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Background & Aims: In Wilson disease (WD), copper accumulation and increased non-ceruloplasmin-bound copper in plasma lead to liver and brain pathology. To better understand the fate of non-ceruloplasmin-bound copper, we used PET/CT to examine the whole-body distribution of intravenously injected 64-copper (64Cu). Methods: Eight patients with WD, five heterozygotes, and nine healthy controls were examined by dynamic PET/CT for 90 min and static PET/CT up to 20 h after injection. We measured 64Cu activity in blood and tissue and quantified the kinetics by compartmental analysis. Results: Initially, a large fraction of injected 64Cu was distributed to extrahepatic tissues, especially skeletal muscle. Thus, across groups, extrahepatic tissues accounted for 45-58% of the injected dose (%ID) after 10 min, and 45-55% after 1 h. Kinetic analysis showed rapid exchange of 64Cu between blood and muscle as well as adipose tissue, with 64Cu retention in a secondary compartment, possibly mitochondria. This way, muscle and adipose tissue may protect the brain from spikes in non-ceruloplasmin-bound copper. Tiny amounts of cerebral 64Cu were detected (0.2%ID after 90 min and 0.3%ID after 6 h), suggesting tight control of cerebral copper in accordance with a cerebral clearance that is 2-3-fold lower than in muscle. Compared to controls, patients with WD accumulated more hepatic copper 6-20 h after injection, and also renal copper at 6 h. Conclusion: Non-ceruloplasmin-bound copper is initially distributed into a number of tissues before being redistributed slowly to the eliminating organ, the liver. Cerebral uptake of copper is extremely slow and likely highly regulated. Our findings provide new insights into the mechanisms of copper control. Impact and implications: Maintaining non-ceruloplasmin-bound copper within the normal range is an important treatment goal in WD as this "free" copper is considered toxic to the liver and brain. We found that intravenously injected non-ceruloplasmin-bound copper quickly distributed to a number of tissues, especially skeletal muscle, subcutaneous fat, and the liver, while uptake into the brain was slow. This study offers new insights into the mechanisms of copper control, which may encourage further research into potential new treatment targets. Clinical trial number: 2016-001975-59.
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INTRODUCTION: The European Neuroendocrine Tumor Society (ENETS) reports variables of prognostic significance in bronchopulmonary neuroendocrine neoplasms (BP-NENs). The aim of this study was to investigate prognostic factors, recurrence-free survival (RFS), and overall survival (OS) for patients with typical carcinoid (TC), atypical carcinoid (AC), and large-cell neuroendocrine carcinoma (LCNEC). Current follow-up practices vary as the evidence is sparse, and we aimed to explore the relevance of routine bronchoscopy in follow-up. METHODS: This was a cohort study of 208 patients with BP-NENs followed at Aarhus University Hospital in 2008-2019. RFS and OS were determined using the Kaplan-Meier method for the variables such as primary tumor, primary treatment, smoking status, gender, and histological subtypes. RESULTS: The study included 153 patients with TC, 29 with AC, and 26 with LCNEC. Median follow-up was 48 months. The majority of patients (n = 191) received surgical resection, of which 22 (11%) recurred over time. Seventeen patients had nonsurgical treatment, of which 10 (59%) progressed. The 5-year OS rate was 86% for operated and 9% for nonoperated patients (p < 0.05). Patients with TC had a 5-year OS of 90% compared with 63% and 39% for AC and LCNEC, respectively. As for prognostic factors, nonsmokers did not secure a significant difference in OS compared with current/previous smokers (p = 0.51). In the follow-up period, only 2 (9%) of the 22 recurrences were found on a routine bronchoscopy. Both of these recurrences were also found by diagnostic imaging. CONCLUSIONS: Surgical treatment, especially, and diagnosis of TC were associated with a good prognosis. Furthermore, our data did not support routine bronchoscopy as part of a follow-up program for bronchial carcinoids.
