[111In]In-CP04 as a novel cholecystokinin-2 receptor ligand with theranostic potential in patients with progressive or metastatic medullary thyroid cancer: final results of a GRAN-T-MTC Phase I clinical trial.

INTRODUCTION: Medullary thyroid cancer (MTC) is a rare malignant tumour of the parafollicular C-cells with an unpredictable clinical course and currently suboptimal diagnostic and therapeutic options, in particular in advanced disease. Overexpression of cholecystokinin-2 receptors (CCK2R) represents a promising avenue to diagnostic imaging and targeted therapy, ideally through a theranostic approach. MATERIALS AND METHODS: A translational study (GRAN-T-MTC) conducted through a Phase I multicentre clinical trial of the indium-111 labelled CP04 ([111In]In-CP04), a CCK2R-seeking ligand was initiated with the goal of developing a theranostic compound. Patients with proven advanced/metastatic MTC or short calcitonin doubling time were enrolled. A two-step concept was developed through the use of low- and high-peptide mass (10 and 50 µg, respectively) for safety assessment, with the higher peptide mass considered appropriate for therapeutic application. Gelofusine was co-infused in a randomized fashion in the second step for the evaluation of potential reduction of the absorbed dose to the kidneys. Imaging for the purpose of biodistribution, dosimetry evaluation, and diagnostic assessment were performed as well as pre-, peri-, and postprocedural clinical and biochemical assessment. RESULTS: Sixteen patients were enrolled. No serious adverse events after application of the compound at both peptide amounts were witnessed; transient tachycardia and flushing were observed in two patients. No changes in biochemistry and clinical status were observed on follow-up. Preliminary dosimetry assessment revealed the highest dose to urinary bladder, followed by the kidneys and stomach wall. The effective dose for 200 MBq of [111In]In-CP04 was estimated at 7±3 mSv and 7±1 mSv for 10 µg and 50 µg CP04, respectively. Administration of Gelofusine reduced the dose to the kidneys by 53%, resulting in the organ absorbed dose of 0.044±0.019 mSv/MBq. Projected absorbed dose to the kidneys with the use of [177Lu]Lu-CP04 was estimated at 0.9±0.4 Gy/7.4 GBq. [111In]In-CP04 scintigraphy was positive in 13 patients (detection rate of 81%) with superior diagnostic performance over conventional imaging. CONCLUSION: In the present study, [111In]In-CP04 was shown to be a safe and effective radiopharmaceutical with promising theranostic characteristics for patients with advanced MTC.

One-Carbon Metabolism Biomarkers and Risks of Incident Neurocognitive Disorder among Cognitively Normal Older Adults.

There is a lack of evidence supporting an association between folate and vitamin B12 exposure with cognitive outcomes. We examined serum folate and vitamin B12 and plasma homocysteine in 690 cognitively-normal adults (aged ≥ 55) from the Singapore Longitudinal Aging Study (SLAS-2) followed-up over 4.5 years on incident neurocognitive disorder (NCD): mild cognitive impairment (MCI) and dementia. At follow-up, 5.7% (39) of participants developed NCD (34 MCI and 5 dementia). Comparing with those who remained cognitively-normal, participants progressed to NCD had significantly lower mean baseline vitamin B12 (420 [SD ± 221] vs. 510 [SD ± 290] pmol/L, p = 0.026), higher homocysteine (14.6 [SD ± 4.2] vs. 12.9 [SD ± 4.3], p = 0.018) and lower one-carbon index (Z-scores: -0.444 [SD ± 0.819] vs. -0.001 [SD ± 0.990], p = 0.006). Adjusted for confounders, significant associations with incident NCD were found for lower vitamin B12 (per-SD OR = 2.10, 95%CI = 1.26-3.52), higher homocysteine (per-SD OR = 1.96, 95%CI = 1.18-3.24) and lower one-carbon index (per-SD OR = 1.67, 95%CI = 1.06-2.64). Folate was not significantly associated with progression to NCD. Notably, low B12 in the presence of high folate was significantly associated with incident NCD (adjusted OR = 3.81, 95%CI = 1.04-13.9). Low B12, high homocysteine, low B12 in the presence of high folate, and a one-carbon index of hypo-methylation were independently associated with progression to NCD among cognitively normal.

Metabolic Syndrome and Cognition: Follow-Up Study of Chinese Over-55-Year-Olds.

BACKGROUND/AIM: Studies of the associations of the metabolic syndrome (MetS) with cognitive function and decline are inconclusive. We investigated the associations of the MetS with cognitive functions in 823 Chinese >55-year-olds followed up over 4.5 years. METHODS: The relationships between the MetS and baseline and follow-up z-scores of cognitive domain functions were examined using mixed model analysis. RESULTS: There were specific inverse cross-sectional associations of single cardiometabolic risk factors with cognition, such as hyperglycemia with processing speed (p = 0.045). The MetS was negatively associated with 3 out of 4 cognitive domains (p = 0.018 to p = 0.003), and the count of cardiometabolic risk factors with all cognitive domains (p = 0.025 to p = 0.002). Longitudinally, dyslipidemia was associated with worse decline in memory and learning (p = 0.022). The count of cardiometabolic risk factors was associated with worse declines in cognition (p = 0.032 for global cognition). CONCLUSION: Among middle-aged and older Asians, an increased number of component cardiometabolic risk factors of the MetS was associated with a worse decline in cognitive function over time.