Urinary Vanillylmandelic Acid Research Articles

Primary Paraganglioma of the Prostate: A Systematic Review of the Literature for A Rare Entity.

Paragangliomas of the urinary tract are exceptionally uncommon, and sporadic case reports of primary paraganglioma of the prostate have been reported in the literature. Systematic research in PubMed/Medline and Scopus databases concerning primary prostatic paraganglioma was performed by two independent investigators. This analysis included 25 adult males, with a mean age of 49.8 ± 22.4 years. 32% of included patients had a history of hypertension. Problems during urination (52%), blood loss (44%), either as hematuria or hemospermia, and catecholamine-related symptoms (36%) comprised the most frequently reported clinical manifestations. Digital rectal examination found a palpable nodule in 36% of patients, while prostatic specific antigen (PSA) was normal in all tested patients. Abdominal ultrasound (44%), computed tomography (44%) and magnetic resonance imaging (28%) helped to identify the primary lesion. 24-hour urine epinephrine, norepinephrine and vanillylmandelic acid (VMA) levels were elevated in 90%, 80% and 90% of included patients. Open surgical excision of the mass was performed in 40%, transurethral resection in 8%, open radical prostatectomy in 24%, transurethral resection of the prostate in 16% and robot-assisted radical prostatectomy in 4% of included patients. Due to atypical clinical manifestation and scarcity of prostatic paraganglioma, urologists should be aware of this extremely rare entity.

Establishment and clinical application of a candidate reference measurement procedure for quantification of urinary vanillylmandelic acid and homovanillic acid using ID-LC-MS/MS method

Neuroblastoma (NB), an embryonic tumor of the autonomous nervous system, poses a significant threat to the health and lives of children. Accurate measurement of vanillylmandelic acid (VMA) and homovanillic acid (HVA) in human urine is crucial for screening and diagnosis of NB. Although various laboratories have developed liquid chromatography tandem mass spectrometry (LC-MS/MS) method to detect VMA and HVA, the comparability between the results obtained from different laboratories and methods was poor. The absence of reference method for VMA and HVA hinders the standardization of their measurements. Therefore, a candidate reference measurement procedure (cRMP) based on isotope dilution LC-MS/MS (ID-LC-MS/MS) for the detection of VMA and HVA in human urine was established. Urine samples were spiked with VMA-d3 and HVA-d5 as internal standards and extracted using a protein precipitation method. The cRMP exhibited desirable precision with the total imprecision below 5 %. The accuracy of this cRMP was demonstrated by the high analytical recovery (98.64 % - 102.22 % and 98.41 % - 100.97 % for VMA and HVA, respectively), and comparability between different reference systems. The limit of detection for HVA and VMA were 15.625 ng/mL and 3.906 ng/mL, respectively; the quantification limits were 62.5 ng/mL and 7.813 ng/mL, respectively, which can meet the clinical detection requirements. The linear range was from 78.125 ng/mL to 20 μg/mL. Specificity evaluations showed no corresponding interference from structurally similar analogs. In conclusion, we have established a cRMP based on ID-LC-MS/MS for the measurement of VMA and HVA in urine samples, demonstrating well-defined method performance including accuracy, precision, and specificity. This newly established cRMP is suitable for routine assay standardization and evaluation of clinical samples. Furthermore, this method has the potential to significantly enhance the diagnostic accuracy for neuroblastoma.

Analysis of the relationship between MYCN gene and serum NSE and urinary VMA levels and neuroblastoma pathological features and prognosis.

The purpose of this study was to explore the relationship between the MYCN gene, serum neuron-specific enolase (NSE), urinary vanillylmandelic acid (VMA) levels, and neuroblastoma pathological features and prognosis. Ninety-four children with neuroblastoma treated in the hospital were selected to compare the differences in MYCN gene amplification, serum NSE, and urinary VMA levels in children with different clinicopathological features and prognoses. The proportion of children with MYCN gene copy number ≥10 in INSS stage 3-4 was higher than that of children with INSS stage 1-2 (P < 0.05); the proportion of children with MYCN gene copy number ≥10 in high-risk children in the COG risk stratification was higher than that of children with intermediate and low risk (P < 0.05); the serum NSE of children aged >12 months higher than that of children aged ≤12 months (P < 0.05); serum NSE of children with tumors >500 cm3 higher than that of children with tumors ≤500 cm3 (P < 0.05); serum NSE and urinary VMA of children with INSS staging of stages 3-4 were higher than that of children with stages 1 to 2 (P < 0.05); serum NSE and urinary VMA in children with lymph node metastasis were higher than that of children without lymph node metastasis (P < 0.05); serum NSE of children with MYCN gene copy number ≥10 was higher than that of children without lymph node metastasis (P < 0.05); the proportion of children with MYCN gene copy number ≥10 who died, and the percentages of serum NSE and urinary VMA were higher than those of the surviving children (P < 0.05). MYCN gene amplification and serum NSE and urinary VMA levels were related to the age, tumor size, INSS stage, COG stage, lymph node metastasis, and prognosis of the children with neuroblastoma.

Pediatric malignant pheochromocytoma with atypical presentation as vision changes, lung metastasis, and recurrence: a case report

BackgroundThis case report documents a case of malignant pheochromocytoma manifested as vision changes with lung metastasis and recurrence.Case presentationA 10-year-old Han Chinese girl presented with vision changes and was eventually diagnosed with pheochromocytoma by contrast-enhanced computed tomography, urine vanillylmandelic acid. After medication for hypertension and surgery, clinical symptoms disappeared. Malignant pheochromocytoma with lung metastasis was confirmed histologically using the Pheochromocytoma of the Adrenal Gland Scaled Score scoring system and genetically with succinate dehydrogenase complex iron sulfur subunit B mutation, and 3 months later, unplanned surgery was performed because of the high risks and signs of recurrence. She is asymptomatic as of the writing of this case report. Our patient’s case highlights the importance of considering a diagnosis of malignant pheochromocytoma, and long-term follow-up for possible recurrence.ConclusionAlthough there are well-recognized classic clinical manifestations associated with pheochromocytoma, atypical presentation, such as vision changes in children, should be considered. In addition, malignant pheochromocytoma children with a high Pheochromocytoma of the Adrenal Gland Scaled Score and succinate dehydrogenase complex iron sulfur subunit B mutation require a long-term follow-up or even unplanned surgery because of the higher risk of recurrence.

Scoring system for diagnosis and pretreatment risk assessment of neuroblastoma using urinary biomarker combinations.

The urinary catecholamine metabolites, homovanillic acid (HVA) and vanillylmandelic acid (VMA), are used for the adjunctive diagnosis of neuroblastomas. We aimed to develop a scoring system for the diagnosis and pretreatment risk assessment of neuroblastoma, incorporating age and other urinary catecholamine metabolite combinations. Urine samples from 227 controls (227 samples) and 68 patients with neuroblastoma (228 samples) were evaluated. First, the catecholamine metabolites vanillactic acid (VLA) and 3-methoxytyramine sulfate (MTS) were identified as urinary marker candidates through comprehensive analysis using liquid chromatography-mass spectrometry. The concentrations of these marker candidates and conventional markers were then compared among controls, patients, and numerous risk groups to develop a scoring system. Participants were classified into four groups: control, low risk, intermediate risk, and high risk, and the proportional odds model was fitted using the L2-penalized maximum likelihood method, incorporating age on a monthly scale for adjustment. This scoring model using the novel urine catecholamine metabolite combinations, VLA and MTS, had greater area under the curve values than the model using HVA and VMA for diagnosis (0.978 vs. 0.964), pretreatment risk assessment (low and intermediate risk vs. high risk: 0.866 vs. 0.724; low risk vs. intermediate and high risk: 0.871 vs. 0.680), and prognostic factors (MYCN status: 0.741 vs. 0.369, histology: 0.932 vs. 0.747). The new system also had greater accuracy in detecting missing high-risk neuroblastomas, and in predicting the pretreatment risk at the time of screening. The new scoring system employing VLA and MTS has the potential to replace the conventional adjunctive diagnostic method using HVA and VMA.

A Large Paraganglioma Neck – Managed Successfully by Transcervical Excision

Abstract Glomus vagale paraganglioma is a slow-growing, benign, and relatively uncommon tumor, accounting for &lt; 3% of head-and-neck paragangliomas. It predominantly arises from vagal nodose ganglion in the carotid sheath and mostly comprises extraadrenal nonchromaffin cells. It usually presents as an asymptomatic cervical mass but rarely can present with local compressive symptoms. Mostly paragangliomas are nonfunctional, however, functional paraganglioma needs to be ruled out by clinical examination (such as tachycardia, hypertension, and facial flushing) and laboratory investigation like vanillylmandelic acid in urine and serum. It also needs to be differentiated from other neck masses, for example, carotid body tumor, carotid aneurysm, nerve sheath tumor, etc., Imaging modalities such as ultrasonography, contrast-enhanced computed tomography or magnetic resonance imaging are required to characterize and diagnose such neck lesions and ascertain their relationship with the neck vessels. Surgical excision is considered the mainstay of treatment which mandates segmental resection of the vagus nerve and results in significant postoperative morbidity. We hereby report a case of 53-year-old female with a large, highly vascular glomus vagale tumor in the neck which was densely adherent to neck vessels (common carotid artery/internal carotid artery/external carotid artery and internal jugular vein) and presented with local compressive symptoms. The patient was successfully managed by preoperative angioembolization followed by transcervical excision of the tumor.

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.

FRI227 Functional Transformation Of An Initially Non-functional Paraganglioma In A Patient With Cyanotic Congenital Heart Disease

Abstract Disclosure: M. McConnell: None. M. Kanin: None. M.S. Auerbach: None. R. Yu: None. Background: Most pheochromocytomas and about half of paragangliomas (P-PGLs) are functional in that they produce catecholamines. Transformation of non-functional to functional P-PGLs is exceedingly rare. We present a case of such transformation in a young male with cyanotic congenital heart disease (CCHD), resulting in catecholamine-induced cardiomyopathy. Clinical Case: A 27-year-old male with CCHD presented to the hospital with tachycardia, hypertension, and hypoxia. He had a newly depressed ejection fraction of &amp;lt;20% and was in florid heart failure. Despite intervention, he decompensated rapidly, requiring extracorporeal membrane oxygenation (ECMO). Five years prior to this presentation, he had had normal 24-hour urine fractionated metanephrines, vanillylmandelic acid (VMA), and homovanillic acid (HVA) levels; on imaging, he had been incidentally found to harbor a 3.3 x 1.6 x 2.5-cm nodule in the upper aortocaval space which could represent a paraganglioma. Subsequent imaging showed slow growth of this mass. Given this pertinent history, urine and plasma free metanephrine studies were repeated during the hospitalization while he was not on vasopressors. 24-hour urine normetanephrines were elevated at 2,644 mcg/d (81-667 mcg/d), metanephrines at 405 mcg/d (55-320 mcg/d) while plasma free metanephrines were elevated at 0.92 nmol/L (0-0.49 nmol/L) and normetanephrines at 11.85 nmol/L (0-0.89 nmol/L). DOTATATE PET/CT revealed a soft tissue mass measuring 4.3 x 3.1 x 4.9 cm with intense DOTATATE activity in the right paravertebral space between the aorta and cava. He was treated with alpha-adrenergic blockade with improvement in blood pressure. Two months later, he underwent resection of the mass with pathology confirming a 4.9 cm paraganglioma. Conclusion: It is very rare for a paraganglioma to undergo transformation from non-functional to functional status although it is reported in the literature. This scenario is supported by our patient’s normal 24-hour urine metanephrines, VMA, and HVA results on initial presentation followed by marked elevation in urine and plasma metanephrines 5 years later when he presented with heart failure. The functional transformation in this patient was accompanied by significant growth of the paraganglioma. We surmise that alterations in gene expression during tumor growth may be responsible for the functional transformation. It is crucial to reassess the functionality of a paraganglioma if the clinical condition suggests catecholamine excess. Presentation: Friday, June 16, 2023

Clinical value of combined serum CA125, NSE and 24-hour urine VMA for the prediction of recurrence in children with neuroblastoma

BackgroundIn this study, we intend to retrospectively analyze the clinical data of postoperative neuroblastoma children, including the results of follow-up examinations and laboratory tests, to explore the clinical value of combined serum Carbohydrate antigen 125 (CA125), neuron-specific enolase (NSE) and 24-hour urine vanillylmandelic acid (VMA) levels at baseline for the prediction of recurrence in children with neuroblastoma.Methods265 children with neuroblastoma were successfully followed up, including 163 cases without recurrence (non-recurrence group) and 102 cases with recurrence (recurrence group). The levels of 24-hour urine VMA were determined using spectrophotometric methods. Additionally, the serum levels of CA125 and NSE were measured using electrochemiluminescence immunoassay.ResultsThe serum CA125, NSE and 24-hour urine VMA levels were significantly higher in the recurrence group than in the non-recurrence group. It demonstrated a significant positive correlation between the levels of serum CA125, NSE, and 24-hour urine VMA in all children with neuroblastoma. All children in stage IV of neuroblastoma had the highest level of serum CA125, NSE and 24-hour urine VMA and vice versa. The combined CA125, NSE and VMA had significantly better sensitivity and specificity than an individual marker.ConclusionsCombined serum CA125, NSE and 24-hour urine VMA had the potential to predict neuroblastoma recurrence more effectively.

Pheochromocytoma with Type 2 Diabetes Mellitus and Subclinical Cushing's Syndrome

Pheochromocytoma is a catecholamine-producing tumor that originates from adrenal medullary chromaffin cells. It affects 1–8 per million people annually and accounts for 5% of adrenal incidentalomas. Here, we report a 62-year-old man with sudden excessive sweating, palpitations, and headaches. He has a history of type 2 diabetes mellitus, hypertension, and an adrenal mass found incidentally by ultrasonography. Clinical history and further imaging suggest a pheochromocytoma; however, the presence of subclinical Cushing's syndrome and a normal urine vanillylmandelic acid level have led to diagnostic challenges. Finally, the patient underwent a left adrenalectomy. Histopathology showed the tumor as thick nests of cells, positive chromogranin A staining, and negative inhibin staining that confirmed the diagnosis of pheochromocytoma. In conclusion, our patient had pheochromocytoma that was thought to produce adrenocorticotropic hormone ectopically, resulting in subclinical Cushing's syndrome.

Changes in blood pressure, blood sugar and creatinine in patients undergoing pheochromocytoma surgery

Objective: To discover the variables that may predict changes in blood pressure and blood sugar levels and to pinpoint the time frame during which such changes occur in patient with pheochromocytoma. Materials and Methodology: Consecutive patients undergoing surgery for pheochromocytoma over a 20-month period were included in this ethics review board-approved, prospective cohort study. Blood pressure and sugar levels were serially monitored using a fixed protocol in the perioperative period and subsequently at 3 months after surgery. Changes were compared and assessed for the predictive factors. Result: Fifty patients undergoing surgical procedures were included in the study of whom 32% developed hypotension and 10% developed hypoglycaemias after surgery. All hypotension episodes occurred within 6 hours of surgery. However, while 7 of 8 patients who developed hypoglycaemia manifest in the first 4 h after surgery, one occurred after 12 h. Occurrence of hypotension correlated with preoperative 24-h urinary vanillylmandelic acid levels (P = 0.024). Out of 21 hypertensive patients, 15 had persistent hypertension at 3 months and this was associated with age (P = 0.04) and diabetes mellitus at presentation. Conclusion: 32% of patients receiving pheochromocytoma surgery experienced postoperative hypotension needing inotropic support. Patients who require greater dosages of alpha-blockers or those with higher 24-h urine VMA levels are more prone to experience this. This happens within the first six hours following surgery. Patients who are older or who have had DM for a long time are more likely to suffer chronic HTN following surgery. Keywords: Pheochromocytoma, hypertension, hypoglycaemia, creatinine.

Risk factors and a predictive nomogram for hemodynamic instability during adrenalectomy for large pheochromocytomas and paragangliomas: A retrospective cohort study

ObjectiveThis study aimed to investigate risk factors for intraoperative hemodynamic instability (HDI) and construct a clinical model for predicting intraoperative HDI for large pheochromocytomas and paragangliomas (PPGLs) patients. MethodsA single-center retrospective study of the clinicopathological data of patients undergoing surgery for PPGLs larger than 5 cm in diameter was conducted. A total of 215 eligible patients were enrolled in the study. Three advanced statistical methods were used to select independent risk factors in the training cohort for constructing a nomogram for predicting intraoperative HDI. The predictive performance of the model was assessed by area under the curve (AUC), positive predictive value (PPV), negative predictive value (NPV), and calibration. Decision curve analysis (DCA) and clinical impact curves (CIC) were used to assess predictive accuracy and clinical utility. The performance of the nomogram of was further internally validated. ResultsComorbid diabetes mellitus, anemia, hypoproteinemia, 24-h urine vanillylmandelic acid and intraoperative blood transfusion (P < 0.05) were identified as independent risk factors for constructing the nomogram. In the training cohort, the AUC, PPV and NPV of the nomogram were 0.846, 91.6% and 69.2%. In the validation cohort, the AUC, PPV and NPV were 0.842, 91.8% and 63.3%. These showed good predictive power of the model. The calibration curves demonstrated an optimal consistency between the nomogram-predicted and the actual observed survival probability. DCA and CIC examination showed superior clinical relevance. ConclusionsThe nomogram can objectively and accurately predict intraoperative HDI in patients with large PPGLs, which can help in individualized pre-treatment decision-making.

HIGH SALT DIET ALTERS CEREBROVASCULAR RESISTANCE IN RESPONSE TO ORTHOSTATIC TEST IN HEALTHY YOUNG INDIVIDUALS

Objective: High salt (HS) diet has been shown to impairs vascular reactivity in animal models, by increasing vasoconstriction to different stimuli. Response to orthostasis occurs via activation of baroreceptor reflex leading to increase in total peripheral resistance that prevents significant fall of arterial blood pressure (ABP) while standing up, aiming to preserve cerebral perfusion pressure. We recently showed that HS diet physiologically suppresses sympathetic arm of autonomic control in healthy humans (Stupin et al. Nutrients 2021; 13:1731. https://doi.org/10.3390/nu13051731). Present study aimed to assess the effect of HS diet on cerebral vasoreactivity in response to orthostatic load. Design and method: Twenty-seven young healthy participants (F:21, M:6, age range 19–24) consumed 7-day low-salt (LS) diet (&lt;2.3 g NaCl /day) and afterwards 7-day HS diet (&gt;11.2 g NaCl/day). In response to orthostatic test cerebral and systemic hemodynamic parameters, arterial blood pressure, heart rate variability and heart rate, and were recorded simultaneously with transcranial Doppler ultrasound and The Task Force® Monitor. Results: Subjects maintained normotension during HS diet. Diastolic blood pressure, as well as mean cerebral blood flow (CBF) and the velocity time integral decreased, while cerebral pulsatility index increased after standing up following both dietary protocols. However, while no change was observed in total peripheral resistance, cerebrovascular resistance significantly increased in response to orthostasis only after HS diet. Baroreflex sensitivity (BRS), sympathetic neural control, serum plasma renin activity and aldosterone, and urine noradrenaline and vanillylmandelic acid concentration was significantly decreased in HS diet. Conclusions: Results demonstrated that following 7-day HS diet, enhanced cerebral autoregulation preserves CBF and is manifested as increased cerebral vascular resistance, in conditions with blunted BRS and sympathetic activity. The study has been published in Eur J Appl Physiol. 2023 Jan 4. doi: 10.1007/s00421-022-05124-w. Online ahead of print.

PHEOCHROMOCYTOMA AS A RARE CAUSE OF MYOCARDIAL INFARCTION

Objective: A 41-year-old man was admitted to the cardiac care unit with acute chest pain radiating to his left arm. For the previous 20 years, he had episodes of high blood pressure accompanied by shivering, sweating, anxiety, and headaches. Electrocardiography revealed ST elevation in the II, III, and aVF leads, as well as reciprocal ST depression in the I and aVL leads. Echocardiography showed hypokinesis of the mid inferior and basal inferior segments. Troponin level increased from 0.005 to 0.177 ng/ml. Aneurysms in the coronary arteries were discovered during an urgent coronary angiography. The patient was prescribed aspirin, angiotensin-converting enzyme inhibitor, and calcium channel blocker and discharged from the hospital. Design and method: Further testing included computed tomography (CT) of the aorta and coronary arteries. The aorta had no pathological findings, but the right coronary artery was dilated in the middle segment. A CT scan of the abdomen revealed a mass in the left adrenal gland, and later abdominal and retroperitoneal magnetic resonance imaging revealed a lipid-poor left adrenal mass. Biomarkers of adrenal gland function were evaluated and blood adrenalin (150 pg/ml normal range ‹125pg/ml) and noradrenalin (680pg/ml normal range ‹600pg/ml) levels were mildly elevated. The 24-hour urinary vanillylmandelic acid level was elevated (76,6umol vs. the normal range of 68umol). Cortisol and aldosterone levels in the blood were within normal ranges. Lateral transperitoneal adrenalectomy was eventually performed successfully. Results: Histological examination of the mass revealed a pheochromocytoma. The patient's blood pressure returned to normal after the left adrenalectomy, and episodes of sweating and anxiety accompanied by an acute increase in blood pressure disappeared. Conclusions: Pheochromocytoma is a rare neuroendocrine tumor that can cause life-threatening cardiovascular complications such as myocardial infarction and cardiac arrhythmias. Unfortunately, the clinical pattern of pheochromocytoma frequently remains without typical manifestations and needs detailed laboratory and radiological confirmation. This case emphasizes the importance of a comprehensive assessment of the patient with arterial hypertension, even in the presence of subclinical sympathetic overactivity.

Abstract 2199: Novel urinary marker for diagnosis and prognosis of neuroblastoma

Abstract Background and Aim: Urinary homovanillic acid (HVA) and vanillylmandelic acid (VMA) concentrations are widely used for diagnosis of neuroblastomas, which are catecholamine-secreting tumors. As recent advances in mass spectrometry have facilitated the measurement of metabolites present at extremely low concentrations, urinary metabolites with better diagnostic or prognostic utility for detection of neuroblastomas could be identified. This study utilized quantitative analyses using liquid chromatography-mass spectrometry (LC-MS) to evaluate the diagnostic and prognostic performance of a novel biomarker candidate: 3-methoxytyramine sulfate [3-MTS]. Materials and Methods: The concentrations of the three urinary metabolites (HVA, VMA, and 3-MTS) in urine samples of 41 patients with primary neuroblastoma and urine samples of 155 control participants were measured using LC-MS. The cut-off values for these metabolites were the mean + 2 standard deviation values of the control. Linear discriminant analysis was used to evaluate the association of urinary marker candidates with unfavorable risk factors such as the International Neuroblastoma Pathology Classification and MYCN amplification. Results: The sensitivity and specificity were as follows: 3-MTS 90.2%, 94.2%; HVA 87.8%, 96.1%; VMA 87.8%, 96.1%; VMA or HVA+3-MTS 97.6%, 92.3%; HVA+VMA 87.8%, 94.8%; respectively. 3-MTS could differentiate between the cases with favorable and unfavorable histology (AUC =0.950). 3-MTS+VMA differentiated between the cases with MYCN amplification and nonamplification (AUC=0.952). Conclusions: 3-MTS might be a useful urine marker for both diagnosis and prognosis of neuroblastoma. Citation Format: Akinari Hinoki, Hizuru Amano, Hiroo Uchida, Atsushi Narita, Shun Kumano, Mayumi Abe, Minoru Sakairi, Chiyoe Shirota, Wataru Sumida, Satoshi Makita, Yoshiyuki Takahashi, Tsuyoshi Osawa. Novel urinary marker for diagnosis and prognosis of neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2199.

A rapid and simple capillary electrophoresis procedure for quantification of vanillylmandelic acid in urine samples

Aim: To develop a one-step vortex-assisted liquid-liquid extraction (VALLE) method, without the need for evaporation and reconstitution steps, to establish a rapid and straightforward treatment procedure based on capillary electrophoresis-diode array detection (CE-DAD) for the determination of vanillylmandelic acid (VMA) in human urine. Methodology: Optimization of VALLE and CE-DAD procedures were studied in detail. The effects of various experimental parameters, such as the type of the extraction solvent, sample pH, salt addition, and extraction time were investigated. Also, CE separation conditions including background electrolyte type, concentration, and pH, injection time and separation voltage were optimized as well. Results: A successful separation of VMA was achieved in less than 6 min using a basic background electrolyte composed of 60 mmol·L-1 acetate/ACN (acetonitrile) 50% (v/v) (final apparent pH is 5.73). The linear response was obtained over the concentration range from 1.0 to 14 μg·mL-1. The limit of detection and quantification were 0.30 and 1.0 μg·mL-1, respectively. The intra- and inter-day precisions were found to be less than 4.3%. The extraction recoveries of VMA were between 95%-97%. Conclusion: The developed method is found to be a simple, rapid, and reliable method for quantitative analysis of urinary VMA.

Validation of Vanillylmandelic Acid (VMA) with Plasma Metanephrine and Normetanephrine for Screening Adrenal Medullary Disorders

Objective: To validate urinary Vanillylmandelic acid (VMA) for screening adrenal medullary disorders, taking plasma-free Metanephrine as the gold standard.&#x0D; Study Design: Cross-sectional validation study.&#x0D; Place and Duration of Study: Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology,Rawalpindi, in collaboration with Armed Forces Institute of Urology, Rawalpindi from Pakistan, Jan 2020 to Mar 2021.&#x0D; Methodology: One hundred and thirty (130) symptomatic hypertensive patients with adrenal masses on ultrasound were selected Urine and blood samples were collected under specified conditions after taking necessary precautions and subsequently analyzed. Taking plasma Metanephrine as a reference, sensitivity, specificity and predictive values were calculated at predefined cut-off values. &#x0D; Results: In a young population with a mean age of 28.55±5.54 years, headache, palpitations and sweating were the predominant symptoms having a frequency of 130(100%), 116(89.2%) and 111(85.4%), respectively. Twenty-four hours urinary Vanillylmandelic acid had lower sensitivity (66.3%) than a random urinary VMA/cr ratio (72.1%) but similar specificity(97.7%). On the other hand, plasma-free Normetanephrine had 100% sensitivity but lower specificity (93.2%). ROC curve was plotted, and AUC for 24 hours urinary VMA, urinary VMA/cr ratio and plasma-free Normetanephrine were 0.820, 0.849 and0.966, respectively.&#x0D; Conclusion: Plasma-free Metanephrine could be used for screening pheochromocytoma and other adrenal medullary disorders like paraganglionoma. In addition, VMA/cr ratio can be used for biochemical confirmation of the disease owing to the high specificity found in our study.

PS-R03-4: TRANSARTERIAL EMBOLIZATION, THORACIC SPINE DECOMPRESSION AND FUSION OF METASTATIC PHEOCHROMOCYTOMA: A CASE REPORT

Surveillance of metastatic lesions and biochemical control of catecholamines in patients with malignant pheochromocytoma remain a fundamental problem to be solved. Here we present a 60-year-old male who visited a local clinic because of headache, sweating, malaise, and loss of body weight. Hypertension, orthostatic hypotension, along with remarkable increase in serum and urine noradrenaline, and urine metanephrine and vanillylmandelic acid were noted, and pheochromocytoma was suspected accordingly. Magnetic resonance imaging failed to reveal adrenal gland or sympathetic plexuses, yet it uncovered metastatic lesions in the liver and spine. Functional imaging study using 131I-Metaiodobenzylguanidine (MIBG) scan detected notable uptake in the spinal lesion, albeit not in the hepatic lesion. On the other hand, positron emission tomography with fluorodeoxyglucose (FDG-PET) disclosed FDG uptake both in the hepatic and spinal masses. Biopsy of the hepatic tumors revealed chromogranin A-positive clusters of cells, a finding consistent with metastatic pheochromocytoma. Transarterial embolization (TAE) of the metastatic tumors in the liver was performed for the purpose of tumor mass reduction. Additionally, TAE followed by resection of the spinal lesion was conducted. Pathological examination of the spinal tumor also showed chromogranin A-positive cells, leading to diagnosis of malignant pheochromocytoma. Crucially, TAE of the liver and spinal tumors resulted in dramatic reduction of catecholamine production, likely constituting an effective therapeutic strategy against metastatic pheochromocytoma (Homma, et al. Hypertens Res 2006). Afterwards, the patient became unable to walk because of weakness in the left leg at the age of 64. It seemed attributed to spinal cord compression from the tumor at the level of thoracic vertebrae 7. The patient underwent posterior decompression and fusion, and his muscle strength of the left leg was recovered. At the age of 65, the patient developed paralytic ileus following a surgery against metastatic tumors in the skull. In this case report, we discuss early detection of metastatic lesions and biochemical control of catecholamines in patients with malignant pheochromocytoma.

Development and validation of a novel nomogram predicting pseudohypoxia type pheochromocytomas and paragangliomas.

Pseudohypoxia type (PHT) pheochromocytomas and paragangliomas (PPGLs) are more likely to metastasize and have a poor prognosis. However, application of genetic tests has many restrictions. The study aims to establish a novel nomogram for predicting the risk of PHT PPGLs. This retrospective cross-sectional study included 242 patients with pathology confirmed PPGLs in one tertiary care center in China in 2010-2021. Clinical and biochemical characteristics were collected. Next-generation sequencing was performed in all PPGLs patients for detection of mutation. Univariate and multivariable logistic regression analyses were used to select risk factors for constructing the nomogram. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the discrimination of the nomogram and the calibration curve was performed. Four variables including age ≤ 35years, hypertension, 24h urinary output of urinary vanillylmandelic acid (VMA) ≥ 100 umol/24h and urinary 17-ketosteroide (17KS) ≤ 50 umol/24h levels were independently associated with PHT PPGLs in the logistic regression analysis and were included in the nomogram. The nomogram showed a good discrimination performance with AUC of 0.829 [95% confidence interval (CI), 0.767-0.891] in the training set and 0.797 (95%CI, 0.659-0.935) in the validation set, respectively. The calibration curve showed a bias-corrected AUC of 0.809 vs. 0.795, and a Hosmer-Lemeshow (H-L) test yielded a p value of 0.801 vs. 0.885, indicating the nomogram's good ability to distinguish PHT PPGLs from non-PHT PPGLs. Our study has proposed a novel nomogram for individualized prediction of the PHT PPGLs, which may make contributions to guide the patients' personalized management, follow-up, and treatment.

Left adrenal aldosteronism coexisting with left paraaortic paraganglioma presenting as bilateral adrenal and left paraaortic tumors– comprehensive adrenal evaluation aiding perfect management: a case report

BackgroundCoexistence of a catecholamine-secreting tumor and an adrenal cortical tumor is quite rare which makes both diagnosis and management challenging. The purpose of this article is to describe the presence of this condition, share a stepwise approach for preoperative evaluation, and review the related literature.Case presentationA 44-year-old male patient had a history of hypertension and aggravating hypokalemia for years. Abdominal computed tomography incidentally found concomitant bilateral adrenal and left para-aortic tumors. Comprehensive adrenal hormone tests revealed a high aldosterone renin ratio and mildly elevated 24-h urine vanillylmandelic acid and norepinephrine levels. Subsequently, a metaiodobenzylguanidine scan showed uptake over the left para-aortic tumor, and NP-59 adrenal scintigraphy showed uptake over the left adrenal tumor. Further confirmatory tests, including captopril suppression, irbesartan suppression, and saline infusion, all confirmed the diagnosis of hyperaldosteronism. Adrenal venous sampling following 2 months of preparation with an alpha blocker demonstrated a left aldosterone-producing adrenal adenoma. Combining hormonal analysis, imaging studies, and adrenal venous sampling, the patient was diagnosed with left adrenal aldosteronoma, right adrenal nonfunctional tumor, and left para-aortic paraganglioma (PGL). Accordingly, laparoscopic left adrenalectomy and left PGL excision were performed smoothly under alpha blocker maintenance. The pathology report confirmed left adrenal cortical adenoma and left para-aortic PGL. Postoperatively, the blood pressure, biochemical tests, and adrenal hormone assays returned to normal, and related symptoms disappeared and were relatively stable during the follow-up period of two years.ConclusionsThis is the first case of left para-aortic PGL coexisting with an ipsilateral aldosterone-producing adenoma presenting as a left para-aortic tumor associated with bilateral adrenal tumors. Awareness of the rarity of this coexistence can avoid unexpected disasters during the process of evaluation and management.