| 1. |
- Daskalakis, Kosmas, et al.
(författare)
-
Anti-tumour activity of everolimus and sunitinib in neuroendocrine neoplasms
- 2019
-
Ingår i: Endocrine Connections. - : Bioscientifica. - 2049-3614. ; 8:6, s. 641-653
-
Tidskriftsartikel (refereegranskat)abstract
- Comparisons between everolimus and sunitinib regarding their efficacy and safety in neuroendocrine neoplasms (NENs) are scarce. We retrospectively analysed the clinicopathological characteristics and outcomes in 92 patients with well-differentiated (WD) NEN of different origin (57 pancreatic NENs (PanNENs)), treated with molecular targeted therapy (MTT) with everolimus or sunitinib, first- (73: 19) or second-line (sequential; 12: 22) for progressive disease. Disease control rates (DCR: partial response or stable disease) at first-line were higher in all patients treated with everolimus than sunitinib (64/73 vs 12/19, P = 0.012). In PanNENs, DCR at first-line everolimus was 36/42 versus 9/15 with sunitinib (P = 0.062). Progression-free survival (PFS) at first-line everolimus was longer than sunitinib (31 months (95% CI: 23.1-38.9) vs 9 months (95% CI: 0-18.5); log-rank P < 0.0001) in the whole cohort and the subset of PanNENs (log-rank P < 0.0001). Median PFS at second-line MTT was 12 months with everolimus (95% CI: 4.1-19.9) vs 13 months with sunitinib (95% CI: 9.3-16.7; log-rank P = 0.951). Treatment with sunitinib (HR: 3.47; 95% CI: 1.5-8.3; P value: 0.005), KI67 > 20% (HR: 6.38; 95% CI: 1.3-31.3; P = 0.022) and prior chemotherapy (HR: 2.71; 95% CI: 1.2-6.3; P = 0.021) were negative predictors for PFS at first line in multivariable and also confirmed at multi-state modelling analyses. Side effect (SE) analysis indicated events of serious toxicities (Grades 3 and 4: n = 13/85 for everolimus and n = 4/41 for sunitinib). Discontinuation rate due to SEs was 20/85 for everolimus versus 4/41 for sunitinib (P = 0.065). No additive toxicity of second-line MTT was confirmed. Based on these findings, and until reliable predictors of response become available, everolimus may be preferable to sunitinib when initiating MTT in progressive NENs.
|
|
| 2. |
- Daskalakis, Kosmas, 1979-, et al.
(författare)
-
Increased autophagy/mitophagy levels in primary tumours of patients with pancreatic neuroendocrine neoplasms
- 2020
-
Ingår i: Endocrine. - : Springer. - 1355-008X .- 1559-0100. ; 68:2, s. 438-447
-
Tidskriftsartikel (refereegranskat)abstract
- Background/aims: We assessed the levels of autophagy and mitophagy, that are linked to cancer development and drug resistance, in well differentiated pancreatic neuroendocrine neoplasms (PanNENs) and correlated them with clinico-pathological parameters.Methods: Fluorescent immunostaining for the autophagy markers LC3 Beta and 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 analysed 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 20 mm; 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 with 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.Conclusions: 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.
|
|
| 3. |
- Daskalakis, Kosmas, et al.
(författare)
-
Magnetic Resonance Imaging or Endoscopic Ultrasonography for Detection and Surveillance of Pancreatic Neuroendocrine Neoplasms in Patients with Multiple Endocrine Neoplasia Type 1?
- 2019
-
Ingår i: Hormone and Metabolic Research. - : GEORG THIEME VERLAG KG. - 0018-5043 .- 1439-4286. ; 51:9, s. 580-585
-
Tidskriftsartikel (refereegranskat)abstract
- Our aim was to compare the clinical utility of Magnetic Resonance Imaging (MRI) and Endoscopic Ultrasonography (EUS) in identifying Pancreatic Neurondocrine Neoplasms (PanNENs) and monitoring size alterations in Multiple Endocrine Neoplasia type 1 (MEN1) patients. Thirty-one MEN1 patients with PanNENs and concurrent screening by EUS and abdominal MRI were included and 129 pancreatic lesions were detected in total. MRI detected fewer lesions than EUS (n=73 vs. 110, p=0.006). MRI sensitivity and specificity compared to EUS at 20 and 10 mm cut-offs of maximal lesion diameter were 96 and 88% (20 mm cut-off) and 90 and 82%(10 mm cut-off), respectively (concordance rates of 97 and 87% and Cohen's kappa=0.912 and 0.718, respectively). Lesions<1 cm were more often detected with EUS (p=0.025). Data from sequential concurrent imaging on lesion growth rate [n=7 (mean +/- SD: 2 mm/year +/- 3.4 mm vs. 1.9 mm/year +/- 3.6 mm)] over a period of at least two years as well as pathology data in connection to preoperative concurrent imaging were available in a small number of patients (n=7, p=0.933 for mean differences in maximal lesion diameter). MRI of the pancreas was more readily available and less expensive than EUS in an outpatient setting. In conclusion, MRI performs well compared to EUS for the detection and subsequent surveillance of MEN1-related panNENs larger than 10 mm and seems to be cost-effective. Both modalities could be used at initial assessment and MRI alone could be utilized thereafter in patient surveillance. EUS retains its value in surgical planning and the detection of small mostly functional PanNENs.
|
|
| 4. |
- Daskalakis, Kosmas, et al.
(författare)
-
The risk of lymph node metastases and their impact on survival in patients with appendiceal neuroendocrine neoplasms : a systematic review and meta-analysis of adult and paediatric patients
- 2020
-
Ingår i: Endocrine. - : Springer. - 1355-008X .- 1559-0100. ; 67:1, s. 20-34
-
Forskningsöversikt (refereegranskat)abstract
- Background There are no clear histopathological parameters determining the risk of lymph node (LN) metastases and appropriateness of completion prophylactic right hemicolectomy (RHC) in patients with appendiceal neuroendocrine neoplasms (ANENs). Materials and methods The PubMed, Cochrane Library, Embase, Web of Science and SCOPUS databases were searched up to November 2018. Quality/risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). Results A total of 526 articles were screened. In 11 adult and 3 paediatric studies, 602 and 77 unique patients, respectively, with ANEN and undergoing RHC, were included. The rate of LN metastases for a cutoff size >10 mm was 48.6% (vs 12.1% for lesions <10 mm) among adult patients, with an odds ratio (OR) of 4.8 (95% CI, 1.5-15.8). For 20 mm size cutoff, these figures were 61% (vs 28.2% for lesions <20 mm) with an OR of 3.2 (95% CI, 1.3-7.8). Vascular-, lymph vessel- and perineural invasions were identified as predictive factors for LN metastases in adult patients. In paediatric patients, there were no strong morphological predictors for LN metastases. The 10-year disease-specific survival (DSS) for adult patients without LN metastases was 99.2% vs 95.6% in patients with LN (OR: 0.2; 95% CI, 0.02-2.4). The complication rate of prophylactic RHC was 11.4%. Conclusions This meta-analysis demonstrates that tumour size >20 mm as well as >10 mm and/or vascular-, lymph vessel- and perineural invasions are associated with increased risk for LN metastases in adult patients with ANEN. The prognostic value of LN positivity remains to be determined in further studies with long-term follow-up.
|
|
