Urinary 5-HIAA Research Articles

Fibroblast activation in cardio-oncology

Abstract Introduction Carcinoid heart disease is a rare disease affecting the right sided heart valves (1) while anthracycline cardiotoxicity is a dreaded sequelae of a common chemotherapeutic agent that can occur early or even years after exposure (2). Activated fibroblasts, a key factor in these diseases, can be imaged with 68Gallium-fibroblast activation protein inhibitor (68Ga-FAPI). Method 12 patients with carcinoid syndrome, 12 patients with previous anthracycline exposure and 10 healthy volunteers underwent hybrid 68Ga-FAPI positron emission tomography and magnetic resonance imaging. Areas of fibroblast activation were quantified as mean and maximum target-to-background ratios (TBRmean and TBRmax). Results Carcinoid syndrome: 2 of the 12 patients had carcinoid heart disease [mean age 70, 50% female] (CHD) (Figure 1A). 68Ga-FAPI uptake was seen in the liver lesions of all patients with known carcinoid liver tumours. Of the 10 patients without cardiac involvement, 6 had significant tricuspid valve 68Ga-FAPI uptake (CHD- FAPI+) (Figure 1B) and 4 did not (CHD- FAPI-). Median tricuspid TBRmax was significantly higher in CHD + [2.38 (IQR 2.35-2.42)], than CHD- patients [CHD- FAPI+: 1.68 (IQR 1.65-1.73), CHD- FAPI-: 1.55 (IQR 1.53-1.65)], although this was higher than healthy volunteers [1.45 (IQR 1.43- 1.61; p<0.05). CHD- FAPI+ patients had significantly elevated urinary 5-HIAA levels compared to CHD- FAPI- patients [Median =188 mg/24hr (IQR 151-196) in CHD- FAPI+ vs 32mg/24hr ( IQR 12-73); p=0.03]. Anthracycline chemotherapy: 3 of the 12 patients had cardiotoxicity [mean age 61, 67% female]. Anthracycline patients had higher left ventricular myocardial 68Ga-FAPI uptake than healthy volunteers with cardiotoxicity patients having the highest. [TBRmean: Cardiotoxicity 1.46 (IQR 1.36- 1.53), No cardiotoxicity 1.37 (IQR 1.19- 1.49), Healthy volunteers 0.73 (IQR 0.66 - 0.81); p<0.01 (Figure 1E). Across the cohort a moderate negative correlation was observed between Left ventricular ejection fraction and 68Ga-FAPI activity (LV TBRmean r =-0.46 and TBRmax (r= -0.66) Discussion 68 Ga-FAPI provides us the ability to assess fibroblast activation and for the first time demonstrated the key role of these cells in both these cardio-oncology conditions. Increased fibroblast activation is observed around the tricuspid valve in patients with carcinoid syndrome both in those with and without overt clinical disease. Similarly increased myocardial fibroblast activation is observed in patients exposed to anthracyclines even many years after exposure and where there is no overt evidence of cardiotoxicity. Conclusion 68Ga-FAPI imaging holds promise in evaluating the role of activated fibroblasts in the pathology of both carcinoid heart disease and cardiotoxicity, providing information beyond the current resolution of current clinical approaches.

Laccase mimetics as sensing elements for amperometric assay of 5-hydroxyindoleacetic acid in urine

Monitoring of the levels of 5-hydroxyindole-3-acetic acid (5-HIAA) is of significant importance for diagnostics of carcinoid tumors. We propose simple catalytic electrochemical sensors for the determination of 5-HIAA in urine using laccase and its mimetics. Laccase-like nanozymes (LacNZs) were synthesized via a chemical reduction, and resulting PtMn and MnO2 nanoflowers (NFs) demonstrated laccase-like activity similar to the laccase from the Trametes zonata. In addition, these LacNZs showed enhanced stability under a wide range of pH (3.0–7.5), temperatures (4–70 °C), and ionic strengths (up to 500 mM NaCl). The developed PtMn NF/graphite electrode, similar to a laccase/graphite electrode, can detect 5-HIAA with a high sensitivity (25 000 ± 12 A·M−1·m−2 and 1900 ± 9 A·M−1·m−2, respectively) and have linear ranges of 0.3 – 15 μM and 2 – 50 μM. The sensors work at low working potentials with a detection limit of 0.16 and 1.4 μM, covering the normal and pathologic ranges of 5-HIAA (1 – 50 μM) content in urine. They have been successfully applied to 5-HIAA assay in urine samples of people with various diseases and revealed good recovery values and reproducibility. Additionally, the LacNZ-sensor has the best stability and can be used up to 20 days.

FMT intervention decreases urine 5-HIAA levels: a randomized double-blind controlled study.

Autism spectrum disorder (ASD) is often linked to gastrointestinal issues and altered serotonin metabolism. Emerging evidence suggests gut microbiota influence both, with fecal microbiota transplantation (FMT) offering a potential therapeutic approach. However, its impact on serotonin metabolism and ASD symptoms is not well understood. In this study, we aimed to evaluate the clinical effects of FMT and examine changes in specific urinary metabolites in children with ASD. A randomized double-blind controlled trial was performed to evaluate the clinical effects of FMT on GI and ASD-related symptoms. Gastrointestinal symptoms were assessed using the Gastrointestinal Symptom Rating Scale (GSRS), and the ASD-related symptoms were assessed using the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), and Social Responsiveness Scale (SRS) scores. Urinary metabolites were analyzed by homogeneous enzyme immunoassay using commercially available kits. Significant improvements in GI and core ASD symptoms were observed following FMT intervention. The average GSRS scores decreased from 30.17 (before) to 19 (after; p < 0.0001), CARS scores decreased from 36.22 to 33.33 (p < 0.0001), SRS scores decreased from 151.17 to 137.5 (p = 0.0002), and the ABC scores decreased 76.39 to 53.17 (p < 0.0001) in the FMT group. However, in the placebo group, GSRS, CARS, and SRS scores showed no significant changes, while ABC scores decreased from 72 to 58.75 (p = 0.034). The FMT group also showed a significant reduction in urinary 5-hydroxyindoleacetic acid (5-HIAA) levels from 8.6 to 7.32 mg/L (p = 0.022), while other metabolites showed no significant changes. FMT is a safe and effective treatment for improving GI and core symptoms in children with ASD, with 5-HIAA showing potential as a urinary biomarker for treatment response.

7242 Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) In A Patient With Recurrent Carcinoid

Abstract Disclosure: F. Woron: None. T.L. Anderson: None. P. Madhavan: None. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare generalized proliferation of pulmonary neuroendocrine cells. It is considered to be a pre-invasive lesion for pulmonary carcinoid, a rare neuroendocrine tumor (NET). DIPNECH is thought to be underdiagnosed, as patients can be asymptomatic or present with nonspecific cough and dyspnea, though it is also associated with fibrotic lung changes. Long-term annual surveillance imaging is recommended for due to the potential for development and metastasis of carcinoid tumors. We present a patient with recurrent pulmonary carcinoid later diagnosed with probable DIPNECH based on CT findings. The patient is a 72-year-old female with a prior 15 pack-year smoking history, who initially had a left lower lobe typical carcinoid tumor diagnosed and resected in 2018, with no evidence of lymph node metastasis. The patient’s medical history also includes pulmonary sarcoidosis, adrenal adenoma, thyroid nodule, hiatal hernia, and prediabetes. She has no family history of neuroendocrine tumors. Physical exam showed stable vitals with blood pressure of 112/70 mmHg in the right upper arm, heart rate of 84 bpm, and a body mass index of 39. Physical exam was unremarkable except for thyroid nodularity and obesity. Extensive biochemical evaluation for markers including chromogranin A and 24-hour urine 5-HIAA levels were within normal limits. In 2022, surveillance CT imaging showed a new 9 mm nodule in the right lobe within the bronchus, which was shown to be carcinoid on FNA. She complained of dyspnea and wheezing at this time, which has been managed with an albuterol inhaler. In 2023, PET/CT copper 64 dotatate scan showed a focal area of activity related to the nodule in the superior segment, also identified on recent CT scan, with the nodule measuring approximately 2.05 cm x 1.8 cm with a maximal SUV of 4.2. Interestingly, somatostatin receptor scintigraphy did not show any pick-up in the lung in 2018 or 2022. In 2023, the patient underwent right lower lobe superior segmentectomy after the nodule was found to have increased in size. Pathology showed G1, well-differentiated 1.1 cm typical carcinoid tumor with margins negative for invasive carcinoma. All 18 regional lymph nodes were negative for tumor. Immunohistochemical tests show that the tumor cells were positive for INSM1 and chromogranin with a low Ki-67 proliferation index (&amp;lt;2%), supporting the diagnosis. The patient is currently being monitored by yearly CT imaging and followed by both endocrinology and pulmonology. Given this case, we propose that DIPNECH should be considered as a differential in cases of pulmonary carcinoid, especially recurrent ones. Given that DIPNECH is thought to be underdiagnosed and a precursor for carcinoid associated with fibrotic lung changes, it is essential for this disease to be identified in order for patients to receive appropriate long-term monitoring. Presentation: 6/1/2024

Regulation of the Metal Center in Lanthanide Nanoparticles to Achieve Multifunctional Sensing.

Development of a multifunctional sensor is highly desirable. In this work, traces of a carcinoid cancer biomarker of 5-hydroxyindole-3-acetic acid (5-HIAA) in real human urine can be detected by lanthanide nanoparticle Eu-CFC (CFC = 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid) and the sensing devices of the test paper and agarose gel, achieving an ultralow LOD of 0.8 × 10-3 ppm within a sensing time of 2.0 min. Interestingly, by metal center regulation of Tb and Eu codoping, nanoparticle TbEu2-CFC shows high-sensitivity and low-LOD (0.019% v/v) sensing of water in ethanol. The sensing mechanisms are revealed by both experiments and quantum chemical studies.

Quantitative Analysis of 5-hydroxyindoleacetic Acid in Rat Urine by High-performance Liquid Chromatography Method

ABSTRACT Background: 5-hydroxyindoleacetic acid (5-HIAA) is a metabolite of serotonin, a neurotransmitter primarily associated with regulating mood, appetite, and sleep. When serotonin is broken down in the body, it forms 5-HIAA, which is then excreted in urine. Quantification of 5-HIAA levels in urine is often used as a diagnostic tool for certain conditions, particularly carcinoid tumors, which can produce excess serotonin. Elevated levels of 5-HIAA in urine can indicate increased serotonin production, which may be indicative of carcinoid tumors or other conditions affecting serotonin metabolism. However, there is limited work on employing high-performance liquid chromatography (HPLC)–ultraviolet to estimate monoamines in biological samples. Aim and Objectives: The present study explores the detection of 5-HIAA in rat urine samples, developing an easy, precise validated HPLC method. Materials and Methods: Mobile phase combination acetonitrile and o-phosphoric acid in the ratio of 30:70% v/v and flow rate 0.5 mL/min was able to separate 5-HIAA distinctly. Results: The detection was observed at λmax 277 nm with better sensitivity. According to the parameters indicated in the international council for harmonisation of technical requirements for pharmaceuticals for human use guidelines (Q2A; Q2B), the procedure was verified. The linearity range was selected from 20 to 45 μg/mL, r 2 = 0.992, limit of detection (4.65 μg/mL), limit of quantification (15.52 μg/mL), retention time (6.3 min). Conclusion: The technique has demonstrated that it is repeatable and recoverable within the given range. Thus can be used for routine analysis of 5-HIAA in urine samples.

The Clinicopathological Significance of Tumor Cell Subtyping in Appendiceal Neuroendocrine Tumors: A Series of 135 Tumors

Appendiceal neuroendocrine tumors (NETs) are common and often are identified as incidental lesions at the time of appendectomy. The guidelines for management are based on tumor size, degree of invasion, and the Ki67 proliferation index. Most small bowel NETs are composed of serotonin-producing EC-cells, but there are multiple other neuroendocrine cell types. In the rectum, there are L-cell tumors that express peptide YY (PYY), glucagon-like peptides (GLPs), and pancreatic polypeptide (PP); they are thought to have a better prognosis than serotonin-producing tumors. We investigated whether the appendix has distinct neuroendocrine tumor types based on cell type and whether that distinction has clinical significance. We collected 135 appendiceal NETs from the pathology archives of UHN Toronto and UHCMC (Cleveland). We analyzed the expression of biomarkers including CDX2, SATB2, PSAP, serotonin, glucagon (that detects GLPs), PYY, and pancreatic polypeptide (PP) and correlated the results with clinicopathologic parameters. Immunohistochemistry identified three types of appendiceal NETs. There were 75 (56%) classified as EC-cell tumors and 37 (27%) classified as L-cell tumors; the remaining 23 (17%) expressed serotonin and one of the L-cell biomarkers and were classified as mixed. EC-cell tumors were significantly larger with more extensive invasion involving the muscularis propria, subserosa, and mesoappendix compared with L-cell tumors. Mixed tumors were intermediate in all of these parameters. Both EC-cell and mixed tumors had lymphatic and/or vascular invasion while L-cell tumors had none. Unlike EC-cell NETs, L-cell tumors were not associated with lymph node metastasis. Tumor type correlated with pT stage and the only patient with distant metastatic disease in this series had an EC-cell tumor. Our study confirms that appendiceal NETs are not a homogeneous tumor population. There are at least three types of appendiceal NET, including EC-cell, L-cell, and mixed tumors. This information is important for surveillance of patients, as monitoring urinary 5HIAA levels is only appropriate for patients with serotonin-producing tumors, whereas measurement of GLPs and/or PP is more appropriate for patients with L-cell tumors. Our data also show that tumor type is of significance with EC-cell tumors exhibiting the most aggressive behavior.

Urine 5-Hydroxyindoleacetic Acid Negatively Correlates with Migraine Occurrence and Characteristics in the Interictal Phase of Episodic Migraine.

Although migraine belongs to the main causes of disability worldwide, the mechanisms of its pathogenesis are poorly known. As migraine diagnosis is based on the subjective assessment of symptoms, there is a need to establish objective auxiliary markers to support clinical diagnosis. Tryptophan (TRP) metabolism has been associated with the pathogenesis of neurological and psychiatric disorders. In the present work, we investigated an association between migraine and the urine concentration of TRP and its metabolites 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QA) in 21 low-frequency episodic migraine patients and 32 controls. We chose the interictal phase as the episodic migraine patients were recruited from the outpatient clinic and had monthly migraine days as low as 1-2 in many cases. Migraine patients displayed lower urinary levels of 5-HIAA (p < 0.01) and KYNA (p < 0.05), but KYN and QA were enhanced, as compared with the controls (p < 0.05 and 0.001, respectively). Consequently, the patients were characterized by different values of the 5-HIAA/TRP, KYN/TRP, KYNA/KYN, and KYNA/QA ratios (p < 0.001 for all). Furthermore, urinary concentration of 5-HIAA was negatively correlated with Migraine Disability Assessment score and monthly migraine and monthly headache days. There was a negative correlation between Patient Health Questionnaire 9 scores assessing depression. In conclusion, the urinary 5-HIAA level may be further explored to assess its suitability as an easy-to-determine marker of migraine.

Optimal follow-up with somatostatin receptor PET/CT imaging in patients with small intestinal neuroendocrine tumours.

Somatostatin receptor positron emission tomography with computerised tomography imaging (SRI) has a high sensitivity for the detection of small intestinal neuroendocrine tumors (siNET), which makes it ideal for follow-up. The aim of the present study was to investigate whether follow-up with SRI in patients with siNET led to any change in the treatment of the patient and if patient and/or tumour factors were associated with such change. Adults with siNET who had undergone at least two SRI scans between 2013 and 2021 were identified. Data on age, sex, comorbidities, tumour stage, grade, and most recent levels of serum Chromogranin A (CgA) and 24-h urine 5-hydroxyindoleacetic acid (5-HIAA) before each SRI scan were obtained. The major change was defined as new treatment previously not received or discontinuation of ongoing treatment. Univariate and multivariate mixed models logistic regression on variables with a presumed biological relationship with major change and with backwards stepwise exclusion of variables with p > .1 was performed. A total of 164 patients with siNET diagnosis had undergone 570 SRI scans. The median follow-up was 3.1 years. Only 82 of 570, 14%, of SRI scans led to a major change in treatment. Female sex, age below 75 years, elevated or missing CgA, elevated or missing urine 5-HIAA, progress on last SRI scan and distant extrahepatic disease were all independently associated with increased odds ratios for major change after follow-up with SRI. A small proportion of SRI scans (14%) led to a major change in treatment. Six independent risk factors with increased odds of major change, all available before each SRI scan, were identified. While validation of these risk factors is needed in a separate cohort, these findings could help clinicians individualise follow-up for siNET patients in the future.

Study on the role of CCM3 gene and lead exposure induced neurotoxicity through neurovascular units

This study aimed to determine the toxic effects of vascular CCM3 gene deficiency and lead (Pb) exposure on the nervous system. Lentiviral transfection was performed to generate a stable strain of brain microvascular endothelial cells with low CCM3 expression. MTT assay assessed the survival rate of cells exposed to Pb, determining the dose and duration of Pb exposure in vitro. Proteomic analysis was performed on the differentially expressed proteins in bEnd3 and HT22 cells and flow cytometry was used to detect cell apoptosis. Finally, urine samples from pregnant and postpartum women were subjected to ICP-MS to detect Pb levels and HPLC to detect neurotransmitter metabolites. Based on the proteomic analysis of bEnd3 (CCM3-/-) cells co-cultured with HT22 cells, it was determined that HT22 cells and CCM3 genes interfered with bEnd3 cell differential proteins,22Abbreviations: SNP, FGF2, EGF, AD including apoptosis and ferroptosis pathways. Electron microscopy observation, ICP-MS iron ion loading detection, and WB determination of protein GPX4 expression confirmed that HT22 cells undergo apoptosis, while bEnd3 cells undergo multiple pathways of iron death and apoptosis regulation. Furthermore, a linear regression model showed the interaction between maternal urine Pb levels, the rs9818496 site of the CCM3 SNP in peripheral blood DNA, and the concentration of the neurotransmitter metabolite 5-HIAA in maternal urine (F=4.198, P < 0.05). bEnd3 cells with CCM3 gene deficiency can induce HT22 cell apoptosis through iron death and apoptosis pathways under Pb exposure in a combined cell culture Pb exposure model, and CCM3 gene deficiency in endothelial cells and Pb exposure interacts with neural cell HT22. Epidemiological studies on maternal and newborn infants further confirmed the interaction between urine Pb levels in mothers and the SNP rs9818496 site of the CCM3 gene in peripheral blood DNA.

Use of perioperative telotristat in a patient with carcinoid heart disease.

Carcinoid heart disease is a rare complication of carcinoid syndrome, resulting in right-sided valvular heart disease and subsequent heart failure due to long-term exposure to vasoactive substances. The management of this condition is complex, often requiring surgical intervention. Current perioperative regimens entail the use of prophylactic somatostatin analogs to prevent carcinoid crisis; however, regimens vary widely among practitioners and evidence supporting their efficacy in this clinical setting is mixed. This case report describes the perioperative management of a 65-year-old man with carcinoid heart disease requiring tricuspid and pulmonary valve replacement surgery. As an adjunct to somatostatin analog therapy, the novel tyrosine hydroxylase inhibitor, telotristat, was initiated preoperatively. This combination resulted in normalization of preoperative urinary 5-HIAA levels. The patient successfully underwent tricuspid and pulmonic valve replacement without evidence of carcinoid crisis. This clinical case is the first published documenting the use of telotristat in the perioperative period in a patient with carcinoid syndrome and carcinoid heart disease and was associated with a good long-term outcome despite the high-risk nature of the case. Carcinoid crisis is a life-threatening complication of carcinoid syndrome, resulting in hemodynamic instability, bronchospasm, and arrhythmia. Cardiac surgical patients with carcinoid syndrome present a unique challenge as they are subject to physiologic conditions and medications which can potentiate intraoperative carcinoid crisis. Perioperative management of patients with carcinoid syndrome currently entails the use of prophylactic somatostatin analogs; however, these agents do not prevent carcinoid crisis in all cases. Telotristat, a tryptophan hydroxylase inhibitor, shows promise as an adjunctive therapy to somatostatin analogs to reduce the risk of intraoperative carcinoid crisis.

Smart dual imprinted Origami 3D-ePAD for selective and simultaneous analysis of vanillylmandelic acid and 5-hydroxyindole-3-acetic acid carcinoid cancer biomarkers using graphene quantum dots coated with dual molecularly imprinted polymers

Measuring the levels of the biomarkers vanillylmandelic acid (VMA) and 5-Hydroxyindole-3-acetic acid (5-HIAA) is a valuable tool for clinical diagnosis not only of neuroblastoma or carcinoid syndrome, but also of essential hypertension, depression, migraine, and Tourette's syndrome. Herein, we explore using graphene quantum dots (GQDs) coated with molecularly imprinted polymer (MIP) as novel dual-imprinted sensors for selective and simultaneous determination of VMA and 5-HIAA in urine and plasma samples. The dual-MIP was successfully coated on the GQDs core via co-polymerization of (3-aminopropyl) triethoxysilane (APTES) and tetraethyl orthosilicate (TEOS), acting as functional and cross-linking monomers, respectively. In addition, we successfully created the dual imprinted VMA and 5-HIAA shell on the GQDs' core via a one-pot synthesis. We fabricated a facile and ready-to-use Origami three-dimensional electrochemical paper-based analytical device (Origami 3D-ePAD) for simultaneous determination of VMA and 5-HIAA using a GQDs@dual-MIP modified graphene electrode (GQDs@dual-MIP/SPGE). The Origami 3D-ePAD was designed to form a voltammetric cell on a three-layer foldable sheet with several advantages. For example, they were quickly assembled and enhanced the device's physical durability with the hydrophobic backup sheet. The developed dual imprinted Origami 3D-ePAD leads to substantially enhanced sensitivity and selectivity to electrochemical signal amplification generated from increasing the electrode-specific surface area, electrocatalytic activity, and the large numbers of dual imprinted sites for VMA and 5-HIAA detection. The synthetic recognition sites are highly selective for 5-HIAA and VMA molecules with an imprinting factor of 8.46 and 7.10, respectively. Quantitative analysis relying on square wave voltammetry reveals excellent linear dynamic ranges of around 0.001–25 μM, with detection limits of 0.023 nM for 5-HIAA and 0.047 nM for VMA (3Sb, n = 3). The Origami 3D-ePAD provides high accuracy and precision (i.e., recovery values of 5-HIAA ranged from 82.98 to 98.40 %, and VMA ranged from 83.28 to 104.39 %), and RSD less than 4.37 %) in urine and plasma samples without any evidence of interference. Hence, it is well suited as a facile and ready-to-use disposable device for point-of-care testing. It is straightforward, cost-effective, reproducible, and stable. Furthermore, it allows for rapid analysis (analysis time ∼20s) useful in medical diagnosis and other relevant fields.

Abstract 12851: Severe Right and Left-Sided Multi-Valvular Carcinoid Heart Disease Associated With Ovarian Carcinoid Tumor

Carcinoid tumors are neuroendocrine neoplasms that secrete vasoactive substances, primarily serotonin, and have an incidence of approximately 2 in 100,000 people. Up to 60% of carcinoid tumors result in carcinoid heart disease (CHD), and unlike other carcinoid tumors, ovarian carcinoid tumors can involve the heart without liver metastasis. By bypassing the liver, ovarian carcinoid tumors can result in CHD in the absence of liver metastasis. We present a rare case of a 40-year-old female who presented in cardiogenic shock requiring inotropic support with echocardiographic evidence of preserved left ventricular systolic function (LVEF 50-55%) and multiple retracted leaflets that exhibited poor coaptation resulting in severe mitral regurgitation, torrential tricuspid regurgitation, and moderate-to-severe aortic regurgitation. Her left heart catheterization revealed non-obstructive coronary artery disease. A non-contrast CT torso revealed an isolated large septated left ovarian cystic mass (7.1x5.2 x7.1cm) without any other mass or lesion. In the setting of an elevated CA-125 (536units/mL, normal 0-35units/mL) and 24-hour urinary 5-HIAA (12.1mg, normal 2-9mg) with a normal CEA, CHD was suspected as the most likely diagnosis given the isolated ovarian mass and severe valvular disease. She underwent triple valve surgery in which valvular pathology revealed myxoid degeneration. Her post-operative course was complicated by multi-organ failure requiring multiple inotropes and V-A ECMO shortly thereafter, but the patient unfortunately passed away. While there are a few documented cases of CHD from ovarian carcinoid (less than 0.5% of cases) and left-sided CHD (less than 10% of cases), this is the first documented case, to our knowledge, describing severe right and left-sided CHD associated with a suspected ovarian carcinoid tumor.

SAT610 Multiple Endocrine Neoplasia Type 1 - The First Reported Case In An Indigenous Australian

Abstract Disclosure: E. Mignone: None. K. Neal: None. Background: Multiple Endocrine Neoplasia type 1 (MEN1) is a rare and under recognised syndrome. It has not been previously reported in Indigenous Australians for this reason. Clinical Case: A 48-year-old Indigenous Australian female was consulted on by an inpatient endocrine team in March 2020 for persistent hypercalcaemia on a background of a parathyroidectomy in 2011 for primary hyperparathyroidism (PHPTH). She was admitted to a remote Australian hospital for investigation and management of acute on chronic abdominal pain. Relevant medical history included a parathyroidectomy at age 40, multiple PE/DVT, MI, AF, CTEPH, right heart failure, HTLV-1 and recurrent abdominal pain presumed secondary to GORD. Gastroscopy from 2013 revealed chronic gastritis with hundreds of gastric polyps discovered on subsequent gastroscopy in 2015. The young age of PHPTH combined with her chronic gastritis and polyps prompted neuroendocrine tumour (NET) screening, including MEN1. At time of consult in 2020, laboratory studies were consistent with recurrence of PHPTH with a corrected calcium of 2.9 mmol/L (2.15-2.57mmol/L), serum PTH level 31.5 pmol/L (1-7pmol/L), vitamin D level 30 nmol/L, 24-hour urinary calcium variable between low and high. NET markers were markedly elevated with a gastrin level of 14042 ng/L (&amp;lt;100 ng/L), pancreatic polypeptide 2905 pmol/L (&amp;lt;55 pmol/L), urine 5HIAA ratio 8 mmol/L (&amp;lt;4 mmol/L), vasoactive intestinal peptide and glucagon levels normal. Pituitary studies, serum calcitonin, plasma metanephrines and PTH related protein levels were within normal limits. A CT of the abdomen showed thickened gastric folds, and persistent liver and IVC lesions from 2018. A diagnosis of Zollinger Ellison Syndrome (ZES) was made. Eventually, genetic testing was positive for a rare heterozygous variant of c.207dupC in exon 2 of MEN1 gene. A 68-gallium-DOTATATE PET/CT showed multiple avid pancreatic, gastric, nodal and liver lesions with high somatostatin receptor expression, suggestive of a neuroendocrine malignancy. Treatment was based largely on symptom control due to poor overall prognosis from underlying cardiorespiratory comorbidities. Abdominal pain from ZES was managed with a high dose PPI, H2 receptor antagonist and subcutaneous somatostatin analogue were trialled. Hypercalcaemia was treated with IV bisphosphonate therapy. Calcimimetic analogues were considered however patient declined. Genetic counselling was attempted however many cultural and logistical barriers were identified and family declined further testing. Unfortunately, our patient died in 2021 from presumed multifactorial respiratory failure. Conclusion: High index of suspicion is required to diagnose MEN1. This is particularly true within the Indigenous Australian population, with no prior documented cases reported. Presentation: Saturday, June 17, 2023

FRI365 A Patient With A Bronchial Carcinoid Presents With Cushingoid Symptoms Due To A Potentially Dangerous Supplement

Abstract Disclosure: T. Morales: None. S. Samarasinghe: None. Introduction: Well-differentiated bronchial neuroendocrine neoplasms often follow a clinically indolent course and rarely cause Ectopic ACTH syndrome. Iatrogenic corticosteroid use is the most common cause of Cushing syndrome and should be considered in all patients regardless of clinical background. Clinical Case: A 59-year-old woman with an 11-year history of a 1.5 cm well differentiated bronchial carcinoid, presented with Cushingoid features. Hormonal activation of her known bronchial carcinoid was considered. Testing resulted in a normal 24-hour urine 5-HIAA (6 mg/d, n&amp;lt;15 mg/dL), elevated chromogranin A (201 ng/mL, n&amp;lt;103 ng/mL), normal histamine (&amp;lt;1.5 ng/mL, n &amp;lt;1.7 ng/mL), low-normal 7 AM serum cortisol (5.1 ug/dL, n 3.6-19.3 ug/dL), normal 7 AM ACTH (17 pg/mL, n&amp;lt;46 pg/mL) and a surprisingly low 24-hr urinary free cortisol (1.8 mcg/hr, n 4.0-50.0 mcg/hr). A late night saliva cortisol was 0.03 mcg/dL (n 3.4-16.8 mcg/dL). Echocardiography showed no evidence of carcinoid heart disease. A Dotatate PET-CT scan to assess for neuroendocrine tumor progression showed a stable right upper lobe pulmonary nodule with no evidence of metastatic disease. Ectopic Cushing syndrome was excluded given the low cortisol levels, and exogenous steroids were suspected, however the patient denied the use of oral, inhaled, or injected steroids. A cosyntropin stimulation test yielded a pre-stimulation cortisol of 6.2 ug/dL with an adequate post-stimulation cortisol of 23.5 ug/dL (n &amp;lt;46 pg/mL). At this stage of evaluation, the patient received an FDA alert regarding a glucosamine supplement she had started 4 months prior for joint pain. The notification advised of hidden drug ingredients including dexamethasone, diclofenac, and methocarbamol contained within Artri King glucosamine supplements not listed on the product label, but verified by FDA lab analysis. The FDA had received several adverse event reports including liver toxicity and death associated with such products. The patient’s symptoms gradually improved after discontinuation of the supplement. Conclusion: Ectopic ACTH production is reported in less than 5% of patients with squamous cell lung cancer and 3% of patients with lung or pancreatic (non-MEN1) neuroendocrine tumors. Factitious corticoid exposure is rare and can be evaluated with synthetic corticosteroid serum testing. Cushing syndrome due to supplements containing unreported corticosteroid doses should be considered in patients with typical Cushingoid features and contradictory hormonal testing.

A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management.

Neuroendocrine neoplasms (NENs) are a group of heterogeneous tumors with neuroendocrine differentiation that can arise from any organ. They account for 2% of all malignancies in the United States. A significant proportion of NEN patients experience endocrine imbalances consequent to increased amine or peptide hormone secretion, impacting their quality of life and prognosis. Over the last decade, pathologic categorization, diagnostic techniques and therapeutic choices for NENs-both well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs)-have appreciably evolved. Diagnosis of NEN mostly follows a suspicion from clinical features or incidental imaging findings. Hormonal or non-hormonal biomarkers (like serum serotonin, urine 5-HIAA, gastrin and VIP) and histology of a suspected NEN is, therefore, critical for both confirmation of the diagnosis and classification as an NET or NEC. Therapy for NENs has progressed recently based on a better molecular understanding, including the involvement of mTOR, VEGF and peptide receptor radionuclide therapy (PRRT), which add to the growing evidence supporting the possibility of treatment beyond complete resection. As the incidence of NENs is on the rise in the United States and several other countries, physicians are more likely to see these cases, and their better understanding may support earlier diagnosis and tailoring treatment to the patient. We have compiled clinically significant evidence for NENs, including relevant changes to clinical practice that have greatly updated our diagnostic and therapeutic approach for NEN patients.

5-HT2-Receptors and 5-HIAA – Therapeutic Targets for Evaluation of Severity, Progression and Effectiveness of Treatment in Immature Male Rats in a Monocrotalin Model of Pulmonary Hypertension

Suppression of the proliferation of vascular endothelial cells and the interaction of endothelial with smooth muscle cells in pulmonary hypertension (PH) are impaired. Participation of the 5-HT2a-receptor in the mitogenic effect on endothelial, and 5-HT2b-receptor – on vascular smooth muscle cells was revealed. The main organ that metabolizes serotonin is the lung. In the endothelial cells of the vessels of the lungs under the action of the enzyme monoamine oxidase And serotonin is converted to 5-hydroxyindoleacetic acid (5-HIAA), which is subsequently excreted in the urine. Currently, the role of 5-HT2-receptors is not taken into account in the treatment of children with pulmonary hypertension. We have modified the monocrotaline model of pulmonary hypertension for immature rats. A scheme for the administration of a 5-HT2-receptor blocker for the prevention and treatment of pulmonary hypertension in immature rats was developed and tested. A positive correlation was found between the concentration of 5-HIAA in urine and the degree of pulmonary hypertension, which can become a potential marker of pulmonary hypertension. The data obtained indicate the development of pulmonary hypertension in immature rats after a single injection of monocrotaline in the form of replacement of lung tissue with fibrous tissue, the development of pneumosclerosis and bronchiectasis. Also, in animals in this model, changes in the structure of the heart muscle and vascular wall are formed with the development of fibrous tissue, which may indicate the involvement of 5HT2-receptors in the activation of fibroblasts and, accordingly, in the pathogenesis of pulmonary hypertension.

Post-Synthetic Modification of a Fluorescent Covalent Organic Framework as a Multifunctional Sensor for Efficient Detection of 5-Hydroxytryptamine and Its Metabolite and Latent Fingerprint Identification

In this study, a functionalized vinyl-linked 2D fluorescent covalent organic framework (COF) (TMT-TA-COOH) is constructed by post-synthetic modification (PSM) of a TMT-TA COF, which is composed of trimethyltriazine (TMT) and terephthalaldehyde (TA). The fluorescent COF (TMT-TA) has the characteristics of good crystallization and stability, but the dispersibility in water is poor, which requires further PSM. After PSM, the obtained TMT-TA-COOH not only exhibits good dispersibility in water but also displays stronger binding ability to analytes, which presents high sensitivity for quantitative identification of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in water. Moreover, TMT-TA-COOH can specifically recognize 5-HT in serum and 5-HIAA in urine with a fast response, good anti-interference performance, and real-time visualization, which enables the TMT-TA-COOH to be a tool for early detection of neurological diseases and biomarkers for carcinoid tumors. In addition, TMT-TA-COOH is also a good candidate for latent fingerprint (LFP) identification, which has the characteristics of high contrast and low background interference. This work not only provides a promising platform for the sensing application of fluorescent COFs in aqueous solution but also opens up a new way for the detection of LFP information.

Well-Differentiated Neuroendocrine Tumors of the Appendix in Children and Adolescents: A Clinicopathologic Study.

Pediatric neuroendocrine tumors (NET) of the GI tract are rare and appendiceal NET are typically incidental. Few studies have been done in the pediatric population and practice guidelines are mainly based on adult data. There are currently no diagnostic studies specific for NET. Our study aimed to identify clinical, radiological, and pathological findings in pediatric appendiceal NET, test criteria for follow up surgical treatment, review potential prognostic pathological findings, and possible pre-operative diagnostic radiological studies. A retrospective data search was conducted for well-differentiated NET of the appendix in patients ≤21 years between 1/1/2003 and 7/1/2022. Available clinical, radiologic, pathological, and follow-up information was recorded. Thirty-seven patients with appendiceal NET were identified. No masses were reported in the patients who underwent presurgical imaging. Appendectomy samples showed NET (0.2->4 cm), most located in the tip. Most cases were WHO G1 (34/37), with negative margins (n = 25). Sixteen cases extended to the subserosa/mesoappendix (pT3). Lymphovascular (6), perineural (2), and both lymphovascular and perineural invasion were also noted (2). The specified tumor stages were pT1 (10/37), pT3 (16/37), and pT4 (4/37). Patients who underwent laboratory testing for chromogranin A (20) and urine 5HIAA (11) had normal limits. Subsequent surgical resection was recommended in 13 cases and performed in 11. To date, all patients have no recurrent or additional metastatic disease. Our study showed that all pediatric well-differentiated appendiceal NET were incidentally found as part of acute appendicitis management. Most NET were localized with low-grade histology. Our small cohort support the previously suggested management guidelines with follow up resection in certain cases. Our radiologic review didn't identify a best modality for NET. Comparing cases with and without metastatic disease, no tumors under 1 cm had metastasis, but serosal and perineural invasion along with G2 status were associated with metastasis in our limited study.

Beneficial Effect of Increased Tryptophan Intake on Its Metabolism and Mental State of the Elderly

The elderly often suffer from sleep disorders and depression, which contribute to mood disorders. In our previous work, we showed that elderly individuals with mood disorders had a lower intake of TRP and recommended a TRP-based dietary intervention to improve the mental state of such individuals. In this work, we assessed the impact of a TRP-rich diet on the mental state of, and TRP metabolism in, elderly individuals with mood disorders. Forty elderly individuals with depression and sleep disorders and an equal number of elderly subjects without mood disorders were enrolled in this study. TRP intake was evaluated with the nutrition calculator. Patients with mood disorders had a lower TRP intake than their normal counterparts and received a TRP-rich diet with TRP content of 25 mg per kilogram of the body per day for 12 weeks. The mental state was assessed before and after this dietary intervention with the Hamilton Depression Rating Scale (HAM-D) and the Insomnia Severity Index (ISI). At those times, urinary levels of TRP and its metabolites 5-hydroxyindoleacetic acid (5-HIAA), L-kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QA) were determined by liquid chromatography with tandem mass spectrometry and related to creatinine level. After TRP-based dietary intervention, the score of ISI and HAM-D decreased by more than half. A correlation analysis reveals that TRP, 5-HIAA, and KYNA might have anti-depressive action, while KYN and QA-pro-depressive. The levels of TRP, 5-HIAA, and KYNA in urine of mood disorder patients increased, while the levels of KYN and QA decreased. In conclusion, dietary consumption of adequate amount of tryptophan has a beneficial effect on mental health of the elderly with mood disorders and improves metabolism of this amino acid. Therefore, a TRP-enriched diet may be considered as a component of the treatment of elderly individuals with mood disorders.