| 1. |
- Aktypis, Charalampos, et al.
(författare)
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Cardiovascular Toxicities Secondary to Biotherapy and Molecular Targeted Therapies in Neuroendocrine Neoplasms : A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:9
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Forskningsöversikt (refereegranskat)abstract
- A broad spectrum of novel targeted therapies with prime antitumor activity and/or ample control of hormonal symptoms together with an overall acceptable safety profile have emerged for patients with metastatic neuroendocrine neoplasms (NENs). In this systematic review and quantitative meta-analysis, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov databases were searched to assess and compare the safety profile of NEN treatments with special focus on the cardiovascular adverse effects of biotherapy and molecular targeted therapies (MTTs). Quality/risk of bias were assessed using GRADE criteria. Placebo-controlled randomized clinical trials (RCTs) in patients with metastatic NENs, including medullary thyroid cancer (MTC) were included. A total of 3695 articles and 122 clinical trials registered in clinicaltrials.gov were screened. We included sixteen relevant RCTs comprising 3408 unique patients assigned to different treatments compared with placebo. All the included studies had a low risk of bias. We identified four drug therapies for NENs with eligible placebo-controlled RCTs: somatostatin analogs (SSAs), tryptophan hydroxylase (TPH) inhibitors, mTOR inhibitors and tyrosine kinase inhibitors (TKI). Grade 3 and 4 adverse effects (AE) were more often encountered in patients treated with mTOR inhibitors and TKI (odds ratio [OR]: 2.42, 95% CI: 1.87-3.12 and OR: 3.41, 95% CI: 1.46-7.96, respectively) as compared to SSAs (OR:0.77, 95% CI: 0.47-1.27) and TPH inhibitors (OR:0.77, 95% CI: 0.35-1.69). MTOR inhibitors had the highest risk for serious cardiac AE (OR:3.28, 95% CI: 1.66-6.48) followed by TKIs (OR:1.51, 95% CI: 0.59-3.83). Serious vascular AE were more often encountered in NEN patients treated with mTOR inhibitors (OR: 1.72, 95% CI: 0.64-4.64) and TKIs (OR:1.64, 95% CI: 0.35-7.78). Finally, patients on TKIs were at higher risk for new-onset or exacerbation of pre-existing hypertension (OR:3.31, 95% CI: 1.87-5.86). In conclusion, SSAs and TPH inhibitors appear to be safer as compared to mTOR inhibitors and TKIs with regards to their overall toxicity profile, and cardiovascular toxicities in particular. Special consideration should be given to a patient-tailored approach with anticipated toxicities of targeted NEN treatments together with assessment of cardiovascular comorbidities, assisting clinicians in treatment selection and early recognition/management of cardiovascular toxicities. This approach could improve patient compliance and preserve cardiovascular health and overall quality of life.
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| 2. |
- Alevroudis, Emmanouil, et al.
(författare)
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Clinical utility of 18f-fdg pet in neuroendocrine tumors prior to peptide receptor radionuclide therapy : A Systematic Review and Meta-Analysis
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:8
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Forskningsöversikt (refereegranskat)abstract
- The role of 18F-FDG PET in patients with variable grades of neuroendocrine tumors (NETs) prior to peptide receptor radionuclide therapy (PRRT) has not been adequately elucidated. We aimed to evaluate the impact of 18F-FDG PET status on disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in neuroendocrine tumor (NET) patients receiving PRRT. We searched the MEDLINE, Embase, Cochrane Library, and Web of Science databases up to July 2020 and used the Newcastle-Ottawa scale (NOS) criteria to assess quality/risk of bias. A total of 5091 articles were screened. In 12 studies, 1492 unique patients with NETs of different origins were included. The DCR for patients with negative 18F-FDG PET status prior to PRRT initiation was 91.9%, compared to 74.2% in patients with positive 18F-FDG PET status (random effects odds ratio (OR): 4.85; 95% CI: 2.27–10.36). Adjusted analysis of pooled hazard ratios (HRs) confirmed longer PFS and OS in NET patients receiving PRRT with negative 18F-FDG PET (random effects HR:2.45; 95%CIs: 1.48–4.04 and HR:2.25; 95% CIs:1.55–3.28, respectively). In conclusion, 18F-FDG PET imaging prior to PRRT administration appears to be a useful tool in NET patients to predict tumor response and survival outcomes and a negative FDG uptake of the tumor is associated with prolonged PFS and OS.
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| 3. |
- Alexandraki, Krystallenia I., et al.
(författare)
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Changing biological behaviour of NETs during the evolution of the disease : progress on progression
- 2021
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Ingår i: Endocrine-Related Cancer. - : BioScientifica Ltd.. - 1351-0088 .- 1479-6821. ; 28:5, s. R121-R140
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Forskningsöversikt (refereegranskat)abstract
- Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancreatic NENs, which become more aggressive during the course of the disease. This is reflected by an increase in the Ki-67 labelling index, as a marker of proliferation, which may lead to an occasion of increase in grading, but generally does not appear to be correlated with histologically confirmed dedifferentiation. A systematic review of the literature was performed in PubMed, Cochrane Library, and Embase until May 2020 to identify cases that have behaved in such a manner. We screened 244 articles: only seven studies included cases in their cohort, or in a subset of the cohort studied, with a proven increase in the Ki-67 during follow-up through additional biopsy. In addition to these studies, we have also tried to identify possible pathophysiological mechanisms implicated in advanced NENs, although currently no studies appear to have addressed the mechanisms implicated in the switch to a more aggressive biological phenotype over the course of the disease. Such progression of the disease course may demand a change in the management. Summarising the overall evidence, we suggest that future studies should concentrate on changes in the molecular pathways during disease progression with sequential biopsies in order to shed light on the mechanisms that render a neoplasm more aggressive than its initial phenotype or genotype.
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| 4. |
- Alexandraki, Krystallenia I., et al.
(författare)
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Endocrinological Toxicity Secondary to Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs)
- 2020
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Ingår i: Trends in endocrinology and metabolism. - : Elsevier. - 1043-2760 .- 1879-3061. ; 31:3, s. 239-255
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Tidskriftsartikel (refereegranskat)abstract
- Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasingly recognized, characterized by prolonged survival even with metastatic disease. Their medical treatment is complex involving various specialties, necessitating awareness of treatment-related adverse effects (AEs). As GEP-NENs express somatostatin receptors (SSTRs), long-acting somatostatin analogs (SSAs) that are used for secretory syndrome and tumor control may lead to altered glucose metabolism. Everolimus and sunitinib are molecular targeted agents that affect glucose and lipid metabolism and may induce hypothyroidism or hypocalcemia, respectively. Chemotherapeutic drugs can affect the reproductive system and water homeostasis, whereas immunotherapeutic agents can cause hypophysitis and thyroiditis or other immune-mediated disorders. Treatment with radiopeptides may temporarily lead to radiation-induced hormone disturbances. As drugs targeting GEP-NENs are increasingly introduced, recognition and management of endocrine-related AEs may improve compliance and the quality of life of these patients.
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| 5. |
- Alexandraki, Krystallenia I., et al.
(författare)
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The effect of prophylactic surgery in survival and HRQoL in appendiceal NEN
- 2020
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Ingår i: Endocrine. - : Springer. - 1355-008X .- 1559-0100. ; 70:1, s. 178-186
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: Long-term outcomes are understudied in patients with well-differentiated appendiceal neuroendocrine neoplasms (WD-ANENs). We aimed to evaluate the validity of currently applied criteria for completion prophylactic right hemicolectomy (pRHC) and determine its association with patient outcomes, including health-related quality of life (HRQoL).METHODS: Eligible patients from five European referral centers were divided between those who underwent appendectomy alone and those who underwent completion pRHC. HRQoL EORTC-QLC-C30 questionnaires and cross-sectional imaging data were prospectively collected. Age- and sex-matched healthy controls were recruited for HRQoL analysis' validation.RESULTS: We included 166 patients (119 women [71.2%]: mean age at baseline: 31 ± 16 years). Mean follow-up was 50.9 ± 54 months. Most patients (152 [92%]) had tumors ≤20 mm in size. Fifty-eight patients (34.9%) underwent pRHC that in final analysis was regarded as an overtreatment in 38/58 (65.5%). In multivariable analysis, tumor size >20 mm was the only independent predictor for lymph node (LN) involvement (p = 0.002). No mortality was reported, whereas 2-, 5- and 10-year recurrence-free survival in patients subjected to postoperative cross-sectional imaging (n = 136) was 98.5%, 97.8%, and 97.8%, respectively. Global HRQoL was not significantly impaired in patients with WD-ANEN compared with age- and sex-matched healthy individuals (median scores 0.83[0.08-1] vs 0.83[0.4-1], respectively; p = 0.929). Among patients with WD-ANEN impaired social functioning (p = 0.016), diarrhea (p = 0.003) and financial difficulties (0.024) were more frequently reported in the pRHC group.CONCLUSIONS: WD-ANEN is a low-malignant neoplasm with unconfirmed associated mortality, low recurrence rate, and overall preserved HRQoL. pRHC comes at a price of excessive surgery, functional HRQoL issues, and diarrhea. The value per se of a prophylactic surgical approach to patients with WD-ANENs <20 mm is challenged.
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| 6. |
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| 7. |
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| 8. |
- Daskalakis, Kosmas, 1979-, et al.
(författare)
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Association of lymph node metastases, grade and extent of mesenteric lymph node dissection in locoregional small intestinal neuroendocrine tumors with recurrence-free survival
- 2022
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Ingår i: Journal of neuroendocrinology. - : Wiley-Blackwell Publishing Inc.. - 0953-8194 .- 1365-2826. ; 34:11
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to assess the prognostic impact of tumor- and patient-related parameters in patients with stage I-III small intestinal neuroendocrine tumors (SI-NETs), who underwent locoregional resective surgery (LRS) with curative intent. We included 229 patients with stage I-III SI-NETs diagnosed from June 15, 1993, through March 8, 2021, identified using the SI-NET databases from five European referral centers. Mean ± SD age at baseline was 62.5 ± 13.6 years; 111/229 patients were women (49.3%). All tumors were well-differentiated; 160 were grade 1 (G1) tumors, 51 were G2, two were G3 and 18 tumors were of unspecified grade (median Ki-67: 2%, range 1%-50%). One-hundred and sixty-three patients (71.2%) had lymph node (LN) involvement. The median number of retrieved lymph nodes was 10 (0-63), whereas the median number of positive LNs was 2 (0-43). After a mean ± SD follow-up of 54.1 ± 64.1 months, 60 patients experienced disease recurrence at a median (range) of 36.2 (2.5-285.1) months. The 5- and 10-year recurrence-free survival (RFS) rates were 66.6% and 49.3% respectively. In univariable analysis, there was no difference in RFS and overall survival (OS) between LN-positive and LN-negative patients (log-rank, p = .380 and .198, respectively). However, in stage IIIb patients who underwent mesenteric lymph node dissection (MLND) with a minimum of five retrieved LN (n = 125), five or more LN metastases were associated with shorter RFS (median RFS [95% CI] = 107.4 [0-229.6] vs. 73.7 [35.3-112.1] months; log-rank, p = .048). In addition, patients with G2 tumors exhibited shorter RFS compared to patients with G1 tumors (median RFS [95% confidence interval (CI)] = 46.9 [36.4-57.3] vs. 120.7 [82.7-158.8] months; log-rank, p = .001). In multivariable Cox-regression RFS analysis in stage IIIb patients, the Ki-67 proliferation index (hazard ratio = 1.08, 95% CI = 1.035-1.131; p < .0001) and the number of LN metastases (hazard ratio = 1.06, 95% CI = 1.001-1.125; p = .047) were independent prognostic factors for RFS. In conclusion, LRS with a meticulous MLND and a minimum number of five harvested LNs appears to be critical in the surgical management of SI-NET patients with locoregional disease. In patients who underwent LRS and MLND, the Ki-67 proliferation index and the LN metastases count were independent predictors of RFS.
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| 9. |
- Daskalakis, Kosmas, 1979-
(författare)
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Functioning and nonfunctioning pNENs
- 2021
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Ingår i: Current Opinion in Endocrine and Metabolic Research. - : Elsevier. - 2451-9650. ; 18, s. 284-290
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Forskningsöversikt (refereegranskat)abstract
- Pancreatic neuroendocrine neoplasms (pNENs) are relatively rare tumors that have been increasingly recognized in recent years. They are highly heterogeneous and exhibit a diverse clinical course, along with a variable metastatic propensity related to their molecular biology profile, grade, primary tumor size, and functional status. The pNENs are divided into functioning and nonfunctioning tumor forms. Their pathological classification is based mainly on their histology and proliferative activity. Clinical challenges in their management include - but are not limited to - the inability to establish an early diagnosis in nonfunctioning pNENs and to accurately localize the source of hormonal secretion in functioning ones. Additionally, the role of active surveillance versus surgery for asymptomatic small nonfunctioning tumors is controversial, same as is the impact of palliative surgery in pNENs with distant metastases. Finally, in terms of an individualized treatment approach, there is a relative paucity of evidence on predictable, effective treatment strategies with respect to tumors and patient-related parameters.
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| 10. |
- 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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| 11. |
- Daskalakis, Kosmas, 1979-, et al.
(författare)
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Increased autophagy/mitophagy levels in primary tumours of patients with pancreatic neuroendocrine neoplasms
- 2020
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Ingår i: Endocrine. - : Springer. - 1355-008X .- 1559-0100. ; 68:2, s. 438-447
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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.
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| 12. |
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| 13. |
- Daskalakis, Kosmas, 1979-, et al.
(författare)
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Modified Histopathological Grading Optimizes Prediction of Survival Outcomes in Small Intestinal Neuroendocrine Tumours
- 2024
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197.
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: One of the major prognostic indices in neuroendocrine tumours (NETs) is Ki67 proliferation index.OBJECTIVE: To identify optimal grading Ki-67 cut-offs to delineate differences in prognosis of patients with small intestinal NETs (SI-NETs).DESIGN, SETTING, PARTICIPANTS: Multicentre retrospective cohort analysis of 551 SI-NET patients diagnosed from 1993 through 2021 at five European referral centres with a mean(±SD) follow-up time of 51.5(±52.9) months.MAIN OUTCOME MEASURES: Overall- and event-free survival (OS and EFS) rates.RESULTS: Median age at baseline was 62.3(range:17-90) years; 252(45.7%) patients were female. All SI-NETs were well-differentiated with 326 being grade 1(G1; 59.2%), 169G2(30.7%), and only 8G3(1.5), while 48 tumours were of unspecified grade (8.7%). The median Ki67 was 2%(range:1-70%). Two-hundred forty-seven patients (44.8%) had distant metastases at baseline (stage IV), 217 locoregional disease (41.1%; stage III), whereas 29(7.1%) and 25(4.5%) presented at stages II and I, respectively. The median OS was 214.7(95%CI:152.7-276.6) months and the median EFS was 79.8(95%CI:68.2-91.5) months, respectively. In multivariable Cox-regression OS analysis, the proposed modified histopathological Ki67 grading system (K67:5-10% group: HR=2.2, 95%CI:1.15-4.31; p=0.018 and K67≥10% group: HR=5.11, 95%CI:2.87-9.09; p<0.001), age (HR=1.07, 95%CI:1.04-1.09; p<0.001), Charlson Comorbidity Index (HR=1.08, 95%CI:1-1.16; p=0.028) and TNM stage (HR=1.79, 95%CI:1.05-3.06; p=0.034) were independent predictors for death. Pertinent EFS analysis, confirmed the proposed modified histopathological Ki67 grading system (K67≥10% group: HR=4.01, 95%CI:2.6-6.37; p<0.001) and age (HR=1.04, 95%CI:1.02-1.05; p<0.001) as independent predictors for recurrence, progression and/or death.CONCLUSIONS: Ki-67 proliferation index was a strong and independent predictor of OS and EFS. A modified histopathological grading system applying Ki-67 cut-offs of 5 and 10% could be superior to predict differences in SI-NET patient survival outcomes.
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| 14. |
- Daskalakis, Kosmas, 1979-, et al.
(författare)
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MODIFIED HISTOPATHOLOGICAL GRADING OPTIMIZES PREDICTION OF SURVIVAL OUTCOMES IN SMALL INTESTINAL NEUROENDOCRINE TUMOURS
- 2024
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Ingår i: British Journal of Surgery. - : Oxford University Press. - 0007-1323 .- 1365-2168. ; 111:Suppl. 4
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: We aimed to identify optimal grading Ki-67 cut-offs to delineate differences in prognosis of patients with small intestinal neuroendocrine tumours (SI-NETs) in terms of overall- and event-free survival rates.Methods: We included 551 patients with SI-NETs diagnosed from June 15th, 1993, through March 8th, 2021, identified using the SI-NET databases from five European referral centers.Results: Median age at baseline was 62.3(17-90) years; 252 patients were women (45.7%). All tumours were well-differentiated; 326 were G1 tumours (59.2%), 169 G2(30.7%), only 8 G3(1.5%), while 48 tumourswere of unspecified grade (8.7%). The median Ki67 was 2%(1-70%). 247 patients(44.8%) had distant metastases at baseline (stage IV), 217locoregional disease (41.1%; stage III), whereas 29(7.1%) and 25(4.5%) presented at stages II and I, respectively. Within a mean(SD) follow-up of 51.5(52.9) months, 94 patients(17.1%) died, whereas overall 188 experienced disease recurrence, progression and/or death(34.1%). The median OS was 214.7(95%CI: 152.7-276.6) months and the median EFS was 79.8(95%CI: 68.2-91.5) months, respectively. In multivariable Cox-regression OS analysis, age (HR=1.07, 95%CI: 1.04-1.09; p<0.001), Charlson Comorbidity Index(HR=1.1, 95%CI: 1.03-1.17; p=0.006) and the proposed modified histopathological Ki67 grading system(K67:5-10% group: HR=2.4, 95%CI: 1.3-4.5; p=0.007 and K67≥10% group: HR=5.1, 95%CI: 2.9-9.2; p<0.001) were independent predictors for death. Pertinent EFS analysis, confirmed age(HR=1.04, 95%CI: 1.02-1.05;p<0.001) and the proposed modified histopathological Ki67 grading system(K67≥10% group: HR=4; 95%CI:2.5-6.2;p<0.001) as independent predictors for recurrence, progression and/or death.Conclusions: Ki-67 proliferation index is an independent predictor of EFS and OS. A modified site-specific histopathological grading system applying Ki-67 cut-offs of 5% and 10% seems more optimal to predict differences in SI-NET patient prognosis
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| 15. |
- 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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| 16. |
- Kaçmaz, Enes, et al.
(författare)
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International survey on opinions and use of minimally invasive surgery in small bowel neuroendocrine neoplasms
- 2022
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Ingår i: European Journal of Surgical Oncology. - : Elsevier. - 0748-7983 .- 1532-2157. ; 48:6, s. 1251-1257
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Although minimally invasive surgery is becoming the standard technique in gastrointestinal surgery, implementation for small bowel neuroendocrine neoplasms (SB-NEN) is lagging behind. The aim of this international survey was to gain insights into attitudes towards minimally invasive surgery for resection of SB-NEN and current practices.METHODS: An anonymous survey was sent to surgeons between February and May 2021 via (neuro)endocrine and colorectal societies worldwide. The survey consisted of questions regarding experience of the surgeon with minimally invasive SB-NEN resection and training.RESULTS: A total of 58 responses from five societies across 20 countries were included. Forty-one (71%) respondents worked at academic centers. Thirty-seven (64%) practiced colorectal surgery, 24 (41%) endocrine surgery and 45 (78%) had experience in advanced minimally invasive surgery. An open, laparoscopic or robotic approach was preferred by 23 (42%), 24 (44%), and 8 (15%) respondents, respectively. Reasons to opt for a minimally invasive approach were mainly related to peri-operative benefits, while an open approach was preferred for optimal mesenteric lymphadenectomy and tactile feedback. Additional training in minimally invasive SB-NEN resection was welcomed by 29 (52%) respondents. Forty-three (74%) respondents were interested in collaborating in future studies, with a cumulative median (IQR) annual case load of 172 (86-258).CONCLUSIONS: Among respondents, 69% applies minimally invasive surgery for resection of SB-NEN. Arguments for specific operative approaches differ, and insufficient training in advanced laparoscopic techniques seems to be a barrier. Future collaborative studies can provide better insight in selection criteria and optimal technique.
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| 17. |
- Kaltsas, G., et al.
(författare)
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THE EFFECT OF PROPHYLACTIC RIGHT HEMICOLECTOMY ON SURVIVAL AND HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH WELL-DIFFERENTIATED APPENDICEAL NEUROENDOCRINE NEOPLASMS
- 2020
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Ingår i: British Journal of Surgery. - : John Wiley & Sons. - 0007-1323 .- 1365-2168. ; 107:Suppl. 2, s. 14-14
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Long-term outcomes, including health-related quality of life (HRQoL) issues are understudied in patients with well-differentiated ppendiceal neuroendocrine neoplasms (WD-ANENs). We aimed to evaluate the validity of currently applied criteria for completion prophylactic right hemicolectomy (pRHC) and determine its association with patient outcomes.Methods: This cohort study included patients with WD-ANENs from five European Centers of Excellence for neuroendocrine tumors. Eligible patients were divided between those who underwent appendectomy alone and those who underwent pRHC. HRQoL EORTCqlqc30 questionnaires and cross-sectional imaging data were prospectively collected.Results: The 166 patients included 119 women (71.2%). Mean age was 31 ± 16 years. Mean follow-up was 51 ± 54 months. Most patients (152[92%]) had tumors≤20 mm. Fifty-eight patients (34.9%) underwent pRHC that was unnecessary in 65.5%(38/58); and in 79.1%(34/43) of tumors≤20 mm. In multivariable analysis, tumor size>20 mm was the only independent predictor for lymph node (LN) positivity(p = 0.021). No disease-specific mortality was reported. Three patients developed recurrence (n = 2inthepRHC group vs. n = 1 in the appendectomy group;p = 0.263). Although global HRQol was not significantly depreciated in patients undergoing pRHC compared to appendectomy alone (median scores 0.79[0.25-1] vs. 0.83[0.08-1], respectively; p = 0.738), impaired social functioning (p = 0.016), diarrhea (p = 0.003) and financial difficulties (0.024) were more frequently reported in the pRHC group. Furthermore, physical-(p = 0.066) and role functioning (p = 0.055), as well as constipation issues(p = 0.072) emerged in the pRHC group with marginal significance.Conclusion: pRHC in WD-ANENs comes at a high rate of unnecessary procedures, functional HRQoL issues and diarrhoea. LN positivity at pRHC may lack prognostic significance, as no disease-specific mortality and scarce recurrence was evident in this series. The validity of contemporary criteria and the value per se of pRHC to patients with WD-ANEN is challenged.
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| 18. |
- Karapanagioti, A., et al.
(författare)
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Aberrant expression pattern of circadian clock genes in type 1 gastric neuroendocrine neoplasms compared to ECL-cell hyperplasia
- 2021
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Ingår i: Journal of neuroendocrinology (Print). - : European Neuroendocrine Association. - 0953-8194 .- 1365-2826. ; 33:S1, s. 37-37
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: There is a continuity of changes from ECL-cell hyperplasia to type 1 gastric neuroendocrine neoplasms (GNEN1) development with important clinical implications. Aim(s): Although the effect of the circadian clock system on neuroendocrine tumorigenesis has been addressed, the role of the peripheral clock system in the transition from ECL-cell hyperplasia to GNEN1 remains to be explored.Materials and methods: Six GNEN1 patients and 10 patients with ECL-cell hyperplasia were included. Blood samples were collected at 8 am, 3pm and 10pm for peripheral blood mononuclear ells (PBMCs) isolation. The mRNA expression of clock-related genes (CLOCK, BMAL1, CRY-1, PER2, ROR-α and REV-ERBβ) were evaluated by real-time quantitative PCR from PBMCs. Results: In GNEN1 patients, BMAL genes where lower expressed at night than early in the morning (p=0.02), whereas patients with ECL-cell hyperplasia expressed lower levels of PER2 and REV-ERBβ (p=0.03 and p=0.05,respectively). In addition, GNEN1 patients expressed lower levels of CLOCK, PER2 and REV-ERBβ in the early evening than in the morning (p=0.04; p=0.03; p=0.05, respectively). When comparing the two groups (GNEN1 vs. ECL-cell hyperplasia) at the three different time points, a marginal increase in CLOCK, PER2 and REV-ERBβ expression early in the morning (p=0.06, 0.02 and 0.07, respectively) along with a marginal increase in REV-ERBβ and BMAL expression in the early evening (p=0.09 and p=0.08, respectively) and a marginal increase in BMAL at night (p=0.09) in GNEN1 patients was observed.Conclusion: Our findings point towards an upregulated expression of clock-related genes in patients with GNEN1 as compared to ECL-cell hyperplasia, suggesting a possible involvement in GNEN1 tumorigenesis that needs to be confirmed in a larger patients group.
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| 19. |
- Koumarianou, Anna, et al.
(författare)
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Efficacy, safety and unmet needs of evolving medical treatments for carcinoid syndrome.
- 2022
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Ingår i: Journal of neuroendocrinology. - : Wiley-Blackwell Publishing Inc.. - 0953-8194 .- 1365-2826. ; 34:7
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Forskningsöversikt (refereegranskat)abstract
- This review reports on the currently available medical treatment options for the control of symptoms due to carcinoid syndrome in patients with neuroendocrine tumors. The efficacy and adverse events (AEs) of approved drugs such as somatostatin analogues (SSA), telotristat ethyl (TE) and interferon-alpha, are reviewed. Somatostatin analogues remain the standard treatment of carcinoid syndrome based on the high expression of somatostatin receptors and the resulting inhibition of secretion of bioactive compounds; their use is associated with relatively mild AEs, involving mainly the gastrointestinal system, and being usually transient. Although dose escalation of SSA remains an unapproved option, it is clinically implemented to alleviate symptoms in refractory carcinoid syndrome and supported by the most recent guidelines. The side effects associated with the increased dose are in general mild and consistent with standard dose of SSA. Telotristat ethyl, an oral inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, represents a rather novel innovative treatment option in patients with carcinoid syndrome suffering from diarrhea and complements the standard therapy of SSA. Given the low toxicity profile, TE may be considered an early add-on treatment to SSA in patients with uncontrolled carcinoid syndrome. However, further prolonged follow-up of patients treated with TE may be needed to exclude potential AEs, such as liver toxicity or depressed mood, in patients with long-term treatment. Interferon alpha is a cytokine with direct inhibitory effect on hormone secretion and tumor cell proliferation and an approved therapy in carcinoid syndrome but is associated with significant AEs in the majority of the patients requiring frequently dose reduction. The finding of a more favorable tolerability of pegylated interferon needs to be confirmed in a prospective study.
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| 20. |
- Koumarianou, Anna, et al.
(författare)
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Pathogenesis and Clinical Management of Mesenteric Fibrosis in Small Intestinal Neuroendocine Neoplasms : A Systematic Review
- 2020
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Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 9:6
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Forskningsöversikt (refereegranskat)abstract
- Mesenteric fibrosis (MF) constitutes an underrecognized sequela in patients with small intestinal neuroendocrine neoplasms (SI-NENs), often complicating the disease clinical course. The aim of the present systematic review, carried out by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, is to provide an update in evolving aspects of MF pathogenesis and its clinical management in SI-NENs. Complex and dynamic interactions are present in the microenvironment of tumor deposits in the mesentery. Serotonin, as well as the signaling pathways of certain growth factors play a pivotal, yet not fully elucidated role in the pathogenesis of MF. Clinically, MF often results in significant morbidity by causing either acute complications, such as intestinal obstruction and/or acute ischemia or more chronic conditions involving abdominal pain, venous stasis, malabsorption and malnutrition. Surgical resection in patients with locoregional disease only or symptomatic distant stage disease, as well as palliative minimally invasive interventions in advanced inoperable cases seem clinically meaningful, whereas currently available systemic and/or targeted treatments do not unequivocally affect the development of MF in SI-NENs. Increased awareness and improved understanding of the molecular pathogenesis of MF in SI-NENs may provide better diagnostic and predictive tools for its timely recognition and intervention and also facilitates the development of agents targeting MF.
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| 21. |
- Kravvariti, Evrydiki, et al.
(författare)
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Meta-analysis of placebo-arm dropouts in osteoporosis randomized-controlled trials and implications for nocebo-associated discontinuation of anti-osteoporotic drugs in clinical practice
- 2023
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Ingår i: Osteoporosis International. - : Springer. - 0937-941X .- 1433-2965. ; 34:3, s. 585-598
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Tidskriftsartikel (refereegranskat)abstract
- Summary: Dropout from placebo arms in randomized-controlled trials is a surrogate for nocebo responses, resulting from patients' negative expectations to treatment. Among 16,460 placebo-treated patients in oral anti-osteoporotic drug trials, nocebo dropouts were 8% on average, being higher in older patients. This implies that nocebo may contribute to the osteoporosis treatment gap in clinical practice.Purpose: Osteoporosis is a common disease requiring long-term treatment. Despite the availability of effective anti-osteoporotic drugs, adherence to treatment is low. Nocebo, a behavior mostly related to the negative expectations to a certain treatment, decreases adherence and negatively affects treatment outcomes and health-related care costs in chronic diseases. Since in double-blind placebo-controlled randomized trials any unfavorable outcome leading to discontinuation in placebo arms is considered as nocebo, we aimed to investigate the size of nocebo response in patients participating in osteoporosis trials.Methods: We searched MEDLINE, EMBASE, SCOPUS, and Cochrane databases for dropouts due to reported adverse events in the placebo arms (nocebo dropouts) in all double-blind trials investigating anti-osteoporotic drugs published between January 1993 and March 2022. Only data on bisphosphonates and selective estrogen receptor modulators (SERMs) were analyzed (Prospero registration number CRD42020212843).Results: Data from 44 trials were extracted. In 16,460 placebo-treated patients, the pooled nocebo-dropout was 8% both for bisphosphonates (average: 0.08; range 0.01-0.27; 95%CI 0.06-0.10) and SERMs (average: 0.08; range 0.03-0.15; 95%CI 0.05-0.13). Nocebo-dropouts were higher in bisphosphonate trials enrolling individuals >= 65 years (11%) (n = 18) compared to trials enrolling younger individuals (6%) (n = 18) (average: 0.11; 95%CI 0.08-0.13 vs. average: 0.06; 95%CI 0.05-0.08, respectively, p = 0.001). Participants' sex, dosing-intervals, publication year, or severity of osteoporosis had no impact on the nocebo-dropouts.Conclusion: Almost 1 in 10 osteoporosis patients receiving placebo in trials of bisphosphonates and SERMs experiences AEs leading to dropout, implying that nocebo contributes to treatment-discontinuation in clinical practice. Efforts to identify and minimize nocebo, especially in older patients, are warranted.
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| 22. |
- Lind, Patrik, 1985-, et al.
(författare)
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Impact of fine-needle aspiration cytology in thyroidectomy extent and associated surgical morbidity in thyroid cancer
- 2024
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Ingår i: Langenbeck's archives of surgery (Print). - : Springer. - 1435-2443 .- 1435-2451. ; 409:1
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To assess the impact of fine-needle aspiration cytology (FNAC) in the extent of surgery in patients with thyroid cancer (TC) and the associated surgical morbidity in primary and completion setting.METHODS: A Swedish nationwide cohort of patients having surgery for TC (n = 2519) from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal surgery between 2004 and 2013 was obtained. Data was validated through scrutinizing FNAC and histology reports.RESULTS: Among the 2519 cases operated for TC, the diagnosis was substantiated and validated through the histology report in 2332 cases (92.6%). Among these, 1679 patients (72%) were female, and the median age at TC diagnosis was 52.3 years (range 18-94.6). Less than total thyroidectomy (LTT) was undertaken in 944 whereas total thyroidectomy (TT) in 1388 cases. The intermediate FNAC categories of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/ FLUS), as well as suspicion for follicular neoplasm (SFN) lesions were more often encountered in LTT (n = 314, 33.3%) than TT (n = 63, 4.6%), whereas FNACs suspicion for malignancy and/or malignancy were overrepresented in TT (n = 963, 69.4%). Completion thyroidectomies were undertaken in 553 patients out of 944 that initially had LTT. In 201 cases with cancer lesions > 1 cm, other than FTC (Follicular TC)/ HTC (Hürthle cell TC) subjected to primary LTT, inadequate procedures were undertaken in 81 due to absent, Bethesda I or II FNAC categories, preoperatively. Complications at completion of surgery in this particular setting were 0.5% for RLN palsy (n = 1) and 1% (n = 2) for hypoparathyroidism 6 months postoperatively. The overall postoperative complication rate was higher in primary TT vs. LTT for RLN palsy (4.8% [n = 67] vs. 2.4% [n = 23]; p = 0.003) and permanent hypoparathyroidism (6.8% [n = 95] vs. 0.8% [n = 8]; p < 0.0001).CONCLUSIONS: FNAC results appear to affect surgical planning in TC as intermediate FNAC categories lead more often to LTT. Overall, inadequate procedures necessitating completion surgery are encountered in up to 15% of TC patients subjected to LTT due to absent, inconclusive, or misleading FNAC, preoperatively. However, completion of thyroidectomy in this setting did not yield significant surgical morbidity. Primary LTT is a safer primary approach compared to TT in respect of RLN palsy and permanent hypoparathyroidism complication rates; therefore, primary TT should probably be reserved for lesions > 1 cm or even larger with suspicion for malignancy or malignant FNAC.
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| 23. |
- Tsoli, Marina, et al.
(författare)
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A Critical Appraisal of Contemporary and Novel Biomarkers in Pheochromocytomas and Adrenocortical Tumors
- 2021
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Ingår i: Biology. - : MDPI. - 2079-7737. ; 10:7
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Forskningsöversikt (refereegranskat)abstract
- Pheochromocytomas/Paragangliomas (PPGLs) and adrenocortical tumors are rare neoplasms with significant heterogeneity in their biologic and clinical behavior. Current diagnostic and predictive biomarkers include hormone secretion, as well as histopathological and genetic features. PPGL diagnosis is based on biochemical measurement of catecholamines/metanephrines, while histopathological scoring systems have been proposed to predict the risk of malignancy. Adrenocortical tumors are mostly benign, but some can be malignant. Currently, the stage of disease at diagnosis and tumor grade, appear to be the most powerful prognostic factors. However, recent genomic and proteomic studies have identified new genetic and circulating biomarkers, including genes, immunohistochemical markers and micro-RNAs that display high specificity and sensitivity as diagnostic or prognostic tools. In addition, new molecular classifications have been proposed that divide adrenal tumors in distinct subgroups with different clinical outcomes.Simple SummaryPheochromocytomas/paragangliomas (PPGLs) and adrenocortical tumors are neoplasms that originate from different regions of the adrenal gland and display significant heterogeneity with respect to their biological and clinical behavior. They may be sporadic or develop in the context of hereditary syndromes. Adrenocortical tumors are mostly benign but less than 2% are carcinomas associated with a poor outcome when diagnosed in advanced disease. The majority of PPGLS are benign, but a subset may develop metastatic disease. In particular, for PPGLs, it is mandatory to identify biomarkers of high sensitivity and specificity that lead to accurate diagnosis and predict patients with a malignant potential that would benefit from aggressive surveillance and administration of early treatment. Current biomarkers include mostly histopathological and genetic parameters but none of them can be considered independent predictive factors. Recent genomic studies have implemented new molecular biomarkers of high accuracy for the diagnosis and management of PPGLs and adrenocortical tumors. In this review, we summarize the current and novel biomarkers that may be considered valuable tools for diagnosis and prediction of malignancy in patients with PPGLs and adrenocortical tumors.
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| 24. |
- Tsoli, Marina, et al.
(författare)
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Anti-Tumor Activity and Safety of Multikinase Inhibitors in Advanced and/or Metastatic Thyroid Cancer : A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials
- 2020
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 52:1, s. 25-31
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Forskningsöversikt (refereegranskat)abstract
- Many trials have demonstrated prime antitumor activity of novel, small molecule multikinase inhibitors (MKIs) in advanced and/or metastatic thyroid cancer (TC). In this work, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, and clinicaltrials.gov databases were searched. Quality/risk of bias were assessed using GRADE criteria. Randomized clinical trials (RCTs) comparing two or more systemic therapies in patients with advanced and/or metastatic thyroid cancer were assessed. A total of 1347 articles and 548 clinical trials in clinicaltrials.gov were screened. We included seven relevant RCTs comprising 1934 unique patients assigned to different MKIs. Two separate network meta-analyses included four RCTs in radioiodine refractory well-differentiated thyroid cancer (RR-WDTC) and three RCTs in medullary thyroid cancer (MTC), respectively; all with a low risk of bias. We identified three therapies for RR-WDTC: sorafenib [disease control rate (DCR) odds ratio (OR): 0.11 (95% CI: 0.03–0.40); progression-free survival (PFS) hazard ratio (HR): 1.99 (95% CI: 1.62–2.46)], vandetanib [DCR_OR:0.26 (95% CI: 0.06–1.24); PFS_HR: 0.99 (95% CI: 0.82–1.20)] and lenvatinib [DCR_OR: 0.26 (95% CI: 0.05–1.33); PFS_HR: 0.99 (95% CI: 0.81–1.22)]; and the following therapies for MTC: vandetanib 300 mg [objective response rate (ORR)_OR: 3.31 (95% CI: 0.68–16.22); vandetanib 150 mg ORR_OR: 0.60 (95% CI: 0.16–2.33)]; and cabozantinib [ORR_OR: 85.32 (95% CI: 5.22–1395.15)]. Serious side effect (SE) analysis per organ/system demonstrated a varying MKI SE profile across both RR-WDTC and MTC diagnoses, more commonly involving metabolic/nutritional disorders [OR: 2.07 [95% CI: 0.82–5.18)] and gastrointestinal SE [OR: 1.63 (95% CI: 1.0–2.66)]. This network meta-analysis on advanced and/or metastatic TC points towards a higher efficacy of lenvatinib in RR-WDTC. The included MKIs exhibit a varying SE profile across different organs/systems favoring a patient-tailored approach with the anticipated toxicities guiding clinicians’ decisions.
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| 25. |
- Tsoli, Marina, et al.
(författare)
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Association of a Palliative Surgical Approach to Stage IV Pancreatic Neuroendocrine Neoplasms with Survival : A Systematic Review and Meta-Analysis
- 2020
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 12:8
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Forskningsöversikt (refereegranskat)abstract
- The role of primary tumor resection in patients with pancreatic neuroendocrine neoplasms (PanNENs) and unresectable distant metastases remains controversial. We aimed to evaluate the effect of palliative primary tumor resection (PPTR) on overall survival (OS) in this setting. We searched the MEDLINE, Embase, Cochrane Library, Web of Science and SCOPUS databases up to January 2020 and used the Newcastle-Ottawa scale (NOS) criteria to assess quality/risk of bias. A total of 5661 articles were screened. In 10 studies, 5551 unique patients with stage IV PanNEN and unresectable metastases were included. The five-year OS for PanNEN patients undergoing PPTR in stage IV was 56.6% vs. 23.9% in the non-surgically treated patients (random effects relative risk (RR): 1.70; 95% CI: 1.53-1.89). Adjusted analysis of pooled hazard ratios (HR) confirmed longer OS in PanNEN patients undergoing PPTR (random effects HR: 2.67; 95% CI: 2.24-3.18). Cumulative OS analysis confirmed an attenuated survival benefit over time. The complication rate of PPTR was as high as 27%. In conclusion, PPTR may exert a survival benefit in stage IV PanNEN. However, the included studies were subject to selection bias, and special consideration should be given to PPTR anchored to a multimodal treatment strategy. Further longitudinal studies are warranted, with long-term follow-up addressing the survival outcomes associated with surgery in stage IV disease.
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