Effects of Peptide Receptor Radiotherapy in Patients with Advanced Paraganglioma and Pheochromocytoma: A Nation-Wide Cohort Study.

INTRODUCTION: Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic ganglia. Management of disseminated or metastatic pheochromocytomas and paragangliomas continues to pose challenges and relies on limited evidence. METHOD: In this study, we report retrospective data on median overall survival (OS) and median progression-free survival (PFS) for all Danish patients treated with peptide receptor radionuclide therapy (PRRT) with 177Lu-Dotatate or 90Y-Dotatate over the past 15 years. One standard treatment of PRRT consisted of 4 consecutive cycles with 8-14-week intervals. RESULTS: We included 28 patients; 10 were diagnosed with pheochromocytoma and 18 with paraganglioma. Median age at first PRRT was 47 (IQR 15-76) years. The median follow-up time was 31 (IQR 17-37) months. Eight patients died during follow-up. Median OS was 72 months, and 5-year survival was 65% with no difference between pheochromocytoma and paraganglioma. Patients with germline mutations had better survival than patients without mutations (p = 0.041). Median PFS after the first cycle of PRRT was 30 months. For patients who previously received systemic treatment, the median PFS was 19 months, compared with 32 months for patients with no previous systemic treatment (p = 0.083). CONCLUSIONS: The median OS of around 6 years and median PFS of around 2.5 years found in this study are comparable to those reported in previous studies employing PRRT. Based on historical data, the efficacy of PRRT may be superior to 131I-MIBG therapy, and targeted therapy with sunitinib and PRRT might therefore be considered as first-line treatment in this patient group.

Dosimetry and pharmacokinetics of [177Lu]Lu-satoreotide tetraxetan in patients with progressive neuroendocrine tumours.

PURPOSE: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). METHODS: This study was part of a phase I/II trial of [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients. RESULTS: In all evaluated organs, maximum [177Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [177Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [177Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles. CONCLUSION: [177Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy. TRIAL REGISTRATION: NCT02592707. Registered October 30, 2015.

High-dose oral thiamine versus placebo for chronic fatigue in patients with primary biliary cholangitis: A crossover randomized clinical trial.

BACKGROUND & AIMS: Fatigue has high negative impact on many patients with primary biliary cholangitis (PBC) and treatment options are limited. Recently we showed favorable effects of four weeks of high-dose thiamine treatment on fatigue in patients with inflammatory bowel disease. We aimed to investigate the effect and safety of high-dose (600-1800 mg daily) oral thiamine treatment on chronic fatigue in patients with PBC. METHODS: Randomized, double-blinded, placebo-controlled crossover trial including patients with severe PBC-related fatigue. Participants were allocated 1:1 to either group 1) 4 weeks of high-dose thiamine, 4 weeks of washout, and 4 weeks of placebo; or group 2) 4 weeks of placebo, washout, and high-dose thiamine, respectively. Fatigue severity was quantified using the fatigue subscale of the PBC-40 questionnaire. The primary outcome was a fatigue reduction of ≥ 5 points after 4 weeks of high-dose thiamine treatment. RESULTS: We enrolled 36 patients; 34 completed the study. The overall mean reduction in fatigue was 5.0 points (95% CI: 2.5 to 7.5; p < 0.001) for the combined group 1 and group 2. Crossover analysis showed a mean increase in fatigue of 0.3 points (95% CI: -4.2 to 3.8) after high-dose thiamine treatment compared to a 1.4 points (95% CI: 6.2 to -3.4) mean reduction after placebo (p = 0.55). Only mild and transient adverse events were recorded. CONCLUSION: Four weeks of high-dose oral thiamine treatment in patients with PBC was well tolerated and safe. However, high-dose thiamine was not superior to placebo in reducing PBC-related fatigue. TRIAL REGISTRATION: The trial was registered in the ClinicalTrials.gov (NCT04893993) and EudraCT (2020-004935-26).

Societal costs and survival of patients with biopsy-verified non-alcoholic steatohepatitis: Danish nationwide register-based study.

INTRODUCTION AND OBJECTIVES: Studies on the societal burden of patients with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD) are sparse. This study examined this question, comparing NAFLD with matched reference groups. MATERIALS AND METHODS: Nationwide Danish healthcare registers were used to include all patients (≥18 years) diagnosed with biopsy-verified NAFLD (1997-2021). Patients were classified as having simple steatosis or non-alcoholic steatohepatitis (NASH) with or without cirrhosis, and all matched with liver-disease free reference groups. Healthcare costs and labour market outcomes were compared from 5 years before to 11 years after diagnosis. Patients were followed for 25 years to analyse risk of disability insurance and death. RESULTS: 3,712 patients with biopsy-verified NASH (n = 1,030), simple steatosis (n = 1,540) or cirrhosis (n = 1,142) were identified. The average total costs in the year leading up to diagnosis was 4.1-fold higher for NASH patients than the reference group (EUR 6,318), 6.2-fold higher for cirrhosis patients and 3.1-fold higher for simple steatosis patients. In NASH, outpatient hospital contacts were responsible for 49 % of the excess costs (EUR 3,121). NASH patients had statistically significantly lower income than their reference group as early as five years before diagnosis until nine years after diagnosis, and markedly higher risk of becoming disability insurance recipients (HR: 4.37; 95 % CI: 3.17-6.02) and of death (HR: 2.42; 95 % CI: 1.80-3.25). CONCLUSIONS: NASH, simple steatosis and cirrhosis are all associated with substantial costs for the individual and the society with excess healthcare costs and poorer labour market outcomes.

A phase I/II study of the safety and efficacy of [177Lu]Lu-satoreotide tetraxetan in advanced somatostatin receptor-positive neuroendocrine tumours.

PURPOSE: We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [177Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity. METHODS: This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [177Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [177Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 µg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow. RESULTS: Median cumulative administered activity of [177Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment­related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3-99.4), and overall response rate was 21.1% (95% CI: 9.6-37.3). CONCLUSION: [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02592707. Registered October 30, 2015.

The role of N-terminal pro-brain natriuretic peptide, chromogranin A, and 5-hydroxyindoleacetic acid in screening for carcinoid heart disease.

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.

A nationwide study of autoimmune liver diseases in the Faroe Islands: Incidence, prevalence, and causes of death 2004 - 2021.

Background and aims: Autoimmune liver diseases are rare diseases, and population-based studies on the epidemiology of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are sparse. We aimed to assess the incidence of AIH, PBC, and PSC in the Faroe Islands.Methods: All cases of AIH, PBC, and PSC diagnosed in the Faroe Islands between January 1st, 2004, and December 31st, 2021, were included in this nationwide registry-based cohort study. In addition, we searched all medical records to assess diagnostic criteria and cause of death.Results: The incidences of AIH, PBC, and PSC in the Faroe Islands were 5.2, 2.5 and 0.7 per 100,000 population per year, respectively. Point prevalence per 100,000 population on December 31st 2021, was 71.8 for AIH, 38.5 for PBC, and 11.0 for PSC. Nine AIH patients died after a median of 3 years, three died of hepatocellular carcinoma (HCC), and two died of liver failure. Five PBC patients died after a median of 7 years, one of HCC and one of liver failure. One PSC patient died of cholangiocarcinoma.Conclusion: The incidence and prevalence of AIH, PBC and PSC in the Faroe Islands are among the highest reported in population-based settings.

Nordic 2023 guidelines for the diagnosis and treatment of lung neuroendocrine neoplasms.

Lung neuroendocrine neoplasms (NEN) are a heterogeneous population of neoplasms with different pathology, clinical behavior, and prognosis compared to the more common lung cancers. The diagnostic work-up and treatment of patients with lung- NEN has undergone major recent advances and new methods are currently being introduced into the clinic. These Nordic guidelines summarize and update the Nordic Neuroendocrine Tumor Group's current view on how to diagnose and treat lung NEN-patients and are meant to be useful in the daily practice for clinicians handling these patients. This review reflects our view of the current state of the art of diagnosis and treatment of patients with lung-NEN. Small cell lung carcinoma (SCLC) is not included in these guidelines.

Exercise increases myocardial free fatty acid oxidation in subjects with metabolic dysfunction-associated fatty liver disease.

BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with dyslipidemia and may promote cardiac lipotoxicity. Myocardial free fatty acids (FFA) oxidation (MOFFA) is normal in pre-diabetes, but reduced in heart failure. We hypothesized that during exercise MOFFA, very low-density lipoprotein triglycerides (VLDL-TG) secretion, hepatic FFA utilization, and lactate production differ among obese subjects with and without MAFLD. METHODS: Nine obese subjects with MAFLD and 8 matched subjects without MAFLD (Control) without a history of heart failure and cardiovascular disease were compared before and after 90-min exercise at 50% Peak oxygen consumption. Basal and exercise induced cardiac and hepatic FFA oxidation, uptake and re-esterification and VLDL-TG secretion were measured using [11C]palmitate positron-emission tomography and [1-14C]VLDL-TG. RESULTS: In the heart, increased MOFFA was observed after exercise in MAFLD, whereas MOFFA decreased in Control (basal vs exercise, MAFLD: 4.1 (0.8) vs 4.8 (0.8) µmol·100 ml-1 min-1; Control: 4.9 (1.8) vs 4.0 (1.1); µmol·100 ml-1 min-1, mean (SD), p < 0.048). Hepatic FFA fluxes were significantly lower in MAFLD than Control and increased ≈ two-fold in both groups. VLDL-TG secretion was 50% greater in MAFLD at rest and similarly suppressed during exercise. Plasma lactate increased significantly less in MAFLD than Control during exercise. CONCLUSIONS: Using robust tracer-techniques we found that obese subjects with MAFLD do not downregulate MOFFA during exercise compared to Control, possibly due to diminished lactate supply. Hepatic FFA fluxes are significantly lower in MAFLD than Control, but increase similarly with exercise. VLDL-TG export remains greater in MAFLD compared to Control. Basal and post-exercise myocardial and hepatic FFA, VLDL-TG and lactate metabolism is abnormal in subjects with MAFLD compared to Control.

The association between soluble CD163, disease severity, and ursodiol treatment in patients with primary biliary cholangitis.

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.

The Prevalence of Inflammatory Bowel Disease in Greenland.

BACKGROUND: Inflammatory bowel disease (IBD) is sparsely investigated in Arctic populations. The aim of this study was to estimate the prevalence of ulcerative colitis (UC) and Crohn's disease (CD) in Greenland. METHODS: Cross-sectional nationwide data on demography, anthropometry, biochemistry, and pharmacotherapy were extracted from the electronic medical records in Greenland. Diagnoses of UC and CD were based on International Classification of Diseases-Tenth Revision and International Classification of Primary Care-Second Edition coding and treatment with mesalazine. Data from Statistics Greenland were used for prevalence calculations. RESULTS: In total, 254 patients in Greenland experienced IBD, with 214 cases of UC and 40 cases of CD. The overall IBD prevalence was 0.45%, distributed as 0.38% with UC and 0.07% with CD. The IBD prevalence was similar across the 5 regions of Greenland. However, a higher prevalence was observed in the region main towns with the largest populations (0.53%) compared with the small towns along the coastline (0.29%). UC patients were prescribed mesalazine treatment with a frequency of 78%. Furthermore, 10% of all IBD patients received treatment with nonspecific immunomodulators and 7% received biologics. CONCLUSIONS: This study estimates the prevalence and uncovers characteristics of IBD in Greenland. Although CD may be underdiagnosed or less prevalent, the overall prevalence of IBD in Greenland parallels Scandinavian countries and North America. These results boost the knowledge on autoimmune diseases in arctic populations and may guide clinicians in their management of IBD in Greenland. Furthermore, the results may encourage research in IBD across the Arctic regions.

The burden of inflammatory bowel disease has never been investigated in Greenland. This nationwide, cross-sectional, register-based study estimates the prevalence of ulcerative colitis and Crohn's disease in Greenland and reports that the overall prevalence of inflammatory bowel disease in Greenland parallels Western countries.

Fatigue and quality of life in patients with neuroendocrine neoplasia.

INTRODUCTION: Neuroendocrine Neoplasms (NEN) are rare tumours arising in the gastro-intestinal tract or lungs. Poor health related quality of life (HRQoL) is associated with the carcinoid syndrome (CS), but fatigue is also important. We aimed to quantify HRQoL and fatigue in out-patients with NEN. METHODS: In a cross-sectional study, we included 231 patients with NEN (G1-G3). We used pre-validated questionnaires MFI-20, EQ-5D-5L and 85% responded. We collected clinical, biochemical, imaging, and pathology data from Electronic Patient files. Normative values for fatigue and HRQoL were derived from background populations. RESULTS: Median age was 68 years (range 21-91) and 52% were male. Patients with NEN reported more fatigue and worse HRQoL compared to the background population (p < .05). Cured patients reported higher HRQoL than patients with current disease, and patients with high grade neoplasms (G2-G3) reported more anxiety and depression compared to patients with low grade G1 disease (p < .05). The CS resulted in a 9% relative loss in Quality Adjusted Life Years compared to patients without CS. (p < .05). More than 50% of patients with CS reported problems with usual activities, pain/discomfort, and anxiety/depression. Overall, 36% of patients with NEN were fatigued and 92% of these had psychological fatigue. Younger patients (<65 years) experienced more fatigue than older patients (p < .05). CONCLUSION: Patients with NEN report significantly lower HRQoL and more fatigue compared to the background population. Especially, patients with CS had pain, discomfort, anxiety, and depression and a relative reduction in HRQoL. However, compared to other cancer types, patients with NEN experience less fatigue.

Spotlight on liver macrophages for halting injury and progression in nonalcoholic fatty liver disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of the metabolic syndrome and is rapidly emerging as the leading cause of liver-related morbidity and mortality. Macrophages play an essential role in the development and progression of NAFLD. AREAS COVERED: In this review, we provide an update on recent studies of drugs, which directly or indirectly affect macrophages in NAFLD, and discuss the implication of macrophage biomarkers to monitor the disease stage and progression/regression. EXPERT OPINION: There is an unmet need for a better understanding of disease pathogenesis from hepatic fat accumulation to disease progression with inflammation and fibrosis. We expect that future research will uncover additional objects/pathways as treatment targets. We speculate that this will involve better characterization of the gut microbiome, damage-associated molecular patterns (DAMPS) or molecules and pathways involved in the development of DAMPS, and advanced molecular biology studies including single-cell sequencing of macrophage subpopulations. In addition, we speculate that studies focusing on pharmaceuticals that improve insulin resistance, diminish the metabolic syndrome, and reduce fibrosis will prevail.

Highly Increased Levels of Inter-α-inhibitor Heavy Chain 4 (ITIH4) in Autoimmune Cholestatic Liver Diseases.

Background and Aims: There is an unmet need for new biomarkers to improve diagnostics and prognostics in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Inter-α-inhibitor heavy chain 4 (ITIH4) is an abundant, liver-produced protein, and its synthesis may be altered in liver diseases. We investigated whether ITIH4 plasma concentrations were affected in PBC and PSC patients. Methods: We developed an immunoassay specific for ITIH4 and determined ITIH4 plasma concentrations in 66 PBC, 126 PSC, 92 autoimmune hepatitis (AIH), 67 chronic hepatitis C (CHC), 33 alcoholic hepatitis (AH) patients and 138 healthy controls (HCs). Hepatic ITIH4 expression was investigated by immunohistochemistry in PBC. Results: The mean plasma concentration of ITIH4 was almost doubled in PBC [409 µg/mL (95% CI: 388-431)] and 35% higher in PSC [308 µg/mL, (95% CI: 296-319)] compared with HCs [226 µg/mL (95% CI: 221-231); p<0.001]. In PBC patients, ITIH4 correlated with IgM (rho=0.49, p<0.001). Responders to ursodeoxycholic acid treatment (UDCA) had lower levels of ITIH4 than incomplete responders [395 µg/mL (95% CI: 364-425)] vs. 460 µg/mL (95% CI: 421-498); p=0.02]. Four weeks of UDCA treatment had no effect (p=0.19). Increased ITIH4 immunohistochemical staining was seen in a liver biopsy from a PBC patient. ITIH4 levels in AIH [224 µg/mL (95% CI: 208-241)] and HCs were similar (p=0.8). ITIH4 levels were lower in AH [199 µg/mL (95% CI: 175-223)] and CHC [202 µg/mL (192-212)] patients than in HCs (p<0.05). Conclusions: The plasma concentration of ITIH4 was highly elevated in patients with PBC and PSC, suggesting that ITIH4 should be further investigated as a biomarker in cholestatic liver disease.

Management of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease in the world, affecting 25% of the population. Around 6% of people with NAFLD will be at risk of developing advanced fibrosis, but symptoms often first occur very late from a decompensated cirrhosis. We need better referral pathways to identify and treat patients with advanced fibrosis. Non-invasive tests such as FIB-4 and NFS can be used in primary care to identify patients who will benefit from a referral to secondary care.

Association between fibrosis markers and kidney function following peptide receptor radionuclide therapy in patients with neuroendocrine tumours.

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.

Plasma protein biomarkers for the detection of pancreatic neuroendocrine tumors and differentiation from small intestinal neuroendocrine tumors.

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.