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- Daskalakis, Kosmas, 1979-, et al.
(författare)
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Increased Autophagy/Mitophagy Levels in Pancreatic Neuroendocrine Neoplasms
- 2020
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Ingår i: Neuroendocrinology. - : S. Karger. - 0028-3835 .- 1423-0194. ; 110:Suppl. 1, s. 7-7
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Autophagy and mitophagy are key homeostatic machineries linked to cancer development and drug resistance.Aim(s): To assess the levels of autophagy and mitophagy in well differentiated pancreatic neuroendocrine neoplasms (PanNENs) and correlate them with clinico-pathological parameters. Materials and methods: Fluorescent immunostaining for the autophagy markers LC3 Βand p62/or LAMP1 was performed on 22 PanNENs and 11 controls of normal pancreatic tissues and validated through Western blotting. Autophagy quantitative scoring was generated for LC3B-positive puncta and analyzed in relation to clinico-pathological parameters. TOMM20/LC3B qualitative assessment of mitophagy levels was undertaken by fluorescent immunostaining. The presence of autophagy/mitophagy was validated by transmission electron microscopy.Results: Autophagy levels (LC3B-positive puncta/cell) were discriminative for normal vs. NEN pancreatic tissue (p=0.007). A significant association was observed between autophagy levels and tumour grade (Ki67<3% vs. Ki67≥3%; p=0.021), but not functionality (p=0.266) size (cut-off of 20mm; p=0.808), local invasion (p=0.481), lymph node- (p=0.849) and distant metastases (p=0.699). Qualitative assessment of TOMM20/LC3B demonstrated strong mitophagy levels in PanNENs by fluorescent immunostaining as compared to normal tissue. Transmission electron microscopy revealed enhanced autophagy and mitophagy in PanNEN tissue. Response to molecular targeted therapies in metastatic cases (n=4) did not reveal any patterns of association to autophagy levels.Conclusion: Increased autophagy levels are present in primary tumours of patients with PanNENs and are partially attributed to upregulated mitophagy. Grade was the only clinico-pathological parameter associated with autophagy scores.
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| 2. |
- Kjellman, M., et al.
(författare)
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A Plasma Protein Biomarker Strategy for Detection of Small Intestinal Neuroendocrine Tumors
- 2021
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 111:9, s. 840-849
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Tidskriftsartikel (refereegranskat)abstract
- Background: Small intestinal neuroendocrine tumors (SI-NETs) are difficult to diagnose in the early stage of disease. Current blood biomarkers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid have low sensitivity (SEN) and specificity (SPE). This is a first preplanned interim analysis (Nordic non-interventional, prospective, exploratory, EXPLAIN study [NCT02630654]). Its objective is to investigate if a plasma protein multi-biomarker strategy can improve diagnostic accuracy (ACC) in SI-NETs. Methods: At the time of diagnosis, before any disease-specific treatment was initiated, blood was collected from patients with advanced SI-NETs and 92 putative cancer-related plasma proteins from 135 patients were analyzed and compared with the results of age- and sex-matched controls (n = 143), using multiplex proximity extension assay and machine learning techniques. Results: Using a random forest model including 12 top ranked plasma proteins in patients with SI-NETs, the multi-biomarker strategy showed SEN and SPE of 89 and 91%, respectively, with negative predictive value (NPV) and positive predictive value (PPV) of 90 and 91%, respectively, to identify patients with regional or metastatic disease with an area under the receiver operator characteristic curve (AUROC) of 99%. In 30 patients with normal CgA concentrations, the model provided a diagnostic SPE of 98%, SEN of 56%, and NPV 90%, PPV of 90%, and AUROC 97%, regardless of proton pump inhibitor intake. Conclusion: This interim analysis demonstrates that a multi-biomarker/machine learning strategy improves diagnostic ACC of patients with SI-NET at the time of diagnosis, especially in patients with normal CgA levels. The results indicate that this multi-biomarker strategy can be useful for early detection of SI-NETs at presentation and conceivably detect recurrence after radical primary resection.
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