in the acceptability of the concept and application or experience of alternative consent models. Patients accepted clinicians acting as proxy-decision makers, with preference for two decision makers as invasiveness of interventions increased. Research regulators were more cautious when approving studies conducted with alternative consent models; however, their views were generally under-represented. Conclusions Third-party, deferred, and waived consent models are broadly acceptable to potential participants, clinicians and/or researchers for emergency research. Further consultation with key stakeholders, particularly with regulators, and studies focused specifically on epi/pandemic research, are required. We highlight gaps and recommendations to inform set-up and protocol development for pandemic research and institutional review board processes

Preconceptional low-dose aspirin for the prevention of hypertensive pregnancy complications and preterm delivery after IVF : a meta-analysis with individual patient data

Study question: Does preconceptionally started low-dose aspirin prevent hypertensive pregnancy complications and preterm delivery in IVF patients? Summary answer: The current data do not support the use of preconceptionally started low-dose aspirin treatment for the prevention of hypertensive pregnancy complications and preterm delivery in IVF women. What is known already: Studies starting low-dose aspirin treatment as prevention in the second trimester of pregnancy found no or only moderate reductions in the relative risk of developing pre-eclampsia. Low-dose aspirin was possibly started too late, that is after the first episode of trophoblast invasion. Study design, size, duration: We performed a meta-analysis with individual patient data (IPD), in which four authors could provide IPD on a total of 268 pregnancies (n ¼ 131 treated with aspirin, n ¼ 137 placebo). Data on hypertensive pregnancy complications and preterm delivery were collected. Participants/materials, setting, methods: All separate databases were merged into a summary database. Treatment effect of aspirin on the incidence of hypertensive pregnancy complications (n ¼ 187) and preterm delivery (n ¼ 180) were estimated with odds ratios (OR) and 95% confidence intervals (95% CI) using multivariable logistic regression. Main results and the role of chance: There were significantly fewer twin pregnancies in the aspirin group (OR 0.55 95% CI 0.30–0.98), but no significant differences for hypertensive pregnancy complications and preterm delivery: for singletons OR 0.62 (95% CI 0.22–1.7) and OR 0.52 (95% CI 0.16–1.7), respectively, as well as for twin pregnancies OR 1.2 (95% CI 0.35–4.4) and OR 1.6 (95% CI 0.51–5.0), respectively. Limitations, reasons for caution: We have to bear in mind that the included studies showed clinical heterogeneity; there was variation in the duration of low-dose aspirin therapy and degree of hypertension between the different studies. Although we combined IPD from four studies, we have to realize that the studies were not powered for the outcome of the current IPD meta-analysis. Wider implications of the findings: Based on the current meta-analysis with IPD we found no confirmation for the hypothesis that preconceptionally started low-dose aspirin reduces the incidence of hypertensive pregnancy complications or preterm delivery in IVF women. Larger studies are warranted. Study funding/competing interest(s): None. Trial registration number: not applicable

Preconceptional low-dose aspirin for the prevention of hypertensive pregnancy complications and preterm delivery after IVF:a meta-analysis with individual patient data

\u3cp\u3eSTUDY QUESTION Does preconceptionally started low-dose aspirin prevent hypertensive pregnancy complications and preterm delivery in IVF patients? SUMMARY ANSWER The current data do not support the use of preconceptionally started low-dose aspirin treatment for the prevention of hypertensive pregnancy complications and preterm delivery in IVF women. WHAT IS KNOWN ALREADY Studies starting low-dose aspirin treatment as prevention in the second trimester of pregnancy found no or only moderate reductions in the relative risk of developing pre-eclampsia. Low-dose aspirin was possibly started too late, that is after the first episode of trophoblast invasion. STUDY DESIGN, SIZE, DURATION We performed a meta-analysis with individual patient data (IPD), in which four authors could provide IPD on a total of 268 pregnancies (n = 131 treated with aspirin, n = 137 placebo). Data on hypertensive pregnancy complications and preterm delivery were collected. PARTICIPANTS/MATERIALS, SETTING, METHODS All separate databases were merged into a summary database. Treatment effect of aspirin on the incidence of hypertensive pregnancy complications (n = 187) and preterm delivery (n = 180) were estimated with odds ratios (OR) and 95% confidence intervals (95% CI) using multivariable logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE There were significantly fewer twin pregnancies in the aspirin group (OR 0.55 95% CI 0.30-0.98), but no significant differences for hypertensive pregnancy complications and preterm delivery: for singletons OR 0.62 (95% CI 0.22-1.7) and OR 0.52 (95% CI 0.16-1.7), respectively, as well as for twin pregnancies OR 1.2 (95% CI 0.35-4.4) and OR 1.6 (95% CI 0.51-5.0), respectively. LIMITATIONS, REASONS FOR CAUTION We have to bear in mind that the included studies showed clinical heterogeneity; there was variation in the duration of low-dose aspirin therapy and degree of hypertension between the different studies. Although we combined IPD from four studies, we have to realize that the studies were not powered for the outcome of the current IPD meta-analysis. WIDER IMPLICATIONS OF THE FINDINGS Based on the current meta-analysis with IPD we found no confirmation for the hypothesis that preconceptionally started low-dose aspirin reduces the incidence of hypertensive pregnancy complications or preterm delivery in IVF women. Larger studies are warranted. STUDY FUNDING/COMPETING INTEREST(S) None.\u3c/p\u3