| 1. |
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| 2. |
- 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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| 3. |
- Ambrosini, Valentina, et al.
(författare)
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Use and perceived utility of [18 F]FDG PET/CT in neuroendocrine neoplasms : A consensus report from the European Neuroendocrine Tumor Society (ENETS) Advisory Board Meeting 2022.
- 2024
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Ingår i: Journal of neuroendocrinology. - 0953-8194 .- 1365-2826. ; 36:1, s. e13359-
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Tidskriftsartikel (refereegranskat)abstract
- Somatostatin receptor (SST) PET/CT is the gold standard for well-differentiated neuroendocrine tumours (NET) imaging. Higher grades of neuroendocrine neoplasms (NEN) show preferential [18F]FDG (FDG) uptake, and even low-grade NET may de-differentiate over time. FDG PET/CT's prognostic role is widely accepted; however, its impact on clinical decision-making remains controversial and its use varies widely. A questionnaire-based survey on FDG PET/CT use and perceived decision-making utility in NEN was submitted to the ENETS Advisory Board Meeting attendees (November 2022, response rate = 70%). In 3/15 statements, agreement was higher than 75%: (i) FDG was considered useful in NET, irrespective of grade, in case of mis-matched lesions (detectable on diagnostic CT but negative/faintly positive on SST PET/CT), especially if PRRT is contemplated (80%); (ii) in NET G3 if curative surgery is considered (82%); and (iii) in NEC prior to surgery with curative intent (98%). FDG use in NET G3, even in the presence of matched lesions, as a baseline for response assessment was favoured by 74%. Four statements obtained more than 60% consensus: (i) FDG use in NET G3 if locoregional therapy is considered (65%); (ii) in neuroendocrine carcinoma before initiating active therapy as a baseline for response assessment (61%); (iii) biopsy to re-assess tumour grade prior to a change in therapeutic management (68%) upon detection of FDG-positivity on the background of a prior G1-2 NET; (iv) 67% were in favour to reconsider PRRT to treat residual SST-positive lesions after achieving complete remission on FDG of the SST-negative disease component. Multidisciplinary opinion broadly supports the use of FDG PET/CT for characterisation of disease biology and to guide treatment selection across a range of indications, despite the lack of full consensus in many situations. This may reflect existing clinical access due to lack of reimbursement or experience with this investigation, which should be addressed by further research.
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| 4. |
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| 5. |
- Baudin, Eric, et al.
(författare)
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Unmet Medical Needs in Pulmonary Neuroendocrine (Carcinoid) Neoplasms
- 2019
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 108:1, s. 7-17
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary carcinoids (PCs) display the common features of all well-differentiated neuroendocrine neoplasms (NEN) and are classified as low- and intermediate-grade malignant tumours (i.e., typical and atypical carcinoid, respectively). There is a paucity of randomised studies dedicated to advanced PCs and management principles are drawn from the larger gastroenteropancreatic NEN experience. There is growing evidence that NEN anatomic subgroups have different biology and different responses to treatment and, therefore, should be investigated as separate entities in clinical trials. In this review, we discuss the existing evidence and limitations of tumour classification, diagnostics and staging, prognostication, and treatment in the setting of PC, with focus on unmet medical needs and directions for the future.
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| 6. |
- Chatzellis, Eleftherios, et al.
(författare)
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Activity and Safety of Standard and Prolonged Capecitabine/Temozolomide Administration in Patients with Advanced Neuroendocrine Neoplasms
- 2019
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Ingår i: Neuroendocrinology. - : S. Karger. - 0028-3835 .- 1423-0194. ; 109:4, s. 333-345
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Tidskriftsartikel (refereegranskat)abstract
- Background: Capecitabine and temozolomide combination (CAPTEM) is associated with high response rates in patients with advanced neuroendocrine neoplasms (NENs). We evaluated the real-world activity and safety of CAPTEM from 3 NEN centers. Methods: Clinicopathological characteristics and outcomes of patients treated with CAPTEM for bulky or progressive disease (PD) were retrospectively analyzed. -Results: Seventy-nine patients with gastroenteropancreatic (grades 1-2 [n = 38], grade 3 [n = 24]) and lung/thymic (n = 17) NENs were included. Median treatment duration was 12.1 months (range 0.6-55.6). Overall, partial responses (PRs) occurred in 23 (29.1%), stable (SD) in 24 (30.4%), and PD in 28 (35.4%) patients. Median progression-free survival (PFS) and overall survival (OS) were 10.1 (6-14.2) and 102.9 months (43.3-162.5), respectively. On univariate analysis, NENs naive to chemotherapy and low Ki67 were associated with favorable responses (partial response [PR] + SD; p = 0.011 and 0.045), PFS (p < 0.0001 and 0.002) and OS (p = 0.005 and 0.001). Primary site (pancreas and lung/thymus) was also a significant prognostic factor for PFS (p < 0.0001) and OS (p < 0.0001). On multivariate analysis, gastrointestinal and unknown primary NENs (hazard ratio [HR] 0.3, 95% CI 0.1-0.8, p = 0.009 and p = 0.018) and prior surgery (HR 2.4, 95% CI 11-4.9, p = 0.021) were independent prognostic factors for PFS. Ki-67 was a poor predictor for favorable response in receiver operating characteristic analysis (area under the curve 0.678). Safety analysis of CAPTEM indicated rare events of serious (grades 3-4) toxicities (n = 4) and low discontinuation rates (n = 8) even in patients with prolonged administration (>12 months). Conclusions: CAPTEM treatment can be an effective and safe treatment even after prolonged administration for patients with NENs of various sites and Ki67 labeling index, associated with significant favorable responses and PFS.
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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-, 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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| 10. |
- Dromain, Clarisse, et al.
(författare)
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ENETS standardized (synoptic) reporting for radiological imaging in neuroendocrine tumours
- 2022
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Ingår i: Journal of neuroendocrinology. - : John Wiley & Sons. - 0953-8194 .- 1365-2826. ; 34:3 SI
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Tidskriftsartikel (refereegranskat)abstract
- This expert consensus document represents an initiative by the European Neuroendocrine Tumor Society (ENETS) to provide guidance for synoptic reporting of radiological examinations critical to the diagnosis, grading, staging and treatment of neuroendocrine neoplasms (NENs). Template drafts for initial tumor staging and follow-up by computed tomography (CT) and magnetic resonance imaging (MRI) were established, based on existing institutional and organisational reporting templates relevant for NEN imaging, and applying the RadLex lexicon of radiological information (Radiological Society of North America), for consistency regarding the radiological terms. During the ENETS Scientific Advisory Board meeting 2018, the template drafts were subject to iterative interdisciplinary discussions among experts in imaging, surgery, gastroenterology, oncology and pathology. Members of the imaging group stated a strong preference for a combination of limited and standardised options by way of drop-down menus. Separate templates were produced for the initial work-up and for follow-up, respectively. To provide a detailed description of the radiological findings of the primary tumor and its local extension and spread, different templates were developed for bronchial, pancreatic and gastrointestinal NENs for CT and MRI, respectively. Each template was structured in 10 sections: clinical details, comparative imaging modality, acquisition technique, primary tumor findings, regional lymph node metastases, distant metastases, TNM classification, reference lesions according to RECIST 1.1, additional findings and conclusion. Two templates were developed for follow-up, for CT and MRI, respectively, and were specifically focused on assessment of therapy response. These included a qualitative response assessment, such as decrease of vascularisation and presence of necrosis, and a quantitative assessment according to RECIST 1.1 and the modified RECIST (mRECIST) for assessing tumor response following transarterial chemoembolisation.
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| 11. |
- Kaltsas, Gregory, et al.
(författare)
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ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : Pre- and Perioperative Therapy in Patients with Neuroendocrine Tumors
- 2017
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 105:3, s. 245-254
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Tidskriftsartikel (refereegranskat)abstract
- Neuroendocrine tumors of the small intestine are the most common causes of the carcinoid syndrome. Carcinoid heart disease occurs in more than half of the patients with the carcinoid syndrome. Patients with carcinoid heart disease who need to undergo surgery should also undergo preoperative evaluation by an expert cardiologist. Treatment with longacting somatostatin analogs aims at controlling the excessive hormonal output and symptoms related to the carcinoid syndrome and at preventing a carcinoid crisis during interventions. Patients with a gastrinoma require pre- and postoperative treatment with high doses of proton pump inhibitors. Patients with a glucagonoma require somatostatin analog treatment and nutritional supplementation. Patients with a VIPoma also require somatostatin analog treatment and intravenous fluid and electrolyte therapy. Insulinoma patients generally require intravenous glucose infusion prior to operation. In patients with localized operable insulinoma, somatostatin analog infusion should only be considered after the effect of this therapy has been electively studied.
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| 12. |
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| 13. |
- Malczewska, Anna, et al.
(författare)
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An Assessment of Circulating Chromogranin A as a Biomarker of Bronchopulmonary Neuroendocrine Neoplasia : A Systematic Review and Meta-Analysis
- 2020
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 110:3-4, s. 198-216
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Forskningsöversikt (refereegranskat)abstract
- Background: Management of bronchopulmonary neuroendocrine neoplasia (NEN; pulmonary carcinoids [PCs], small-cell lung cancer [SCLC], and large cell neuroendocrine carcinoma) is hampered by the paucity of biomarkers. Chromogranin A (CgA), the default neuroendocrine tumor biomarker, has undergone wide assessment in gastroenteropancreatic neuroendocrine tumors.Objectives: To evaluate CgA in lung NEN, define its clinical utility as a biomarker, assess its diagnostic, prognostic, and predictive efficacy, as well as its accuracy in the identification of disease recurrence.Methods: A systematic review of PubMed was undertaken using the preferred reporting items for systematic reviews and meta-analyses guidelines. No language restrictions were applied. Overall, 33 original scientific papers and 3 case reports, which met inclusion criteria, were included in qualitative analysis, and meta-analysis thereafter. All studies, except 2, were retrospective. Meta-analysis statistical assessment by generic inverse variance methodology.Results: Ten different CgA assay types were reported, without consistency in the upper limit of normal (ULN). For PCs (n = 16 studies; median patient inclusion 21 [range 1-200, total: 591 patients]), the CgA diagnostic sensitivity was 34.5 +/- 2.7% with a specificity of 93.8 +/- 4.7. CgA metrics were not available separately for typical or atypical carcinoids. CgA >100 ng/mL (2.7 x ULN) and >600 ng/mL (ULN unspecified) were anecdotally prognostic for overall survival (n = 2 retrospective studies). No evidence was presented for predicting treatment response or identifying post-surgery residual disease. For SCLC (n = 19 studies; median patient inclusion 23 [range 5-251, total: 1,241 patients]), the mean diagnostic sensitivity was 59.9 +/- 6.8% and specificity 79.4 +/- 3.1. Extensive disease typically exhibited higher CgA levels (diagnostic accuracy: 61 +/- 2.5%). An elevated CgA was prognostic for overall survival (n = 4 retrospective studies). No prospective studies evaluating predictive benefit or prognostic utility were identified.Conclusion: The available data are scarce. An assessment of all published data showed that CgA exhibits major limitations as an effective and accurate biomarker for either PC or SCLC. Its utility especially for localized PC/limited SCLC (when surgery is potentially curative), is limited. The clinical value of CgA remains to be determined. This requires validated, well-constructed, multicenter, prospective, randomized studies. An assessment of all published data indicates that CgA does not exhibit the minimum required metrics to function as a clinically useful biomarker for lung NENs.
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| 14. |
- Malczewska, Anna, et al.
(författare)
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NETest Liquid Biopsy Is Diagnostic of Lung Neuroendocrine Tumors and Identifies Progressive Disease
- 2019
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 108:3, s. 219-231
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Tidskriftsartikel (refereegranskat)abstract
- Background: There are no effective biomarkers for the management of bronchopulmonary carcinoids (BPC). We examined the utility of a neuroendocrine multigene transcript "liquid biopsy" (NETest) in BPC for diagnosis and monitoring of the disease status.Aim: To independently validate the utility of the NETest in diagnosis and management of BPC in a multicenter, multinational, blinded study.Material and Methods: The study cohorts assessed were BPC (n = 99), healthy controls (n = 102), other lung neoplasia (n = 101) including adenocarcinomas (ACC) (n = 41), squamous cell carcinomas (SCC) (n = 37), small-cell lung cancer (SCLC) (n = 16), large-cell neuroendocrine carcinoma (LCNEC) (n = 7), and idiopathic pulmonary fibrosis (IPF) (n = 50). BPC were histologically classified as typical (TC) (n = 62) and atypical carcinoids (AC) (n = 37). BPC disease status determination was based on imaging and RECIST 1.1. NETest diagnostic metrics and disease status accuracy were evaluated. The upper limit of normal (NETest) was 20. Twenty matched tissue-blood pairs were also evaluated. Data are means +/- SD.Results: NETest levels were significantly increased in BPC (45 +/- 25) versus controls (9 +/- 8; p < 0.0001). The area under the ROC curve was 0.96 +/- 0.01. Accuracy, sensitivity, and specificity were: 92, 84, and 100%. NETest was also elevated in SCLC (42 +/- 32) and LCNEC (28 +/- 7). NETest accurately distinguished progressive (61 +/- 26) from stable disease (35.5 +/- 18; p < 0.0001). In BPC, NETest levels were elevated in metastatic disease irrespective of histology (AC: p < 0.02; TC: p = 0.0006). In nonendocrine lung cancers, ACC (18 +/- 21) and SCC (12 +/- 11) and benign disease (IPF) (18 +/- 25) levels were significantly lower compared to BPC level (p < 0.001). Significant correlations were evident between paired tumor and blood samples for BPC (R: 0.83, p < 0.0001) and SCLC (R: 0.68) but not for SCC and ACC (R: 0.25-0.31).Conclusions: Elevated - NETest levels are indicative of lung neuroendocrine neoplasia. NETest levels correlate with tumor tissue and imaging and accurately define clinical progression.
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| 15. |
- Malczewska, Anna, et al.
(författare)
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NETest liquid biopsy is diagnostic of small intestine and pancreatic neuroendocrine tumors and correlates with imaging
- 2019
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Ingår i: Endocrine Connections. - : BIOSCIENTIFICA LTD. - 2049-3614. ; 8:4, s. 442-453
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Current monoanalyte biomarkers are ineffective in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). NETest, a novel multianalyte signature, provides molecular information relevant to disease biology. Aim(s): Independently validate NETest to diagnose GEP-NETs and identify progression in a tertiary referral center. Materials and methods: Cohorts are 67 pancreatic NETs (PNETs), 44 small intestine NETs (SINETs) and 63 controls. Well-differentiated (WD) PNETs, n = 62, SINETs, all (n = 44). Disease extent assessment at blood draw: anatomical (n = 110) CT (n = 106), MRI (n = 7) and/or functional Ga-68-SSA-PET/CT (n = 69) or F-18-FDG-PET/CT (n = 8). Image-positive disease (IPD) was defined as either CT/MRI or Ga-68-SSA-PET/CT/F-18-FDG-PET/CT-positive. Both CT/MRI and Ga-68-SSA-PET/CT negative diagnosis in WD-NETs was considered image-negative disease (IND). NETest (normal: 20): PCR (spotted plate s). Data: mean +/- SD. Results: Diagnosis: NETest was significantly increased in NETs (n = 111; 26 +/- 21) vs controls (8 +/- 4, p < 0.0001). Seventy-five (42 PNET, 33 SINET) were image positive. Eleven (8 PNET, 3 SINET; all WD) were IND. In IPD, NETest was significantly high er (36 +/- 22) vs IND (8 +/- 7, P < 0.0001). NETest accuracy, sensitivity and specificity are 97, 99 and 95%, respectively. Concordance with imaging: NETest was 92% (101/110) concordant with anatomical imaging, 94% (65/69) with Ga-68-SSA-PET/CT and 96% (65/68) dual modality (CT/MRI and Ga-68-SSA-PET/CT). In 70 CT/MRI positive, NETest was elevated in all (37 +/- 22). In 40 CT/MRI negative, NETest was normal (11 +/- 10) in 31. In 56 Ga-68-SSA-PET/CT positive, NETest was elevated (36 +/- 22) in 55. In 13 Ga-68-SSA-PET/CT negative, NETest was normal (9 +/- 8) in ten. Disease status: NETest was significantly higher in progressive (61 +/- 26; n = 11) vs stable disease (29 +/- 14; n = 64; P < 0.0001) (RECIST 1.1). Conclusion: NETest is an effective diagnostic for PNETs and SINETs. Elevated NETest is as effective as imaging in diagnosis and accurately identifies progression.
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| 16. |
- Malczewska, Anna, et al.
(författare)
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The clinical applications of a multigene liquid biopsy (NETest) in neuroendocrine tumors
- 2020
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Ingår i: Advances in Medical Sciences. - : Elsevier BV. - 1896-1126 .- 1898-4002. ; 65:1, s. 18-29
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Forskningsöversikt (refereegranskat)abstract
- Purpose: There are few effective biomarkers for neuroendocrine tumors. Precision oncology strategies have provided liquid biopsies for real-time and tailored decision-making. This has led to the development of the first neuroendocrine tumor liquid biopsy (the NETest). The NETest represents a transcriptomic signature of neuroendocrine tumor (NETs) that captures tumor biology and disease activity. The data have direct clinical application in terms of identifying residual disease, disease progress and the efficacy of treatment. In this overview we assess the available published information on the metrics and clinical efficacy of the NETest. Material and methods: Published data on the NETest have been collated and analyzed to understand the clinical application of this multianalyte biomarker in NETs. Results: NETest assay has been validated as a standardized and reproducible clinical laboratory measurement. It is not affected by demographic characteristics, or acid suppressive medication. Clinical utility of the NETest has been documented in gastroenteropancreatic, bronchopulmonary NETs, in paragangliomas and pheochromocytomas. The test facilitates accurate diagnosis of a NET disease, and real-time monitoring of the disease status (stable/progressive disease). It predicts aggressive tumor behavior, identifies operative tumor resection, and efficacy of the medical treatment (e.g. somatostatin analogues), or peptide receptor radionuclide therapy (PRRT). NETest metrics and clinical applications out-perform standard biomarkers like chromogranin A. Conclusions: The NETest exhibits clinically competent metrics as an effective biomarker for neuroendocrine tumors. Measurement of NET transcripts in blood is a significant advance in neuroendocrine tumor management and demonstrates that blood provides a viable source to identify and monitor tumor status.
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| 17. |
- Matar, Somer, et al.
(författare)
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Blood Chromogranin A Is Not Effective as a Biomarker for Diagnosis or Management of Bronchopulmonary Neuroendocrine Tumors/Neoplasms
- 2020
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 110:3-4, s. 185-197
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Tidskriftsartikel (refereegranskat)abstract
- Background: Identification of circulating tumor markers for clinical management in bronchopulmonary (BP) neuroendocrine tumors/neoplasms (NET/NEN) is of considerable clinical interest. Chromogranin A (CgA), a "universal" NET biomarker, is considered controversial as a circulating biomarker of BPNEN.Aim: Assess utility of CgA in the diagnosis and management of BPNEN in a multicentric study.Material and Methods: CgA diagnostic metrics were assessed in lung NET/NENs (n = 200) and controls (n = 140), randomly assigned to a Training and Test set (100 BPC and 70 controls in each). Assay specificity was evaluated in neoplastic lung disease (n = 137) and nonneoplastic lung disease (n = 77). CgA efficacy in predicting clinical status was evaluated in the combined set of 200 NET/NENs. CgA levels in bronchopulmonary neuroendocrine tumor (BPNET) subtypes (atypical [AC] vs. typical [TC]) and grade was examined. The clinical utility of an alteration of CgA levels (+/- 25%) was evaluated in a subset of 49 BPNET over 12 months. CgA measurement was by NEOLISA(TM) kit (EuroDiagnostica).Results: Sensitivity and specificity in the training set were 41/98%, respectively. Test set data were 42/87%. Training set area under receiver operator characteristic analysis differentiated BPC from control area under the curve (AUC) 0.61 +/- 0.05 p = 0.015. Test set the data were AUC 0.58 +/- 0.05, p = 0.076. In the combined set (n = 200), 67% BPNET/NEN (n = 134) had normal CgA levels. CgA levels did not distinguish histological subtypes (TC vs. AC, AUC 0.56 +/- 0.04, p = 0.21), grade (p = 0.45-0.72), or progressive from stable disease (AUC 0.53 +/- 0.05 p = 0.47). There was no correlation of CgA with Ki-67 index (Pearson r = 0.143, p = 0.14). For nonneoplastic diseases (chronic obstructive pulmonary disorder and idiopathic pulmonary fibrosis), CgA was elevated in 26-37%. For neoplastic disease (NSCLC, squamous cell carcinoma), CgA was elevated in 11-16%. The neuroendocrine SCLC also exhibited elevated CgA (50%). Elevated CgA was not useful for differentiating BPNET/NEN from these other pathologies. Monitoring BPNET/NEN over a 12-month period identified neither CgA levels per se nor changes in CgA were reflective of somatostatin analog treatment outcome/efficacy or the natural history of the disease (progression).Conclusions: Blood CgA levels are not clinically useful as a biomarker for lung BPNET/NEN. The low specificity and elevations in both nonneoplastic as well as other common neoplastic lung diseases identified limited clinical utility for this biomarker.
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| 18. |
- Modlin, Irvin M., et al.
(författare)
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Early Identification of Residual Disease After Neuroendocrine Tumor Resection Using a Liquid Biopsy Multigenomic mRNA Signature (NETest)
- 2021
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Ingår i: Annals of Surgical Oncology. - : Springer. - 1068-9265 .- 1534-4681. ; 28:12, s. 7506-7517
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Surgery is the only cure for neuroendocrine tumors (NETs), with R0 resection being critical for successful tumor removal. Early detection of residual disease is key for optimal management, but both imaging and current biomarkers are ineffective post-surgery. NETest, a multigene blood biomarker, identifies NETs with >90% accuracy. We hypothesized that surgery would decrease NETest levels and that elevated scores post-surgery would predict recurrence. Methods This was a multicenter evaluation of surgically treated primary NETs (n = 153). Blood sampling was performed at day 0 and postoperative day (POD) 30. Follow-up included computed tomography/magnetic resonance imaging (CT/MRI), and messenger RNA (mRNA) quantification was performed by polymerase chain reaction (PCR; NETest score: 0-100; normal <= 20). Statistical analyses were performed using the Mann-Whitney U-test, Chi-square test, Kaplan-Meier survival, and area under the receiver operating characteristic curve (AUROC), as appropriate. Data are presented as mean +/- standard deviation. Results The NET cohort (n = 153) included 57 patients with pancreatic cancer, 62 patients with small bowel cancer, 27 patients with lung cancer, 4 patients with duodenal cancer, and 3 patients with gastric cancer, while the surgical cohort comprised patients with R0 (n = 102) and R1 and R2 (n = 51) resection. The mean follow-up time was 14 months (range 3-68). The NETest was positive in 153/153 (100%) samples preoperatively (mean levels of 68 +/- 28). In the R0 cohort, POD30 levels decreased from 62 +/- 28 to 22 +/- 20 (p < 0.0001), but remained elevated in 30% (31/102) of patients: 28% lung, 29% pancreas, 27% small bowel, and 33% gastric. By 18 months, 25/31 (81%) patients with a POD30 NETest >20 had image-identifiable recurrence. An NETest score of >20 predicted recurrence with 100% sensitivity and correlated with residual disease (Chi-square 17.1, p < 0.0001). AUROC analysis identified an AUC of 0.97 (p < 0.0001) for recurrence-prediction. In the R1 (n = 29) and R2 (n = 22) cohorts, the score decreased (R1: 74 +/- 28 to 45 +/- 24, p = 0.0012; R2: 72 +/- 24 to 60 +/- 28, p = non-significant). At POD30, 100% of NETest scores were elevated despite surgery (p < 0.0001). Conclusion The preoperative NETest accurately identified all NETs (100%). All resections decreased NETest levels and a POD30 NETest score >20 predicted radiologically recurrent disease with 94% accuracy and 100% sensitivity. R0 resection appears to be ineffective in approximately 30% of patients. NET mRNA blood levels provide early objective genomic identification of residual disease and may facilitate management.
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| 19. |
- Nesti, Cedric, et al.
(författare)
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Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size : a retrospective, Europe-wide, pooled cohort study
- 2023
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Ingår i: The Lancet Oncology. - : Elsevier. - 1470-2045 .- 1474-5488. ; 24:2, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAwareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1–2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1–2 cm in size in patients with or without right-sided hemicolectomy.MethodsIn this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1–2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693.Findings282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1–2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0–15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 –21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36–2·17]; p=0·71).InterpretationThis study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1–2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort.
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| 20. |
- Toumpanakis, Christos, et al.
(författare)
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Unmet Needs in Appendiceal Neuroendocrine Neoplasms
- 2019
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 108:1, s. 37-44
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Tidskriftsartikel (refereegranskat)abstract
- Appendiceal neuroendocrine neoplasms (ANEN) are mostly discovered coincidentally during appendicectomy and usually have a benign clinical course; thus, appendicectomy alone is considered curative. However, in some cases, a malignant potential is suspected, and therefore additional operations such as completion right hemicolectomy are considered. The existing European Neuroendocrine Tumour Society (ENETS) guidelines provide useful data about epidemiology and prognosis, as well as practical recommendations with regards to the risk factors for a more aggressive disease course and the indications for a secondary operation. However, these guidelines are based on heterogeneous and retrospective studies. Therefore, the evidence does not seem to be robust, and there are still unmet needs in terms of accurate epidemiology and overall prognosis, optimal diagnostic and follow-up strategy, as well as identified risk factors that would indicate a more aggressive surgical approach at the beginning and a more intense follow-up. In this review, we are adopting a critical approach of the ENETS guidelines and published series for ANEN, focusing on the above-noted "grey areas".
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| 21. |
- Tsoli, Marina, et al.
(författare)
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Pancreatic metastases in patients with neuroendocrine neoplasms : A multi-centre cohort study
- 2023
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Ingår i: Journal of neuroendocrinology. - : Blackwell Publishing. - 0953-8194 .- 1365-2826. ; 35:4
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic metastases (PMs) from neuroendocrine neoplasms (NENs) are rare but the increased sensitivity of new diagnostic tools such as 68 Ga-DOTATATE PET/CT has resulted in their increased recognition at initial diagnosis or follow-up. A retrospective analysis of the data of patients from six tertiary referral centres was performed in order to identify the characteristics and the prognostic significance of PMs in patients with NENs. We used a control group of 69 age-, sex- and primary tumour - matched NEN patients from the same cohort with stage IV disease but no PMs. Overall survival (OS) was assessed using the Kaplan-Meier method log-rank analysis was used to assess the impact of various clinical and histopathological variables in OS. We identified 25 patients (11 females) with PMs with a median age at diagnosis of 60 years. The small intestine was the most common primary (80%) with a prevalence of 4.2% PMs (21/506). Fourteen patients presented with synchronous PMs whereas 11 developed metachronous PMs after a median time of 28 months (range: 7-168 months). Grading was available in 24 patients; 16 patients had G1 tumours, four G2, two atypical lung carcinoid, one typical and one atypical thymic carcinoid. Most patients had other concomitant metastases (12 hepatic, 4 lung and 6 bone) while five patients exhibited peritoneal carcinomatosis. Median OS in the PMs group was not reached compared with 212 months in the control group (95% CI: 26-398). The univariate analysis identified no prognostic factors statistically significantly associated with the OS. In conclusion, PMs are encountered with a low prevalence among NEN patients mostly developing in patients with advanced metastatic disease. The presence of PMs does not seem to be associated with a negative prognostic impact in OS.
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