Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70-100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin's mechanism of anticancer activity in this context is unclear. METHODS: Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. DISCUSSION: Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. TRIAL REGISTRATION: ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.

Establishing Reference Intervals for Gadolinium Concentrations in Blood, Plasma, and Urine in Individuals Not Previously Exposed to Gadolinium-Based Contrast Agents.

OBJECTIVES: Over the recent years, there have been increasing concerns that exposure to gadolinium-based contrast agents (GBCAs) may be associated with retention of Gd within the skin, bones, and solid organs in patients with normal renal function, although the clinical implications of this deposition remain to be established. There are no published data available to guide the development of reference intervals for Gd concentrations in biological samples from healthy people. The aims of this study were to (1) determine whether healthy individuals who have not received GBCAs have detectable concentrations of Gd in their blood and urine, and (2) to develop a reference range for Gd concentrations in blood and spot urine samples for healthy individuals. MATERIALS AND METHODS: Whole blood, plasma, and spot urine samples were taken from 120 healthy volunteers with estimated glomerular filtration rate 70 mL/min per 1.73 m or greater. Gd concentrations were measured in these samples using inductively coupled plasma mass-spectrometry. The reference intervals for Gd concentrations in whole blood, plasma, and urine were estimated as the 2.5th percentile and the upper reference limit as the 97.5th percentile. RESULTS: Ten (8.33%) of the 120 subjects had detectable concentrations of Gd in their whole blood (n = 5) or spot urine (n = 5) samples; no subjects had detectable concentrations of Gd in their plasma samples. Our proposed reference intervals for Gd are as follows: whole blood, <0.008 ng/mL or <0.050 nmol/L; plasma, <0.009 ng/mL or <0.057 nmol/L; spot urine, <0.036 µg/g or <0.0250 nmol/mmol. CONCLUSIONS: The results of this study provide reference intervals for whole blood, plasma, and urine Gd concentrations in healthy subjects who have not previously received GBCAs and will assist clinicians in assessing patients who have concerns regarding potential Gd retention postexposure and help guide further clinical studies to explore the pharmacokinetics of GBCAs in patients with normal renal function.