Camilla Schalin-Jäntti

Objective: Acromegaly has been associated with increased cardiovascular morbidity, but it is unclear to what extent this holds true in contemporary acromegaly cohorts and when the cardiovascular diseases (CVDs) evolve in relation to the time of diagnosis. Design: Retrospective cohort study. Methods: Cardiovascular morbidity was studied in the Finnish acromegaly cohort (n = 565) and 5629 controls using Kaplan–Meier analysis from 10 years before the diagnosis of acromegaly and continuing up to >30 years after the diagnosis. Hazard ratios for CVD-related hospital visits were calculated with Cox regression analyses in the post-diagnosis period. The effects of received treatments, hypopituitarism, and biochemical control of acromegaly were studied with multivariable analyses among the patients. Results: Cardiovascular morbidity increased years before the diagnosis of acromegaly and remained elevated compared to controls [hazard ratio (HR) 1.59 (95% CI 1.42–1.78)] throughout the follow-up (median 17.2 years, IQR 8.7–26.5 years). The highest increase was observed in diseases of pulmonary arteries [HR 2.74 (1.87-4.02)], valvular diseases and cardiomyopathies [HR 2.68 (2.09-3.44)], and hypertension [HR 2.11 (1.85-2.42)]. Radiotherapy, hypopituitarism, and post-treatment Insulin-Like Growth Factor-1 (IGF-1) above or below the reference range were associated with increased cardiovascular morbidity. Even patients who achieved biochemical remission and normal pituitary function after surgery suffered from increased morbidity compared to controls. Conclusions: Patients with acromegaly are still characterized by increased morbidity across a wide range of CVDs. Cardiovascular morbidity is already present before diagnosis and persists despite acromegaly-specific therapy. This underlines the importance of early diagnostics and CVD prevention for these patients.

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 3.14 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.]

Purpose: In patients with multiple endocrine neoplasia type 1 (MEN1) followed up at ENETS centers of Excellence, chromogranin A (CgA) and pancreatic polypeptide (PP) are widely used screening tools for pancreatic neuroendocrine tumors (panNETs). Previous studies have demonstrated conflicting results regarding their performance in MEN1. This retrospective study aims to bring clarity to the question by investigating a well-characterized MEN1 cohort. We studied the impact of long-term biomarker follow-up on the clinical management of panNETs in MEN1. Methods: We calculated the sensitivity and specificity and performed ROC analysis of CgA and PP for diagnosing any panNET, ≥20 mm panNET, and metastatic panNET in comparison to imaging reference standard in 58 MEN1 patients. All patients had undergone somatostatin receptor PET/CT and conventional imaging. Longitudinal impact of 10-year annual biomarker measurements on real-life clinical management was analyzed from patient records. Results: Sensitivity of CgA (n = 48) and PP (n = 47) for diagnosing any panNET, ≥20 mm panNET, and metastatic panNET was 35%, 30%, and 60 and 23%, 33%, and 0%, respectively. For CgA, the AUC for diagnosing any panNET, ≥20 mm panNET, and metastatic panNET was 0.30 (95% CI 0.09–0.51), 0.49 (95% CI 0.29–0.68), and 0.69 (95% CI 0.42–0.95), respectively. For PP, the AUC for detection of metastatic panNET was 0.28 (95% CI 0.11–0.46). The annual biomarker measurements during 514 patient-years of follow-up did not affect the clinical management of panNETs. Conclusion: CgA and PP are not helpful in diagnosing panNETs in MEN1. It is time to revise the surveillance protocols in practice.

Background: Small intestinal neuroendocrine tumors (SI-NETs) are characterized by carcinoid syndrome and carcinoid heart disease (CHD). The aim of the present study was to identify early risk markers for carcinoid heart disease and survival in a prospective median-term follow-up setting. Methods: We measured 5-HIAA and cumulative 5-HIAA exposure (Cum-5-HIAA) based on repeated measurements, proBNP, vascular function, hepatic tumor load, and transthoracic echocardiography (TTE) at baseline and during the median 5-year follow-up. Of 65 patients with SI-NETs, 54 patients underwent a prospective follow-up. In addition, survival was evaluated during the median follow-up of 6 years. Results: At baseline, three patients had CHD. During the median follow-up of 5 years, two patients (4%) developed CHD. Cum-5-HIAA and proBNP correlated with CHD (Westberg score, Spearman’s ρ = 0.32 and 0.31, respectively). Cum-5-HIAA had a superior diagnostic capability, predicting CHD in receiver operator characteristic analysis with an AUC of 0.98 (95% CI: 0.94–1.00) and outperformed proBNP, chromogranin A (CgA), and individual serum 5-HIAA measurements (AUC = 0.75, 0.85, and 0.91, respectively). Minor changes in valve regurgitation were frequently detected but did not correlate with vascular function. Regurgitation increased or decreased in 29% of tricuspid and 30% of pulmonic valves. CHD, hepatic tumor load, serum 5-HIAA, and elevated aortic pulse wave velocity (PWV) were associated with increased mortality in SI-NET patients. Conclusions: Cum-5-HIAA is a promising biomarker for CHD risk and outperformed other biomarkers. CHD and hepatic tumor load are the strongest predictors of mortality. PWV is a novel predictor of survival. The incidence of CHD was low among the SI-NET patients, probably reflecting successful treatment regimens.

Primary hyperparathyroidism (PHPT) associated with multiple endocrine neoplasia type 1 (MEN1) impairs bone mineral density and causes osteoporosis already in young patients. We aimed to investigate bone mineral density (BMD) in a contemporary cohort of patients with MEN1-related PHPT after long-term follow-up and compare these results with that of healthy controls. Thirty-five patients with genetically confirmed MEN1 were diagnosed with MEN1 at mean age 28.7 ± 13.6 years. Thirty-two (91.4%) underwent primary parathyroidectomy at mean age 33.3 ± 13.7 years; 12 had undergone at least 2 surgeries with on average 7.3 ± 5.9 years between the operations. BMD was assessed by DXA at the end of mean follow-up, 13.2 years after the primary parathyroidectomy and compared with that of 35 age- and gender-matched controls. More than 10 years after the first parathyroidectomy, mean BMD in patients with MEN1 is in the normal range. However, it is still significantly lower compared with healthy controls.

Background Small intestinal neuroendocrine tumors (SI-NETs) are characterized by carcinoid syndrome and carcinoid heart disease (CHD). The aim of study was to identify early risk markers for carcinoid heart disease and survival in a prospective median-term follow-up setting. Methods We measured 5-HIAA, cumulative 5-HIAA exposure (Cum-5-HIAA) based on repeat measurements, proBNP, vascular function, hepatic tumor load and transthoracic echocardiography (TTE) were assessed at baseline and during median 5-year follow-up. Of 65 patients with SI-NETs; 54 patients underwent prospective follow-up. In addition, survival was evaluated during median follow-up of 6 years. Results At baseline three patients had CHD. During median follow-up of 5 years, two patients (4%) developed CHD. Cum-5-HIAA and proBNP correlated with CHD (Westberg Score, Spearman’s ρ = 0.32 and 0.31, respectively). Cum-5-HIAA had a superior diagnostic capability, predicting CHD in receiver operator characteristics analysis with AUC of 0.98 (95% CI: 0.94–1.00) and outperformed proBNP, chromogranin A (CgA), as well as individual serum 5-HIAA measurements (AUC = 0.75, 0.85, and 0.91, respectively). Minor changes in valve regurgitation were frequently detected but did not correlate with vascular function. In 29% of tricuspid and 30% of pulmonic valves regurgitation increased or decreased. CHD, hepatic tumor load, serum 5-HIAA, and elevated aortic pulse wave velocity (PWV) associated with increased mortality in SI-NET patients. Conclusions Cum-5-HIAA is a promising biomarker for CHD risk and outperformed other biomarkers. CHD and hepatic tumor load are strongest predictors of mortality. PWV is a novel predictor of survival. The incidence of CHD was small among the SI-NET patients, probably reflecting successful treatment regimens.