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Neuroendocrine tumours (NETs) can arise in different locations in the body, and may give rise to hormonal symptoms, which amongst other factors may affect patients' health-related quality of life (HRQoL). Up to four cycles of peptide receptor radionuclide therapy (PRRT) have been shown effective for symptom alleviation and prolonging progression-free survival. The aim of this study was to assess the patient's perspective regarding changes in their HRQoL during PRRT. HRQoL was assessed using the questionnaires for cancer in general, EORTC QLQ-C30, and the gastrointestinal NET-specifically EORTC QLQ-GINET21. Patients with NET (n = 204) rated their HRQoL before PRRT cycles one and four. The medical records of patients were reviewed and their HRQoL was compared to a matched reference population (n = 4910). HRQoL was found to improve during PRRT in aspects of global quality of life; role, social, and emotional functioning, and multiple symptom relief. Potential risk groups for worse HRQoL during PRRT were patients with overweight (BMI >25) who completed four cycles of PRRT and older patients (>65 years old). In conclusion, we found that PRRT improves HRQoL in patients with NETs. The results of this study may be used to improve person-centred care., (© 2023 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

The incidence of neuroendocrine neoplasms (NENs) has increased over the last decades. The prevalence of NENs has to a lesser extent been previously reported. We wanted to study the trends in incidence and prevalence of NEN in Norway from 1993 to 2021 through the Cancer Registry of Norway. This registry, which covers the whole population, has been found to be 99% complete. The neoplasms were classified as neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). From 1993 to 2021 altogether 10.288 NETs and 13,982 (1.756 outside the lungs) NECs were diagnosed. The incidence of NETs increased from 3.72 to 9.97 per 100,000 per year, corresponding to a 268% increase, p < .001. The largest increase in incidence for NETs was found for pancreas (338%), lung (330%) and small intestine (303%). For NECs there was no change in the incidence, from 9.74 to 9.95 per 100,000 per year, p = .4, but there was an increase in the incidence of NECs originating from the skin (Merkel cell carcinoma) (287%), p < .001, and the GI tract (200%), p = .03. There were no changes in stage distribution at diagnosis for NETs and NECs. The prevalence for NENs increased 666% during the study period, NETs increased from 10.77 to 99.37 per 100.000 (927%), p < .001. For NECs the increase was from 7.4 to 21.56 per 100.000 (291%), p < .001. GI-NECs increased the most from 0.005 to 0.94 (1880%), p = .002. In conclusion, there was a substantial increase in incidence and prevalence of neuroendocrine neoplasms in Norway from 1993 to 2021. This is the first study to report complete prevalence of NENs for a whole nation., (© 2023 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Small intestinal neuroendocrine tumours (Si-NET) are often studied as a uniform group. Proliferation index Ki-67 influences prognosis and determines tumour grade. We hypothesized that Si-NET grade 2 (G2) tumours, which have a higher Ki-67 than G1 tumours, might benefit less from established treatments for metastatic disease. We conducted a retrospective cohort study of 212 patients with metastatic Si-NET G2 treated in two Swedish hospitals during 20 years (2000-2019). Median cancer-specific survival on first-line somatostatin analogues (SSA) was 77 months. Median progression-free survival (PFS) was 12.4 months when SSA was given as monotherapy and 19 months for all patients receiving first-line SSA. PFS after SSA dose escalation was 6 months in patients with radiological progression. Treatment efficacies of SSA and peptide receptor radionuclide treatment (PRRT) were studied separately in patients with Ki-67 of 3-5%, 5-10% and 10-20%. For SSA, PFS was significantly shorter at higher Ki-67 levels (31, 18 and 10 months, respectively), while there was only a minor difference in PFS for PRRT (29, 25 and 25 months). Median PFS for sequential treatment with interferon-alpha (IFNα), everolimus and chemotherapy was 6, 5 and 9 months. IFNα seemed to be effective in tumours with low somatostatin-receptor expression. In conclusion, established treatments appeared effective in Si-NET G2, despite their higher proliferation index compared to G1 tumours. However, efficacy of SSA but not PRRT was reduced at higher Ki-67 levels. SSA dose escalation provided limited disease stabilization.

Background: Awareness 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., Methods: In 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., Findings: 282 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)., Interpretation: This 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., Funding: Swiss Cancer Research foundation., Competing Interests: Declaration of interests MBe reports funding from Novartis, Pfizer, and Ipsen; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Novartis, Pfizer, Ipsen, and Advanced Accelerator Applications (AAA); support for attending meetings or travel from Novartis, Pfizer, and Ipsen; and participation on data safety monitoring board or advisory boards from Pfizer and AAA. IB reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Bristol Myers Squibb (BMS) and Bayer Vital and support for attending meetings or travel for European Musculo-Skeletal Oncology Society 2022 conference from PharmaMar. RG-C reports funding of investigator-initiated clinical trials from Pfizer, BMS, and MSD, and an real-world data project from Servier; consulting fees from AAA/Novartis, Advanz Pharma, Amgen, Bayer, BMS, Boehringer (Ingelheim), Esteve, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, PharmaMar, and Pierre Fabre; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Roche. GC reports grants or contracts from AAA; consulting fees from AAA; payments or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AAA, Ipsen, and Keocyt; and support for attending meetings or travel from AAA, Ipsen, and Keocyt. MPa reports payments for advisory boards or lectures from AAA and Novartis; payments for advisory boards, consultancy, or lectures from Ipsen; payment for lectures from Boehringer Ingelheim, MSD, Lilly, and Recordati; payment for advisory boards from Riemser; payment for services (radiological review of phase 3 study) from Hutchmed; payment for travel for participation in study steering committee meeting from Rayzebio; payment to institution from Crinetics and AAA; and unpaid roles as ENETS vice president, European Society for Medical Oncology (ESMO) Education Committee, ESMO scientific steering committee NET track, advisor on the International Neuroendocrine Cancer Alliance board, and advisor for German patient support group. GR reports payments for speaker bureaus from AAA. AR reports being an ENETS Advisory Board member. TV reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Ipsen; support for attending meetings or travel from Ipsen; and an unpaid position as secretary in the Dutch Belgian Neuroendocrine Tumor Society. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

There is an unmet need for novel biomarkers to diagnose and monitor patients with neuroendocrine neoplasms. The EXPLAIN study explores a multi-plasma protein and supervised machine learning strategy to improve the diagnosis of pancreatic neuroendocrine tumors (PanNET) and differentiate them from small intestinal neuroendocrine tumors (SI-NET). At time of diagnosis, blood samples were collected and analyzed from 39 patients with PanNET, 135 with SI-NET (World Health Organization Grade 1-2) and 144 controls. Exclusion criteria were other malignant diseases, chronic inflammatory diseases, reduced kidney or liver function. Prosed Oncology-II (i.e., OLink) was used to measure 92 cancer related plasma proteins. Chromogranin A was analyzed separately. Median age in all groups was 65-67 years and with a similar sex distribution (females: PanNET, 51%; SI-NET, 42%; controls, 42%). Tumor grade (G1/G2): PanNET, 39/61%; SI-NET, 46/54%. Patients with liver metastases: PanNET, 78%; SI-NET, 63%. The classification model of PanNET versus controls provided a sensitivity (SEN) of 0.84, specificity (SPE) 0.98, positive predictive value (PPV) of 0.92 and negative predictive value (NPV) of 0.95, and area under the receiver operating characteristic curve (AUROC) of 0.99; the model for the discrimination of PanNET versus SI-NET providing a SEN 0.61, SPE 0.96, PPV 0.83, NPV 0.90 and AUROC 0.98. These results suggest that a multi-plasma protein strategy can significantly improve diagnostic accuracy of PanNET and SI-NET., (© 2022 Ipsen. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Background: The diagnostic work-up and treatment of patients with gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) has undergone major advances and new methods are introduced. Furthermore, an update of the WHO classification has resulted in a new nomenclature for GEP-NEN that is implemented in the clinic., Aim: These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat GEP-NEN patients and aims to be useful in the daily practice for clinicians.

Background: Small intestinal neuroendocrine tumors (SI-NETs) are difficult to diagnose in the early stage of disease. Current blood biomarkers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid have low sensitivity (SEN) and specificity (SPE). This is a first preplanned interim analysis (Nordic non-interventional, prospective, exploratory, EXPLAIN study [NCT02630654]). Its objective is to investigate if a plasma protein multi-biomarker strategy can improve diagnostic accuracy (ACC) in SI-NETs., Methods: At the time of diagnosis, before any disease-specific treatment was initiated, blood was collected from patients with advanced SI-NETs and 92 putative cancer-related plasma proteins from 135 patients were analyzed and compared with the results of age- and sex-matched controls (n = 143), using multiplex proximity extension assay and machine learning techniques., Results: Using a random forest model including 12 top ranked plasma proteins in patients with SI-NETs, the multi-biomarker strategy showed SEN and SPE of 89 and 91%, respectively, with negative predictive value (NPV) and positive predictive value (PPV) of 90 and 91%, respectively, to identify patients with regional or metastatic disease with an area under the receiver operator characteristic curve (AUROC) of 99%. In 30 patients with normal CgA concentrations, the model provided a diagnostic SPE of 98%, SEN of 56%, and NPV 90%, PPV of 90%, and AUROC 97%, regardless of proton pump inhibitor intake., Conclusion: This interim analysis demonstrates that a multi-biomarker/machine learning strategy improves diagnostic ACC of patients with SI-NET at the time of diagnosis, especially in patients with normal CgA levels. The results indicate that this multi-biomarker strategy can be useful for early detection of SI-NETs at presentation and conceivably detect recurrence after radical primary resection., (© 2020 S. Karger AG, Basel.)

Background: Patients with metastatic small-intestinal neuroendocrine tumours (NET) have been shown to have a reduced quality of life compared to the general population and many have disabling symptoms during somatostatin analogue (SSA) treatment. The aim of this prospective study was to document the patient-reported symptoms, coping and quality of life during SSA treatment and to measure patients' fat-soluble vitamin levels., Methods: Patients with metastatic small-intestinal NET on treatment with long-acting SSA were included. Data on patient characteristics, blood samples, questionnaires (EORTC-QLQ-C30 and GI.NET-21) and structured patient interviews were collected at inclusion and after 1 year., Results: Eighty-eight patients were included, 77 (88%) attended 1 year follow-up. Approximately 50% of patients reported symptoms, the most common symptoms at baseline and after 1 year follow-up were diarrhoea, flatulence, fatigue, abdominal discomfort and sore injection lumps. Diarrhoea and fatigue were reported as their main complaint, 23% had > 5 daily episodes of diarrhoea and 59% reported fatigue. However, patients reported a high perceived quality of life, high daily activity, coped with their symptoms and managed their daily life well. Deficiency of vitamin D (27%) and A (13%) were observed., Conclusions: Patients with metastatic small-intestinal NET on SSA treatment reported a high frequency of symptoms. Minor improvements were seen after 1-year of follow-up, illustrating that many symptoms might be difficult to improve, or may not be recognised by the health service. Patients, however, generally reported a high quality of life. Care for NET patients on SSA treatment should include a regular systematic symptom registration and vitamin measurements.

Background: There are several treatment modalities for unresectable neuroendocrine tumors. Traditionally, the aim of these treatments has been to reduce the tumor load; referred to as objective response (OR). Less emphasis has been put on inducing the tumors to stop growing without a reduction in total tumor load; termed as stable disease (SD). We wanted to investigate whether achieving OR compared to obtaining SD predicted a longer time to progression (TTP) in patients with neuroendocrine tumors (WHO Grade 1 and 2) treated with peptide receptor radionuclide therapy, chemotherapy or molecular targeted therapy., Methods: Patients treated with either peptide receptor radionuclide therapy (PRRT) with 177 Lutetium-DOTA-octreotate, the chemotherapy combination streptozotocin/5-fluorouracil or everolimus were retrospectively assessed to evaluate the effect of the treatments on disease progression. We analyzed the TTP for patients for each treatment modality and compared the TTP between those who achieved OR and those who achieved SD., Results: Altogether 56 patients treated with PRRT, 32 treated with streptozotocin/5-fluorouracil and 52 treated with everolimus were included in the analyses. The median TTP for those treated with PRRT and achieving OR was 31 months, the TTP for those achieving SD was 43 months (p = 0,2). For patients treated with streptozotocin/5-fluorouracil the results were: OR: 18 months, SD: 23 months (p = 0,9) and for those treated with everolimus; OR: 9 months, SD: 20 months (p = 0,5), respectively. We found no differences between patients achieving OR compared to SD regarding age, sex, stage, primary tumor location, Ki-67% or ongoing treatment with somatostatin analogues., Conclusions: We found no treatment benefit with regard to TTP for our patients that experienced OR compared to those who achieved SD.

Background: Retrospective studies are conflicting but most of them report that an increase in plasma chromogranin A (CgA) predicts tumor progression in neuroendocrine tumor (NET) patients. Prospectively, we investigated if a change in plasma CgA is associated with tumor burden changes in NET patients with disseminated disease., Methods: We included 239 patients treated at 5 NET centers from December 2010 to December 2013. CgA was measured within 6 weeks of a CT or MRI in a patient undergoing at least 2 scan examinations performed over a period of 1-24 months. In a post hoc analysis, CgA measured 3-6 months prior to the CT/MRI was analyzed. Changes in tumor size were evaluated by RECIST1.1. A 25% change in CgA was chosen to discriminate between increased, decreased, or unchanged levels., Results: In 671 events (2 CT/MRI scans and 2 corresponding CgA measurements), we found a weak positive correlation between the RECIST 1.1 responses and change in plasma CgA from baseline (Spearman's rank correlation coefficient: 0.15; p < 0.05). Of 304 events in the post hoc analysis, 58 showed progression, 228 showed stable disease, and 18 showed regression, with a median change in CgA of 19% (IQR: 57 to -20%), -12% (23 to -38%), and -73% (-55 to -83%), respectively. The correlation coefficient for all sites was 0.17 (p = 0.003), and it was 0.16 (p = 0.07), 0.18 (p = 0.04), and 0.20 (p = 0.21) for small-intestinal (n = 137), pancreatic (n = 123), and unknown primary NET (n = 40), respectively. In the 58 patients showing tumor progression, the sensitivity and specificity of an increased CgA concentration were 36 and 82%, respectively, with positive and negative predictive values of 32 and 85%., Conclusions: In this prospective study of gastroenteropancreatic NET patients, we observed only a weak association between a change in plasma CgA and changes in tumor burden. CgA as a single biomarker was thus inadequate to predict tumor progression., (© 2019 S. Karger AG, Basel.)

Aim: Evaluate associations between clinical outcomes and SNPs in patients with well-differentiated pancreatic neuroendocrine tumors receiving sunitinib. Patients & methods: Kaplan-Meier and Cox proportional hazards models were used to analyze the association between SNPs and survival outcomes using data from a sunitinib Phase IV (genotyped, n = 56) study. Fisher's exact test was used to analyze objective response rate and genotype associations. Results: After multiplicity adjustment, progression-free and overall survivals were not significantly correlated with SNPs; however, a higher objective response rate was significantly associated with IL1B rs16944 G/A versus G/G (46.4 vs 4.5%; p = 0.001). Conclusion: SNPs may predict treatment response in patients with pancreatic neuroendocrine tumors. VEGF pathway SNPs are potentially associated with survival outcomes.IL1B SNPs may predict treatment response in patients with pancreatic neuroendocrine tumors. VEGF pathway SNPs are potentially associated with survival outcomes.

Objective: The Response Evaluation Criteria In Solid Tumors (RECIST) is the most used radiological method for evaluating response after peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine tumors. This method may give too positive estimates of response in slow growing tumors as it allows a substantial increase in tumor size before patients are classified as having progressive disease. We wanted to compare RECIST with a conventional method in routine use for estimating treatment effect based on defining any unequivocal increase in size of tumor load as progressive disease. We also wanted to investigate whether any differences had clinical implications., Methods: Patients treated with 177 Lutetium-DOTA-octreotate having at least one follow-up radiological response evaluation were included. Radiological examinations were retrospectively evaluated by RECIST and compared to the radiological evaluations performed at regular follow-up examinations., Results: Seventy-nine patients were included, 33 (42%) were women, median age 65 years. The primary tumors was located in the small intestine in 35 (44%) and the in the pancreas in 27 (34%) of the patients. Indication for treatment was progressive disease in 71 (90%) patients. Based on RECIST, 67 (85%) patients had objective response or stable disease as best effect versus 59 (75%) patients based on the conventional method (p < 0.001). Median progression free survival was 33 months estimated by RECIST and 28 months estimated with the conventional method (p < 0.001). Eight (10%) patients received tumor-targeted therapy due to progressive disease based on the conventional method while still having stable disease according to RECIST., Conclusion: Response evaluation after PRRT with RECIST gave more positive estimates for treatment effects compared to a method where any equivocal change in tumor load was regarded as significant. These differences had clinical implications.

Neuroendocrine neoplasms (NENs) are heterogeneous tumors originating from neuroendocrine cells. Their malignant potential varies from indolence to high-grade malignancy (carcinomas). We studied the survival of all NENs in Norway according to malignant potential and different primary sites. We identified all NEN cases diagnosed in 1993 to 2015 and reported to the national population-based Cancer Registry of Norway. We included 62 morphological types. According to morphological characteristics and known disease behavior, we stratified the tumors into two different groups: low/intermediate aggressiveness and high aggressiveness. A total of 17,128 NENs were analyzed. Median age was 67 years and 47.6% were females. The most common primary sites were in the lungs and the gastroenteropancreatic (GEP) system. The 5-year relative survival in patients with low/intermediate aggressive NENs was 64.8% (95% CI, 63.3-66.2) and high aggressive NENs 8.4% (95% CI, 7.8-9.1). Females had higher survival rates than males (p <0.001). The relative 5-year survival rate in patients younger than 50 years was 89.1% (95% CI, 87.4-90.7) vs 41.0% (95% CI, 34.9-46.9) in patients ≥80 years. In multivariable analysis gender, age at diagnosis, time of diagnosis, stage and primary sites were all predictors of outcome both in patients with low/intermediate tumors and high aggressive tumors. Survival improved significantly over time, regardless of sex, age and tumor stage., (© 2017 UICC.)

Background: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data., Methods: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs)., Results: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%)., Conclusions: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib., (© 2018 S. Karger AG, Basel.)

Background: Epidemiological studies show an increasing trend in the incidence of neuroendocrine neoplasms (NENs). A significant number of NENs occur in less common primary sites, but they are often excluded from the population-based studies. We studied the incidence trends of all NENs in Norway according to different primary sites., Materials and Methods: Our analyses were based on cancer cases diagnosed between 1993 and 2010 and reported to the national population-based Cancer Registry of Norway. A total of 65 morphological codes were identified as neuroendocrine and stratified into 3 different groups of aggressiveness: low, intermediate and high., Results: We identified 16,075 NENs of which 49.5% were in women. The median age at diagnosis was 65 years. The most common primary sites were the lung (48.1%) and the gastroenteropancreatic system (18.0%). Stage at diagnosis was local in 40.4% of the cases, regional in 17.5% and distant in 42.1%. The stage distribution was stable throughout the study period. The age-standardized (European) incidence rate (per 100,000 person-years) increased from 13.3 in 1993 to 21.3 in 2010 with an estimated annual increase of 5.1% in women and 2.1% in men. The increase was most pronounced for tumors of intermediate aggressiveness from 3.3 in 1993 to 7.3 in 2010. The largest annual increases were estimated for the adrenal gland (8.8%), the pancreas (6.9%) and the lungs (6.1%)., Conclusion: The incidence of NENs increased. Most primary tumors were found in the lungs or in the gastroenteropancreatic system. The increase in the incidence differed according to the primary site, gender and tumor aggressiveness., (© 2015 S. Karger AG, Basel.)

Background: The diagnostic work-up and treatment of patients with neuroendocrine neoplasms (NENs) has undergone major recent advances and new methods are currently introduced into the clinic. An update of the WHO classification has resulted in a new nomenclature dividing NENs into neuroendocrine tumours (NETs) including G1 (Ki67 index ≤ 2%) and G2 (Ki67 index 3-20%) tumours and neuroendocrine carcinomas (NECs) with Ki67 index > 20%, G3. Aim. These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat NEN-patients and are meant to be useful in the daily practice for clinicians handling these patients.

Objectives: Pancreatic neuroendocrine tumors (P-NETs) account for 2-3% of all pancreatic neoplasms. The aim of our study was to investigate survival and prognostic factors in patients with P-NETs., Material and Methods: We retrospectively reviewed the medical records of 114 patients diagnosed with well-differentiated P-NETs from 1982 through 2010. We studied demographical, clinical, radiological, and histopathological characteristics., Results: Median age at diagnosis was 57 years (range 32-83); 53% were men and 78% had nonfunctional tumors. The most common presenting symptoms were abdominal pain (41%), weight loss (36%), and diarrhea (25%); 19% of the tumors were incidental findings. Median duration of symptoms before diagnosis was 4 months, 3 months for nonfunctional, and 12 months for functional tumors (p < 0.001). At diagnosis, 32.5% patients had local, 22.8% had regional, and 44.7% had distant disease. Men had more often distant disease at diagnosis (p = 0.02). Median survival was 6.6 years (95% confidence interval [CI]: 4.0-9.2). Overall 5-year survival was 53.9% (95% CI: 43.4-63.3). For those with local disease and those with distant disease at diagnosis, the 5-year survivals were 70.2% (95% CI: 49.9-83.6) and 33.0% (95% CI: 19.7-46.7), respectively. Surgery with curative intent was performed on 46 patients. Newly detected liver metastases were diagnosed up to 10 years after surgery in this group. In patients with metastases, palliative surgery (debulking) did not have a significant effect on survival compared to those who had no surgery., Conclusion: Distant metastases, Ki-67 > 2%, nonfunctional tumors, elevated level of chromogranin A, and palliative treatment were associated with poor survival.

The diagnostic work-up and treatment of patients with neuroendocrine tumours has undergone a major change during the last decade. New diagnostic possibilities and treatment options have been developed. These Nordic guidelines, written by a group with a major interest in the subject, summarises our current view on how to diagnose and treat these patients. The guidelines are meant to be useful in the daily practice for clinicians handling patients with neuroendocrine tumours.

Background: Carcinoid heart disease, a known complication of neuroendocrine tumors, is characterized by right heart fibrotic lesions. Carcinoid heart disease has traditionally been defined by the degree of valvular involvement. Right ventricular (RV) dysfunction due to mural involvement may also be a manifestation. Connective tissue growth factor (CCN2) is elevated in many fibrotic disorders. Its role in carcinoid heart disease is unknown. We sought to investigate the relationship between plasma CCN2 and valvular and mural involvement in carcinoid heart disease., Methods: Echocardiography was performed in 69 patients with neuroendocrine tumors. RV function was assessed using tissue Doppler analysis of myocardial systolic strain. Plasma CCN2 was analyzed using an enzyme-linked immunosorbent assay. Mann-Whitney U, Kruskal-Wallis, Chi-squared and Fisher's exact tests were used to compare groups where appropriate. Linear regression was used to evaluate correlation., Results: Mean strain was -21% +/- 5. Thirty-three patients had reduced RV function (strain > -20%, mean -16% +/- 3). Of these, 8 had no or minimal tricuspid and/or pulmonary regurgitation (TR/PR). Thirty-six patients had normal or mildly reduced RV function (strain < or = -20%, mean -25% +/- 3). There was a significant inverse correlation between RV function and plasma CCN2 levels (r = 0.47, p < 0.001). Patients with reduced RV function had higher plasma CCN2 levels than those with normal or mildly reduced RV function (p < 0.001). Plasma CCN2 > or = 77 microg/L was an independent predictor of reduced RV function (odds ratio 15.36 [95% CI 4.15;56.86]) and had 88% sensitivity and 69% specificity for its detection (p < 0.001). Plasma CCN2 was elevated in patients with mild or greater TR/PR compared to those with no or minimal TR/PR (p = 0.008), with the highest levels seen in moderate to severe TR/PR (p = 0.03)., Conclusions: Elevated plasma CCN2 levels are associated with RV dysfunction and valvular regurgitation in NET patients. CCN2 may play a role in neuroendocrine tumor-related cardiac fibrosis and may serve as a marker of its earliest stages.

Objective: Small intestinal neuroendocrine tumors (SI-NETs) make up 38% of gastroenteropancreatic neuroendocrine tumors. We report our experience with SI-NETs at the National Center for Neuroendocrine Tumors in Norway, focusing on prognostic factors and survival., Material and Methods: The medical records of 258 patients with SI-NETs diagnosed between 1983 and 2007 were retrospectively reviewed. Demographic, clinical and tumor characteristics were registered in a database., Results: Median age at diagnosis was 62 years (range 28-84); 53% of patients were men. Median survival was 9.3 years [95% confidence interval (CI) 7.6; 10.8]. Survival did not improve for patients diagnosed between 1998 and 2007 compared with those diagnosed between 1990 and 1997 (p=0.44), median survival 8.1 [7.1;9.1] versus 6.8 [4.0; 9.5] years. Overall 5-year survival was 72%, while expected 5-year survival in the general population was 92%. The corresponding relative 5-year survival for the patient group was 78%. Distant metastases, urinary 5-hydroxyindoleacetic acid ratio > or =3.7 times the upper limit of normal, chromogranin A ratio > or =6.2 times the upper limit of normal, age > or =64, male gender, carcinoid heart disease, and Ki-67 > or =5% were associated with decreased survival. Using multivariate analysis, only distant metastases (hazard ratio (HR) 1.98 [1.04;3.76], p=0.04), chromogranin A ratio > or =6.2 (HR 1.90 [1.12; 3.20], p=0.02), and age > or =64 (3.12 [1.93; 5.04], p<0.001) remained independent predictors., Conclusions: Survival did not improve over the study period. Overall and relative 5-year survival compared favorably with that in population-based studies. Distant metastases, elevated chromogranin A levels, and advanced age were the only independent predictors of poor survival.

Background As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. Patients and methods Data from advanced GI-NEC patients diagnosed 2000–2009 were retrospectively registered at 12 Nordic hospitals. Results The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67 < 55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67 < 55% had a lower response rate (15% versus 42%, P < 0.001), but better survival than patients with Ki-67 ≥ 55% (14 versus10 months, P < 0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. Conclusions Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67 < 55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity. [ABSTRACT FROM PUBLISHER]