Tobias Stemann Lau

Typical carcinoids (TC) are neuroendocrine malignancies of the lung with low risk of recurrence and a favorable prognosis. It is unclear whether lymph node status and tumor size affect the recurrence risk. Following radical surgery, current guidelines recommend comprehensive follow‐up including regular computed tomography (CT) imaging. We aimed to estimate the risk of recurrence in curatively treated patients with TC and to discuss the justification of the current comprehensive follow‐up program. We identified all patients diagnosed with TC from 2009 to 2020 at Aarhus University Hospital, Denmark and Copenhagen University Hospital, Rigshospitalet, Denmark. Patients without distant metastases (M0) who underwent radical surgery (R0) were included in the analysis. The risk of recurrence was estimated using the Aalen‐Johansen method treating death as a competing risk. Fine‐Gray models were used to evaluate the effect of lymph node status and tumor size. Three‐hundred and thirty patients were included in the analysis, of whom 40 had lymph node involvement and 290 did not. During a total follow‐up time of 2806 years across all patients, with an individual median of 8.1 years (IQR: 5.9–11.2), 10 patients had recurrence: four in the node‐negative group and six in the node‐positive group. The 10‐year cumulative risk of recurrence for all patients was 3.4% (95% confidence interval (CI): 1.7–6.0), for patients without lymph node involvement 1.6% (95% CI: 0.5–3.8), and for patients with lymph node involvement 15.6% (95% CI: 6.3–28.8). Of the four recurrences in the node‐negative group, one led to re‐resection with curative intent. Patients with TC without lymph node involvement have a very low risk of recurrence. Thus, we recommend tailoring the follow‐up program based on lymph node status, with node‐negative patients being excluded from regular follow‐up programs.

Objective: Carcinoid heart disease (CHD) is a severe fibrotic complication affecting cardiac valves in patients with neuroendocrine neoplasms (NENs). Early detection is crucial to improve prognosis. The value of the recommended screening biomarker, NT-proBNP, is uncertain. Biomarkers reflecting extracellular matrix (ECM) remodeling may capture early fibrogenesis. We aimed to evaluate circulating ECM biomarkers for the detection of CHD and to compare their performance with NT-proBNP. Design and methods: In this cross-sectional study, we prospectively included patients with disseminated small intestinal NENs (siNENs). We performed transthoracic echocardiography (TTE) for CHD diagnosis, and blood samples were analyzed for 10 ECM biomarkers. Biomarker levels were compared between patients with and without CHD, and diagnostic performance was assessed using the area under the receiver operating characteristic (AUROC) curve. Results: Among 98 patients, 16 (16%) had CHD. PRO-C3 levels were significantly elevated in patients with CHD compared with patients without CHD (median: 19.3 ng/mL (IQR: 15.6–24.0) vs 14.3 ng/mL (IQR: 12.4–17.5), P = 0.002). The AUROC curve of PRO-C3 for CHD detection was 0.77 (95% CI: 0.64–0.90). At a cutoff level of 15.4 ng/mL, the sensitivity was 85%, the specificity was 56%, the positive predictive value was 27%, and the negative predictive value was 95%. In the direct comparison between PRO-C3 and NT-proBNP, PRO-C3 did not outperform NT-proBNP (P = 0.09). Conclusion: PRO-C3, reflecting collagen type III formation, demonstrated good performance in CHD detection and may represent a complementary or potentially earlier marker than NT-proBNP. However, the performance of PRO-C3 was insufficient as a stand-alone tool, and further evaluation and exploration of new biomarkers in larger cohorts is required.

Introduction: Decline in kidney function due to renal fibrosis is a potential side effect in patients with neuroendocrine neoplasm (NEN) undergoing Peptide Receptor Radionuclide Therapy (PRRT). We aimed to investigate the potential of circulating fibrosis markers reflecting formation and degradation of collagens in predicting decline in kidney function in NEN-patients undergoing PRRT.Material and methods: We included NEN-patients referred for PRRT treatment. We measured two biomarkers of type III and VI collagen formation, reflecting fibrogenesis (PRO-C3 and PRO-C6), and a degradation biomarker of type III collagen, reflecting fibrolysis (C3M) in serum and urine before initiation of PRRT and after each treatment. A kidney function test was performed before initiation of PRRT and three months after end of treatment (EOT) and when possible 6, 12, 18, and 24 months after EOT. We performed a linear mixed model to evaluate differences in the levels of fibrosis markers between patients who declined in kidney function vs patients who did not.Results: Fourteen patients (57% men and median age 67 years (IQR: 61-75)), completed PRRT treatment with at least one kidney function test following EOT. Median time from EOT to last kidney function test was 12 months (IQR: 12-21). Six patients (43%) experienced a more than 25% decline in kidney function from baseline to last kidney function test. For urinary (u) C3M, the overall linear mixed model was marginally significant (p = 0.078). Specifically, after the first treatment (74 ng/mg (95% CI: 49-113) vs 135 ng/mg (95% CI: 93-194)) and three months after EOT (56 ng/mg (95% CI: 37-86) vs 118 (95% CI: 81-173)), levels of uC3M were significantly lower in patients who subsequently had decline in kidney function.Conclusion: At specific time points, levels of uC3M significantly differed in patients who subsequently declined in kidney function. From these exploratory results, we believe that uC3M holds the potential as a prognostic biomarker, and we suggest that this should be further investigated in larger studies to draw firm conclusions about the usefulness.

Carcinoid heart disease (CHD) is a serious complication for patients with neuroendocrine tumors (NETs), and early detection is crucial. We aimed to investigate N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), chromogranin A (CgA), and plasma 5‐hydroxyindoleacetic acid (P‐5‐HIAA) as a screening tool for detection of CHD. We prospectively included patients with disseminated small intestinal NETs (SI‐NETs) and performed transthoracic echocardiography (TTE), questionnaires, and biochemical assessment of NT‐proBNP, CgA, and P‐5‐HIAA. The presence and severity of CHD was assessed using a scoring system based on echocardiographic characteristics. A total of 93 patients were included in the final analysis. Fifteen (16%) were diagnosed with CHD. The median NT‐proBNP (219 ng/L vs. 124 ng/L, p = .05), CgA (3930 pmol/L vs. 256 pmoL/L, p < .0001), and P‐5‐HIAA (1160 nmol/L vs. 210 nmoL/L, p < .0001) were significantly higher in patients with CHD compared to non‐CHD patients. For NT‐proBNP, the area under the receiver operating characteristic (AUROC) curve for detection of CHD was 0.67 (95% CI: 0.50–0.84), and at a 260 ng/L cutoff level, the sensitivity and specificity were 46% and 79%. For CgA, the AUROC was 0.91 (95% CI: 0.84–0.97), and at a cutoff level of 598 pmol/L, the sensitivity and specificity were 100% and 69%. For P‐5‐HIAA, the AUROC was 0.89 (95% CI: 0.80–0.98), and at a cutoff level of 752 nmol/L, the sensitivity and specificity were 92% and 85%. In conclusion, CgA and P‐5‐HIAA proved excellent markers of CHD while NT‐proBNP lacked the required diagnostic accuracy to be used as a screening tool.

Introduction: The macrophage activation marker soluble (s)CD163 is associated with disease severity and prognosis in patients with primary biliary cholangitis (PBC). Ursodeoxycholic acid (UDCA) treatment attenuates fibrosis progression in PBC patients, but its effect on macrophage activation is unclear. We examined the effect of UDCA on macrophage activation, as determined by sCD163 levels. Methods: We included 2 cohorts of PBC patients; 1 cohort with prevalent PBC patients, and 1 cohort of incident PBC patients before start of UDCA treatment and with follow-up after 4 weeks and 6 months. We measured sCD163 and liver stiffness in both cohorts. Further, we measured sCD163 and TNF-α shedding in vitro in monocyte-derived macrophages after UDCA and lipopolysaccharide incubation. Results: We included 100 patients with prevalent PBC [93% women, median age 63 y (interquartile range: 51–70)] and 47 patients with incident PBC [77% women, median age 60 y (49–67)]. Prevalent PBC patients had a lower median sCD163 of 3.54 mg/L (2.77–4.72) than incident PBC patients with a median sCD163 of 4.33 mg/L (2.83–5.99) at inclusion. Patients with an incomplete response to UDCA and patients with cirrhosis had higher sCD163 than responders to UDCA and noncirrhosis patients. After 4 weeks and 6 months of UDCA treatment median sCD163 decreased by 4.6% and 9.0%, respectively. In in vitro experiments, UDCA attenuated shedding of TNF-α, but not sCD163, from monocyte-derived macrophages. Conclusion: In PBC patients, sCD163 levels correlated with liver disease severity and treatment response to UDCA. Further, after 6 months of UDCA treatment, we observed a decrease in sCD163, which may be related to the treatment. Export

Peptide receptor radionuclide therapy (PRRT) is a treatment for neuroendocrine tumours (NET). Renal impairment is a known side effect due to kidney fibrosis. We investigated the association between novel specific fibrosis markers and kidney function following PRRT. We included 38 patients who had all finished PRRT. In serum and urine, we analysed levels of three different fibrosis markers, PRO-C6 (type VI collagen formation), PRO-C3 (type III collagen formation) and C3M (type III collagen degradation). We determined kidney function by the ⁵¹Cr-EDTA plasma clearance. We used Wilcoxon rank sum test and Spearman’s rank correlation to evaluate the association between the fibrosis markers and kidney function. We included 38 NET patients, 25 small-intestinal NET, 6 pancreatic NET, 2 pulmonary NET and 5 other types of NET. Median age was 69 years (IQR: 61–73). Median time from last PRRT to inclusion was 8 months (IQR: 3–20). We found significantly increased levels of serum PRO-C6 (p = .007) and urinary PRO-C6 (p = .033) and significantly decreased levels of urinary C3M (p = .035) in patients with impaired kidney function. Further, we observed a negative association between serum PRO-C6 and kidney function (rho = −0.33, p = .04) and a positive association between urinary C3M and kidney function (rho = 0.37, p = .02). We showed an association between the three fibrosis markers, serum PRO-C6, urinary PRO-C6 and urinary C3M and kidney function. These markers may help to improve the understanding of potential pathological tissue turnover and potentially improve monitoring of kidney function after PRRT in NET patients.