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Ectopic hormone secretion from neuroendocrine neoplasms in the lung (lung-NENs) is rare and poorly explored. Emerging evidence indicates that hormone-secreting NENs carry a worse prognosis. We hypothesised that ectopic hormone production and secretion in lung-NENs is a negative prognostic marker. A retrospective cohort of 167 patients with lung-NENs (121 females, median age: 68 (min-max: 15-85) years), excluding small cell lung cancer, was analysed for clinical and biochemical data and outcome. Tumour tissue was evaluated for serotonin and calcitonin expression. Among 127 patients with hormone measurements, 52 had increased levels, with 5-hydroxyindoleacetic acid (5-HIAA) predominating (n = 38), followed by calcitonin (n = 20). There was no correlation between serotonin expression in tumour tissue and elevated levels of 5-HIAA, while high calcitonin levels were strongly correlated with calcitonin expression in tumour samples (OR: 21.86, P = 0.002). Furthermore, diffuse calcitonin staining was associated with a shorter overall survival (OS) (P = 0.036). Hormone-secreting tumours had a significantly shorter OS than non-secreting tumours (62 vs 124 months, P = 0.024), and multiple hormone secretion further worsened survival (33 vs 69 vs 124 months, P = 0.002). In multivariate analysis, multiple hormone secretion remained an independent negative prognostic factor (P = 0.042). In conclusion, hormone secretion in lung-NENs is associated with a shorter OS, particularly in patients with multiple hormone secretion. Diffuse calcitonin expression in tumour tissue is an additional negative prognostic marker. We recommend routine hormone testing at baseline and at disease progression in metastatic lung-NEN patients and suggest a more intensified therapeutic strategy in cases with detectable hormone secretion.

There is an unmet need for new methods to predict disease course in patients with neuroendocrine tumors (NET). We investigated 92 putative cancer-related plasma proteins including chromogranin A (CgA) and clinical parameters at the time of diagnosis to identify early factors associated with progressive (PD) or stable disease (SD). Patients with NET grade 1 and 2 of the small intestine (siNET) and pancreas (pNET) were included in this prospective study. Blood samples were obtained at the time of diagnosis before tumor-related therapy was initiated. During 3 years of follow-up, SD or PD was determined according to current clinical practice by each investigator. Association rule mining (ARM) was used to identify combinations of biomarkers and clinical parameters associated with SD or PD. Altogether, 115 patients with siNET and 30 with pNET with complete clinical and biomarker data were included in the analysis representing 3 years of follow-up. Several novel plasma proteins and clinical factors were associated with either PD or SD. In siNET, CgA (>4 upper limits of normal [ULN]) was the most frequent biomarker associated with PD. Females, in contrast to males, with CgA >4 ULN showed a high risk of progression (PPV 100%, NPV 63%). In the siNET cohort, Carboxypeptidase E (CPE) was a discriminating factor between SD and PD. CPE <3.03 was associated with SD, whereas CPE >3.14 was associated with PD (p = 0.003). In the pNET cohort, among clinical variables, only the presence of liver metastasis was associated with PD. CgA was not among the top biomarkers associated with PD. Several parameters, both clinical and biomarker data, as well as combinations of these, were associated with PD or SD 3 years after diagnosis. We identified novel biomarkers improving the association with PD or SD. [Correction added on 28 August 2025, after first online publication: Abstract has been updated.]

Neuroendocrine tumours (NET) constitute a heterogenous population of malignancies most often originating from the gastrointestinal tract. NETs cause substantial morbidity, both from local growth and from their ability to produce hormones that affect systemic physiology. About 20% of patients with metastatic NET disease and carcinoid syndrome develop carcinoid heart disease, a condition dominated by primarily right-sided heart failure caused by structural deterioration of the tricuspid and pulmonary valves. Ultimately, valve replacement may be indicated and has been shown to reduce heart failure symptoms and increase long-term survival. Bioprostheses are the valves of choice but have been shown to degenerate early in some patients due to chronic tumour-associated hormonal activity. New transcatheter treatment options are emerging, both as valve-in-valve procedures but potentially also as primary interventions, both in the tricuspid and pulmonary valve position.

Background

Pheochromocytoma and paraganglioma are neoplasms originating in the adrenal medulla and extraadrenal paraganglia, respectively. Most cases of metastatic pheochromocytoma and paraganglioma are driven by dysregulation of the hypoxia-inducible factor 2 alpha (HIF-2 alpha) pathway. Belzutifan is a HIF-2 alpha inhibitor that may provide antitumor activity in patients with advanced pheochromocytoma or paraganglioma.

Methods

We conducted a phase 2, international, single-group trial involving 72 participants with locally advanced or metastatic pheochromocytoma or paraganglioma that was not amenable to surgery or curative-intent treatment. Participants received belzutifan at a dose of 120 mg once daily until the occurrence of progression, unacceptable toxic effects, or withdrawal from the trial. The primary end point was confirmed objective response (complete or partial response) as assessed by blinded independent central review. Secondary and other key end points included the duration of response, disease control, progression-free survival as assessed by blinded independent central review, overall survival, safety, and a reduction from baseline in antihypertensive medication.

Results

At a median follow-up of 30.2 months (range, 23.3 to 37.6), the percentage of participants with a confirmed objective response was 26% (95% confidence interval [CI], 17 to 38) and the percentage of participants with disease control was 85% (95% CI, 74 to 92). The median duration of response was 20.4 months (95% CI, 8.3 to not reached), with a median duration of progression-free survival of 22.3 months (95% CI, 13.8 to not reached). Overall survival was 76% at 24 months. Among the 60 participants who were receiving antihypertensive medications, 19 (32%) had a reduction of at least 50% in the total daily dose of at least one antihypertensive medication for at least 6 months after starting treatment with belzutifan. Treatment-related adverse events occurred in 71 participants (99%); anemia of grade 3 was noted in 22% of the participants. Eight participants (11%) had treatment-related serious adverse events.

Conclusions

Belzutifan showed antitumor activity with durable responses in participants with advanced pheochromocytoma or paraganglioma. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; LITESPARK-015 ClinicalTrials.gov number, NCT04924075.)

Neuroendocrine neoplasms (NEN) themselves and also their treatment may cause malnutrition, inducing changes in physiological behaviour and eventually leading to increased rates of morbidity and mortality. Malnutrition is a common, under-recognised and under-treated condition in patients with NEN, and there are limited data available on the role of optimising nutrition in this setting. There are no formal evidence-based European Neuroendocrine Tumor Society (ENETS) guidelines on nutrition evaluation and management in patients with NEN to date. This manuscript was initiated during the 2024 ENETS Advisory Board meeting by using an expert panel consensus methodology and specific structured questions, which were identified and addressed through a structured review of the literature. The manuscript aims to identify the presence of specific nutrient deficits and define unmet needs and controversies regarding nutrition and NEN in a succinct manner, to promote collaborative and multidisciplinary research in the field, and to offer practical guidance in terms of how to assess malnutrition and dietary interventions by means of formulating a structured questionnaire.

Locally advanced neuroendocrine neoplasms (NENs) are defined by extensive local invasion in the absence of distant metastases, although specific definitions may vary among study groups. While most patients with NENs present with localized or metastatic disease, a smaller subset is diagnosed with locally advanced tumors. Management of this subgroup remains particularly challenging, owing to the limited evidence base and lack of consensus regarding optimal therapeutic strategies. This guidance document synthesizes the current evidence and expert knowledge on the management of locally advanced NENs of the small intestine and pancreas, addressing four clinically relevant key questions that aim to inform best practice in these patients.

Several inflammation scores have shown association with survival outcomes for patients with neuroendocrine tumours (NET) treated with peptide receptor radionuclide therapy (PRRT). However, whether these scores add value to established prognostic factors remains unknown. In this retrospective, cohort study of 557 NET patients undergoing PRRT in a tertiary referral centre from 2005 to 2015, we examined inflammatory markers and scores previously associated with cancer outcomes, using Cox proportional hazard models and Akaike's information criterion. Lower albumin (hazard ratio [95% confidence interval], .91 [.87-.95] per unit), as well as higher C-reactive protein (CRP; 1.02 [1.01-1.02]), Glasgow Prognostic Score (GPS; 1 vs. 0: 1.67 [1.14-2.44], 2 vs. 0 3.60 [2.24-5.79]), CRP/albumin ratio (1.84 [1.43-2.37]) and platelet count (Plt) x CRP, but not white blood cell, neutrophil and thrombocyte counts or derived neutrophil to lymphocyte ratio (dNLR), were associated with shorter median overall survival (OS) in an adjusted analysis. The addition of parameters based on albumin and CRP, but not dNLR, to a base model including age, chromogranin A, the cell proliferation marker Ki-67, performance status, tumour site and previous treatments improved the predictive accuracy of the base model. In an exploratory analysis of patients with available erythrocyte sedimentation rate (ESR) and CRP, ESR emerged as the most powerful predictor. When added to a prognostic model for OS in NET patients treated with PRRT, most inflammation scores further improved the model. Albumin was the single marker adding most value to the set of established prognostic markers, whereas dNLR did not seem to improve the model's prognostic ability.

Background

Ectopic Cushing syndrome (ECS), related to neuroendocrine neoplasms (NENs), is a rare condition with high morbidity and mortality. We hypothesised that both the severity of hypercortisolaemia and hypokalaemia correlates with prognosis.

Materials and methods

Fifty-five patients with ECS (37 females), with a mean age of 54 ± 14 (standard deviation) years were identified in our database for further analysis of clinical parameters, biochemical data, symptomatic treatment and outcome.

Results

Twenty-eight patients had bronchial, 16 pancreatic, 4 thymic and 1 a rectal NEN. In six patients, the primary tumour was unknown. The proliferation index, Ki-67, was ≀20% in 31 patients and hypokalaemia correlated negatively with Ki-67 (P = 0.043). Severe hypokalaemia at diagnosis (<2.5 mmol/l) was found in 50% of the patients. Hypokalaemia and high doses of potassium substitution were associated with shorter overall survival (P = 0.009 and P = 0.019, respectively). However, only severe hypercortisolaemia remained an independent negative factor for survival in multivariate analysis (P = 0.042). Potassium substitution was required in 87% of patients and the dose was positively correlated to baseline hormone levels including urinary free cortisol (P < 0.001), s-cortisol (P < 0.001) and adrenocortical hormone (ACTH) (P = 0.016). Steroidogenesis inhibitors (SIs) were used as initial treatment in 46 patients to improve symptoms. However, within 1 month, 17 proceeded to bilateral adrenalectomy and 3 died.

Conclusions

We conclude that only hypercortisolaemia was independently prognostic for shorter survival. Furthermore, we suggest that hypercortisolaemia, especially in combination with severe hypokalaemia (<2.5 mmol/l), indicates an acute life-threatening situation. For these patients, immediate actions should be considered to reduce cortisol levels and bilateral adrenalectomy should be discussed upfront.

Small intestinal neuroendocrine tumors are often diagnosed at an advanced stage, with up to 70% of patients presenting with stage IV disease. While some guidelines recommend prophylactic resection of the primary tumor and mesenteric lymph node metastasis in patients without abdominal symptoms at diagnosis to prevent future abdominal complications, the benefit of this approach remains uncertain.This retrospective cohort study included 44 asymptomatic patients with stage IV small intestinal neuroendocrine tumors treated at Uppsala University Hospital between 2014 and 2019. Additional ten symptomatic patients who underwent at least two computed tomography scans before planned surgery were included in the analysis of mesenteric metastasis volume change and tumor growth rate. The primary outcomes were abdominal symptoms development requiring surgical intervention and the assessment of mesenteric metastasis size progression. During a 10-year follow-up, only four initially asymptomatic patients (9%) developed symptoms leading to surgery. Among all 54 patients, the median volume change in mesenteric metastases was -298 mm3 (IQR: -2,785-1,294), with no significant difference between baseline and most recent scans (P = 0.38). The median interval between scans was 29 months, and the median tumor growth rate was -0.6% per month (IQR: -3.6-1.9%). Similar results were observed in the asymptomatic group. These findings suggest that a non-operative management in stage IV patients without abdominal symptoms is associated with a low incidence of symptom development and limited progression of mesenteric metastases.

Multiple Endocrine Neoplasia type 1 (MEN1) Clinical Practice Guidelines (2012) are predominantly based on expert opinion due to limited available evidence at the time, leaving room for interpretation and variation in practices. Evidence on the natural course of MEN1-related neuroendocrine tumours (NET) and the value of screening programs has increased and new imaging techniques have emerged. The aim of this study is to provide insight in the current practices of screening and surveillance for MEN1-related NETs in ENETS Centers of Excellence (CoEs). A clinical practice questionnaire was distributed among all 65 ENETS CoEs. Response rate was 91% (59/65). In 14% of CoEs <10 patients, in 50% 10-49, in 31% 50-100 and in 3 centres (5%) >100 patients with MEN1 are seen. Practices with regard to screening and surveillance of NETs were markedly heterogeneous. Differences between countries were noted in the use of gut hormones for biochemical screening and the choice for imaging modality for screening/surveillance of pancreatic NETs (PanNETs). Magnetic resonance imaging (MRI) is the preferred modality for screening and surveillance of PanNETs, whereas this is computed tomography (CT) for thoracic NETs. Practices regarding screening for thoracic NETs were more homogeneous among larger volume CoEs, with longer screening intervals. The majority of CoEs tailored the surveillance of small pancreatic and lung NETs to observed growth rate. 68% of CoEs advise patients with clinical MEN1 with negative genetic testing to undergo periodic screening like mutation-positive patients. In conclusion, there is still marked heterogeneity in practice, although there are also common trends. Differences were sometimes associated with volume or country, but often no association was found. This underscores the need for clear and evidence-based practice recommendations.