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- Botling, Johan, et al.
(författare)
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High-grade progression confers poor survival in pancreatic neuroendocrine tumors
- 2020
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 110:11-12, s. 891-898
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Little is known about how Pancreatic Neuroendocrine Tumors (PanNETs) evolve over time and if changes towards a more aggressive biology correlates with prognosis. The purpose of this study was to characterize changes PanNET differentiation and proliferation over time, and to correlate findings to overall survival (OS).PATIENTS AND METHODS: In this retrospective cohort study we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were re-evaluated with regard to tumor histopathology and Ki-67 index.RESULTS: Forty-six patients with 106 tumor samples (56 available for pathology re-evaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1-38%), grade 1 n=8, grade 2 n=36, and grade 3 n=2. The median change in Ki-67 index (absolute value; follow-up - baseline) was +14% (range -11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 (n=24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (HR 3.89, 95% CI 1.91-7.94, P<0.001).CONCLUSIONS: A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET.
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- Edfeldt, Katarina, 1979-, et al.
(författare)
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DcR3, TFF3 and Midkine are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors
- 2017
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 105:2, s. 170-181
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Tidskriftsartikel (refereegranskat)abstract
- Small intestinal neuroendocrine tumors (SI-NETs) are amine- and peptide producing neoplasms. Most patients display metastases at the time of diagnosis, they have an unpredictable individual disease course and the tumors are often therapy resistant. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are the clinically most used biomarkers today, but there is a great need for novel diagnostic and prognostic biomarkers and new therapeutic targets. Sixty-nine biomarkers were screened in serum from 23 SI-NET patients and 23 healthy controls using multiplex PLA (proximity ligation assay). A refined method, PEA (proximity extension assay), was used to analyze 76 additional biomarkers. Statistical testing and multivariate classification were performed. Immunohistochemistry and ELISA assays were performed in an extended cohort. Using PLA, 19 biomarkers showed a significant difference in serum concentrations between patients and controls, and PEA revealed difference in concentrations in 13 proteins. Multivariate classification analysis revealed decoy receptor 3 (DcR3), trefoil factor 3 (TFF3) and Midkine to be good biomarkers for disease, which was confirmed by ELISA analysis. All three biomarkers were expressed in tumor tissue. DcR3 concentrations were elevated in patients with stage IV disease. High concentrations of DcR3 and TFF3 were correlated to poor survival. DcR3, TFF3 and Midkine exhibited elevated serum concentrations in SI-NET patients compared to healthy controls, and DcR3 and TFF3 were associated with poor survival. DcR3 seems to be a marker for liver metastases while TFF3 and Midkine may be new diagnostic biomarkers for SI-NETs.
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- Yamamoto, Shinji, et al.
(författare)
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11C-Hydroxyephedrine Positron Emission Tomography in the Postoperative Management of Pheochromocytoma and Paraganglioma
- 2014
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 100:1, s. 60-70
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Tidskriftsartikel (refereegranskat)abstract
- Aim:Accurate detection of recurrent disease and restaging are essential in the postoperative surveillance of many patients with pheochromocytomas (PHEOs) and paragangliomas (PGLs). In this study, the impact of positron emission tomography (PET) and PET/computed tomography (CT) with 11C-hydroxyephedrine (HED) was evaluated for the postoperative surveillance and diagnosis of recurrent disease and for functional monitoring of locoregional and systemic therapy.Methods:One hundred and eleven HED-PET and PET/CT examinations performed in 48 patients after surgical intervention for PHEO/PGL were analyzed retrospectively. In a subgroup of 16 patients who underwent systemic and locoregional therapies, the tracer uptake in tumors was also measured as the functional volume (FV), maximum standardized uptake value (SUVmax), mean SUV (SUVmean) and as the total catecholamine transporter tumor volume (TCTTV) calculated as TCTTV = FV × SUVmean. The PET imaging results were correlated with CT/magnetic resonance imaging findings and biochemical and clinical follow-up data.Results: In the first postoperative examination, HED-PET was positive in 24/48 and negative in 24/48 patients with no false-positive results, yielding 92.3% sensitivity and 100% specificity. For the 16 patients, there was a significant correlation between FV and SUVmax and SUVmax and TCTTV. TCTTV correlated significantly with plasma and urinary catecholamines. In 11/16 patients, SUVmax and TCTTV increased/decreased in parallel but not in the remaining 5 patients. Conclusion:HED-PET and PET/CT were found to be valuable in the postoperative follow-up in detecting recurrent and metastatic disease. In a subgroup of patients, functional monitoring of systemic and locoregional therapies was feasible by assessing the changes of the TCTTV, and therefore warrants further prospective evaluation.
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- Yu, Di, 1985-, et al.
(författare)
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Preclinical Evaluation of AdVince, an Oncolytic Adenovirus Adapted for Treatment of Liver Metastases from Neuroendocrine Cancer
- 2017
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Ingår i: Neuroendocrinology. - : S. Karger. - 0028-3835 .- 1423-0194. ; 105:1, s. 54-66
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Tidskriftsartikel (refereegranskat)abstract
- Cancer immunotherapy is becoming a cornerstone in the clinical care of cancer patients due to the breakthrough trials with immune checkpoint blockade antibodies and chimeric antigen receptor T cells. The next breakthrough in cancer immunotherapy is likely to be oncolytic viruses engineered to selectively kill tumor cells and deceive the immune system to believe that the tumor is a foreign entity that needs to be eradicated. We have developed AdVince, an oncolytic adenovirus for treatment of liver metastases from neuroendocrine tumor (NET). AdVince includes the gene promoter from human chromogranin A for selective replication in neuroendocrine cells, miR122 target sequences for reduced liver toxicity, and a cell-penetrating peptide in the capsid for increased infectivity of tumor cells and optimized spread within tumors. This paper describes the preclinical evaluation of AdVince on freshly isolated human gastrointestinal NET cells resected from liver metastases and freshly isolated human hepatocytes as well as in fresh human blood. AdVince selectively replicates in and kills NET cells. Approximately, 73-fold higher concentration of AdVince is needed to induce similar level of cytotoxicity in NET cells as in hepatocytes. AdVince did not activate complement or induce considerable amount of proinflammatory cytokines or chemokines in human blood. The data presented herein indicate that AdVince can be safely evaluated in a phase I/IIa clinical trial for patients with liver-dominant NET.
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