Circulating tumour DNA (ctDNA) in metastatic melanoma, a systematic review and meta-analysis.

INTRODUCTION: Circulating tumour DNA (ctDNA) is an emerging biomarker in melanoma. We performed a systematic review and meta-analysis to explore its clinical utility as a prognostic, pharmacodynamic (PD) and predictive biomarker. METHODS: A systematic search was conducted from Jan 2015 to April 2021, of the electronic databases PubMed, Cochrane Library and Ovid MEDLINE to identify studies. Studies were restricted to those published in English within the last 5 years, evaluating ctDNA in humans in ≥10 patients. Survival data were extracted for meta-analysis using pooled treatment effect (TE), i.e. log hazard ratios (HRs) and corresponding standard error of TE for progression-free survival or overall survival differences in patients who were ctDNA positive or negative. PRISMA statement guidelines were followed. RESULTS: A meta-analysis of 19 studies grouped according to methodology of ctDNA detection, revealed a combined estimate for HR of progression-free survival (13 studies using droplet digital Polymerase Chain Reaction (ddPCR) methodology (N = 1002) of 2.10 (95% CI: 1.71-2.59) revealing a poorer prognosis when ctDNA was detected. This result was confirmed in the smaller analysis of (non-ddPCR, N = 347) five studies: HR = 2.45 (95% CI: 1.29-4.63). Similar findings were found in the overall survival analysis of nine studies (ddPCR methodology, N = 841) where the combined HR was 2.78 (95% CI: 2.21-3.49) and of the five studies (non-ddPCR methodology, N = 326) where the combined HR was 2.58 (95% CI: 1.74-3.84). Serial ctDNA levels on treatment showed a pharmacodynamic role reflecting response or resistance earlier than radiological assessment. CONCLUSIONS: Circulating tumour DNA is a predictive, prognostic and PD biomarker in melanoma. Technical standardisation of assays is required before clinical adoption.

Direct tests of measurement uncertainty relations: what it takes.

The uncertainty principle being a cornerstone of quantum mechanics, it is surprising that, in nearly 90 years, there have been no direct tests of measurement uncertainty relations. This lacuna was due to the absence of two essential ingredients: appropriate measures of measurement error (and disturbance) and precise formulations of such relations that are universally valid and directly testable. We formulate two distinct forms of direct tests, based on different measures of error. We present a prototype protocol for a direct test of measurement uncertainty relations in terms of value deviation errors (hitherto considered nonfeasible), highlighting the lack of universality of these relations. This shows that the formulation of universal, directly testable measurement uncertainty relations for state-dependent error measures remains an important open problem. Recent experiments that were claimed to constitute invalidations of Heisenberg's error-disturbance relation, are shown to conform with the spirit of Heisenberg's principle if interpreted as direct tests of measurement uncertainty relations for error measures that quantify distances between observables.