Clinical Significance of Random Urinary Vanillylmandelic Acid in Patients with Neuroblastoma / 임상소아혈액종양

BACKGROUND: To evaluate the value of random urinary vanillylmandelic acid (VMA) as a surrogate marker for monitoring tumor response and predicting outcome in patients with neuroblastoma (NB). METHODS: Medical records of 91 patients newly diagnosed with NB at the Samsung Medical Center between June 2014 and August 2017 were reviewed. Clinical associations and other prognostic factors, including age at diagnosis, stage, pathologic subtype, MYCN amplification, and other cytogenetic aberrations, were analyzed. Furthermore, the significance of random urinary VMA level in predicting outcome and tumor response was also evaluated. RESULTS: The median random urinary VMA level at diagnosis was 27.9 (range: 1.7–600) mg/g creatinine. Abdominal primary site, male sex, advanced stage, less differentiated pathology (poorly differentiated, undifferentiated), 11q deletion, and high-risk tumor were associated with a higher VMA level at diagnosis. The VMA level decreased during chemotherapy (28.4%, 16.9%, and 9.6% of the VMA level at diagnosis after 3, 6, and 9 cycles of chemotherapy, respectively). A higher VMA level at diagnosis tends to be associated with a better overall survival in high-risk patients with borderline significance (58.3±18.6% vs. 76.5±13.4%, P=0.050). However, in the multivariate analysis, the VMA level was not a significant predictor of survival. A slower reduction in VMA level during chemotherapy was not associated with a worse overall survival. However, event free survival was significantly better in the rapid responder group. CONCLUSION: A higher VMA level was associated with high-risk features at diagnosis of NB. Random urinary VMA is a valuable marker for monitoring NB response during chemotherapy.

Report on the External Quality Assessment Scheme for Metabolite Testing in Korea (2016–2017)

External quality assessment (EQA) trials of conventional newborn screening tests for phenylketonuria, galactosemia, congenital adrenal hyperplasia, maple syrup urine disease, homocystinuria, and congenital hypothyroidism, as well as extended newborn screening tests using tandem mass spectrometry, were performed twice in 2016 and 2017. A total of 44 specimens in the form of dried blood spots were distributed in each trial to 16 laboratories. The response rate of these laboratories was 100%. The mean, standard deviation, coefficient of variation, median, and cut-offs were evaluated for each analyte in the newborn screening tests. EQA trials for the analyses of methylmalonic acid, vanillylmandelic acid, catecholamines, metanephrines, organic acids, and amino acids were also performed. A well-designed EQA program and continuous education would improve the performance of metabolite testing.

Pheochromocytoma Developed in a Boy with Multiple Endocrine Neoplasia Type 2A Confirmed by the RET Proto-Oncogene Mutation / 임상소아혈액종양

A 9-year-old boy presented with increased sweating and abdominal pain. His mother and uncle had been diagnosed with bilateral pheochromocytoma and medullary thyroid carcinoma. Magnetic resonance imaging of the boy's abdomen revealed a 7.5 cm×7.0 cm×6.0 cm mass with a thick peripheral enhancing wall and fluid-fluid level at the right suprarenal region. His ¹²³I-meta-iodobenzylguanidine (MIBG) scan showed a large mass with increased MIBG uptake in the right adrenal gland. The levels of serum norepinephrine, urine epinephrine/norepinephrine, metanephrine, and vanillylmandelic acid were elevated. He, his mother, and two sisters tested positive for the known mutation of multiple endocrine neoplasia type 2A, Cys634Tyr in RET proto-oncogene. Laparoscopic tumor excision and right adrenalectomy were performed. Final diagnosis was pheochromocytoma with malignant behavior, based on adrenal gland scoring scale. However, there was no overt metastasis. After surgery, his symptoms resolved and abnormal laboratory tests were normalized.

Pheochromocytoma Developed in a Boy with Multiple Endocrine Neoplasia Type 2A Confirmed by the RET Proto-Oncogene Mutation / 임상소아혈액종양

A 9-year-old boy presented with increased sweating and abdominal pain. His mother and uncle had been diagnosed with bilateral pheochromocytoma and medullary thyroid carcinoma. Magnetic resonance imaging of the boy's abdomen revealed a 7.5 cm×7.0 cm×6.0 cm mass with a thick peripheral enhancing wall and fluid-fluid level at the right suprarenal region. His ¹²³I-meta-iodobenzylguanidine (MIBG) scan showed a large mass with increased MIBG uptake in the right adrenal gland. The levels of serum norepinephrine, urine epinephrine/norepinephrine, metanephrine, and vanillylmandelic acid were elevated. He, his mother, and two sisters tested positive for the known mutation of multiple endocrine neoplasia type 2A, Cys634Tyr in RET proto-oncogene. Laparoscopic tumor excision and right adrenalectomy were performed. Final diagnosis was pheochromocytoma with malignant behavior, based on adrenal gland scoring scale. However, there was no overt metastasis. After surgery, his symptoms resolved and abnormal laboratory tests were normalized.

Annual Report on the External Quality Assessment Scheme for Biochemical Genetics in Korea (2015)

Two external quality assessment (EQA) trials of conventional newborn screening tests for phenylketonuria, galactosemia, congenital adrenal hyperplasia, maple syrup urine disease, homocystinuria, and congenital hypothyroidism, as well as newborn screening tests using tandem mass spectrometry, were performed in 2015. A total of 44 specimens in the form of dried blood spots were distributed to 16 laboratories and the response rate of these laboratories was 100%. The mean, standard deviation, coefficient of variation, median, and cut-offs were evaluated for each analyte in the newborn screening tests. Two EQA trials for the analyses of methylmalonic acid, vanillylmandelic acid, catecholamines, metanephrines, organic acids, and amino acids were also performed. A well-designed EQA program and continuous education would improve the performance of biochemical genetics tests.

Annual Report on the External Quality Assessment Scheme for Biochemical Genetics in Korea (2014)

Two trials of external quality assessment (EQA) of conventional newborn screening tests for phenylketonuria, galactosaemia, congenital adrenal hyperplasia, maple syrup urine disease, homocystinuria, and congenital hypothyroidism, as well as newborn screening tests were performed using tandem mass spectrometry in 2014. A total of 39 specimens in the form of dried blood spots were distributed to 16 laboratories and the response rate of these laboratories was 100%. Screening tests for phenylketonuria and congenital hypothyroidism did not meet the accepted performance criteria in some laboratories. The mean, standard deviation, coefficient of variation, median, and cut-offs were evaluated for each analyte in the newborn screening tests. Two trials of EQA for the analyses of methylmalonic acid, vanillylmandelic acid, catecholamines, metanephrines, organic acids, and amino acids were also performed. A well-designed EQA program and continuous education would improve the performance of biochemical genetic testing.

Determination of four biogenic amine metabolites in urine by high-performance liquid chromatography / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To establish a method for simultaneously determining vanilmandelic acid (VMA), 5-hydroxyindoleacetic (5-HIAA), 3, 4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in urine by high-performance liquid chromatography (HPLC).</p><p><b>METHODS</b>After being filtered with a 0.45 µm membrane syringe filter, the urinary samples were injected directly into the HPLC system using a C18 chromatographic column and a fluorescence detector. The excitation and emission wavelengths were chose as 280 nm and 315 nm, respectively, and the urinary samples were carried with a mobile phase of methanol-0.1 mol/L phosphate buffered solution (V/V = 20:80) at a flow rate of 1.0 ml/min and an injection volume of 20 µl.</p><p><b>RESULTS</b>Using the method reported here, the correlation coefficients of VMA, 5-HIAA, DOPAC, and HVA were 0.9999, 0.9998, 0.9997, 0.9999, respectively, over linear ranges of 0-2.5, 0-2.0, 0-2.0, and 0-2.5 µg/ml, the minimum detectable concentrations were 0.006, 0.008, 0.012, and 0.0082 µg/ml, the average precisions were 4.2%, 3.7%, 4.9%, and 3.6%, and the recovery rates were 91%∼102%, 93%∼101%, 94%∼101%, and 89%∼ 102%.</p><p><b>CONCLUSION</b>This determination method is simple, efficient, accurate, and sensitive for the simultaneous detection of VMA, 5-HIAA, DOPAC, and HVA in urine.</p>

Annual Report on External Quality Assessment of Biochemical Genetics in Korea (2013) / 임상검사와정도관리

Two trials of external quality assessment (EQA) of conventional newborn screening tests for phenylketonuria, galactosaemia, congenital adrenal hyperplasia, maple syrup urine disease, homocystinuria, and congenital hypothyroidism, as well as of newborn screening tests using tandem mass spectrometry were performed in 2013. A total of 32 specimens in the form of dried blood spots were distributed to 16 laboratories and the response rate of these laboratories was 100%. Total T4, free T4, 17-hydroxyprogesterone, leucine, isoleucine, galactose, methionine, alanine, C8/C2, C8/C10, and C5-OH did not meet the accepted performance criteria. The mean, standard deviation, coefficient of variation, median, and cut-offs were evaluated for each analyte in the newborn screening tests. Two trials of EQA for the analyses of methylmalonic acid, vanillylmandelic acid, very long fatty acids, organic acids, and amino acids were also performed. A well-designed EQA program and continuous education would improve the performance of biochemical genetic tests.

Left-sided giant adrenal myelolipoma secreting catecholamine.

Adrenal myelolipoma (AML) is a rare benign tumor composed of mature adipose and hematopoietic tissue. Most of these patients are asymptomatic and the tumors are non-secreting. We present a case with a large functional adrenal myelolipoma, wherein the patient was hypertensive and biochemistry revealed increase in 24 hours urinary Vanillylmandelic Acid (VMA), a metabolite of catecholamine. The mass was removed surgically and diagnosed as adrenal myelolipoma on histopathological examination. Both his blood pressure and urinary VMA returned to normal following surgery, which suggested that the mass was functioning and was secreting catecholamine. To the best of our knowledge, a catecholamine secreting adrenal myelolipoma has been reported in the literature only once previously. The association of hypertension and adrenal myelolipoma may not be entirely coincidental, as it may be associated with secreting catecholamine, as seen in our case. We also review the literature on functioning adrenal myelolipoma.

A Case of Paroxysmal Pheochromocytoma with Normal Catecholamine Levels / 대한내과학회지

A 53-year-old woman had a 1.7 cm left adrenal mass on an abdominal computed tomography (CT) scan. She presented with paroxysmal headache, palpitation, sweating, and hypertension. The patient was highly suspected of having a pheochromocytoma, but measurements of 24-hour urinary metanephrine, catecholamines, and vanillylmandelic acid were normal. Plasma and urine catecholamine levels were within the normal range even during paroxysmal episodes. A scintigraphic study with 131I-metaiodobenzylguanidine (MIBG) revealed selective concentration of the radiotracer, corresponding to the CT mass. The patient underwent a left adrenalectomy and the pathological examination confirmed the diagnosis of pheochromocytoma. In this report, we describe a rare case of a symptomatic pheochromocytoma with normal catecholamine levels. Our case illustrates that routine nuclear scintigraphy, such as 131I-MIBG, should be performed even in cases with normal hormonal testing for all patients with high clinical suspicion of pheochromocytoma.

The predictive value of urinary vanillylmandelic acid testing in the diagnosis of phaeochromocytoma at the University Hospital of the West Indies / El valor predictivo de la prueba del ácido vanilmandélico en orina para el diagnóstico de la feocromositoma en el Hospital Universitario de West Indies

OBJECTIVE: To investigate the positive predictive value (PPV) of urinary vanillylmandelic acid (VMA) testing in the diagnosis of phaeochromocytoma and to describe the features associated with phaeo chromocytoma at the University Hospital of the West Indies (UHWI). SUBJECTS AND METHODS: There were 551 VMA tests performed from January 2003 to June 2009 and 122 tests in 85 patients were elevated (ie > 35 µmol/24 hr). The study patients were categorized as: (i) 'surgical' (5 patients who underwent surgery) or (ii) 'non-surgical' (remaining 80 patients). Forty medical charts (out of 85) were reviewed using a standardized data extraction form. RESULTS: The median age for patients in the non-surgical group (with charts reviewed, n = 35) was 36 years (range 9-70) and the median VMA was 43 µmol/24 hr (IQR 38-51). Of these patients, 83% had one or no symptom typical of phaeochromocytoma. In the surgical group the median VMA was 58 µmol/24 hr (IQR 44-101); phaeochromocytoma was confirmed histologically in 3 patients, all of whom had several symptoms typical of catecholamine excess. VMA testing had a PPV of 8%, specificity of 79% and sensitivity of 100%. CONCLUSIONS: VMA testing at UHWI has poor specificity and high sensitivity. These results contrast with international data showing that VMA testing is poorly sensitive but highly specific. The use of assays with higher specificity (egplasma or urinary metanephrines) may represent a more cost-effective approach to biochemical screening at UHWI.

OBJETIVO: Investigar el valor predictivo positivo (VPP) de las pruebas del ácido vanilmandélico urinario (VMA) en el diagnóstico de la feocromositoma y describir las características asociadas con la feocromositoma en el Hospital de la Universidad de West Indies (HUWI). SUJETOS Y MÉTODOS: Se realizaron unas 551 pruebas de VMA de enero de 2003 a junio de 2009, y 122 de las pruebas en 85 pacientes tuvieron resultados elevados (ie > 35 µmol/24 hr). Los pacientes del estudio fueron clasificados como: (i) "quirúrgicos" (5 pacientes que se sometieron a cirugía) ó (ii) "no quirúrgicos" (los 80 pacientes restantes). Se revisaron cuarenta historias clínicas (de 85) mediante un formulario estandarizado de extracción de datos. RESULTADOS: El promedio de edad de los pacientes en el grupo no quirúrgico (con historias clínicas, n = 35) fue de 36 años (rango 9-70) y la mediana VMA fue 43 µmol/24 h (IQR 38-51). De estos pacientes, 83% tenían uno o ningún síntoma típico de la feocromositoma. En el grupo quirúrgico la mediana VMA fue 58 µmol/24 h (IQR 44-101). La feocromositoma fue confirmada histológicamente en 3 pacientes, cada uno de los cuales presentó síntomas típicos de exceso de catecolaminas. Las pruebas de VMA tuvieron un VPP de 8%, una especificidad de 79%, y una sensibilidad de 100%. CONCLUSIONES: Las pruebas de VMA en HUWI poseen pobre especificidad y alta sensibilidad. Estos resultados contrastan con los datos internacionales que muestran que la prueba de VMA es pobremente sensible pero altamente específica. El uso de ensayos con mayor especificidad (por ejemplo, metanefrinas plasmáticas o urinarias) puede representar un método costo-efectivo a la hora de realizar el pesquisaje bioquímico en HUWI.

Predictive Characteristics of Malignant Pheochromocytoma

PURPOSE: The prognosis of patients with malignant pheochromocytoma is poor, but the predictive factors are not well understood. We aimed to identify the clinical characteristics predictive of malignancy after initial surgical removal in patients with pheochromocytoma. MATERIALS AND METHODS: We retrospectively reviewed the records of 152 patients diagnosed with pheochromocytoma, including 5 (3.3%) with metastasis at the time of the initial surgical excision and 12 (7.9%) who developed metastasis during follow-up. To determine the factors predictive of malignancy, we compared clinical, radiographical, and urinary chemical findings between patients with benign and malignant disease. Mean follow-up was 41.5 months (range, 0.9-298 months) after surgery. RESULTS: Malignant tumors were significantly larger than benign tumors (11.1+/-4.0 cm vs. 6.2+/-3.4 cm, p5.5 cm; 90.6% vs. 81.2%, p=0.025) and higher 24-hour secretion of vanillylmandelic acid (>2.1 vs. 5.5 cm) and minimally elevated 24-hour urinary vanillylmandelic acid (< or =2.1 mg/day/cm) were significantly associated with a higher probability of a malignant pheochromocytoma portending a lower metastasis-free survival and mandating more rigorous follow-up after surgery.

Role of specific clone of lymphocytes, [CD4[+] and CD8[+]] and the sympathetic activity in pathophysiology of altered immunity in ischemic stroke

Ischemic stroke is one of the major causes of high morbidity and mortality allover the world. The understanding of the pathophysiology of post-ischemic immune response is very limited. Cerebral ischemic stroke affects the normally well-balanced interplay of the 2 super systems: the nervous and the immune system. T-cell lymphocytes, [CD4[-], CD8[-]], may contribute to altered immunity associated with stroke. Increased sympathetic activity during ischemic stroke may have a role in altered lymphocytes function. The present study investigated the contribution of CD4[-] and CD8[-] and the sympathetic activity in altered immunity in ischemic stroke. Determination of CD4[-] and CD8[-] percentage in patient's blood was done by flowcytometry. Evaluation of sympathetic activity done by measuring urinary vanilmandelic acid [VMA] levels by spectrophotometry. The study also correlated the changes of these parameters with specific clinical and diagnostic variables in stroke. The study showed that CD4[-] and CDS percentage were significantly lower [p<0.001], while CD4[-] /CD8[-] ratio was significantly higher [p<0.001] in patients than controls. There was also significantly increased [p<0.001] mean urinary VMA excretion levels [mg/day] in patients compared to control group. Significantly lower CD4[-]% and CD4[-] /CD8[-] ratio and higher CD8[-]% were found in patients with recurrent stroke or history of transient ischemic attacks, progressive strokes and large size of infarction in comparison to other comparable patients. The study indicated that patients with ischemic strokes may have altered immunity and sympathetic over-activity which may be one of the mechanisms by which modulation of immune response can be induced after stroke. This brain-immune interaction after stroke may have protective, destructive, or regenerative effects in the brain, therefore the development of therapeutic strategies is not straightforward, and must take all these factors into consideration

Pheochromocytoma Damanhour teaching hospital experience

Pheochromocytoma has low incidence of 2-8 case per million persons annually, but it is a lethal disease when it is functioning and undiagnosed. It constitutes 0.1% to 1% of hypertensive patients that is curable by surgery. Our study included twelve patients operated upon at our institute in the last 3 years. Two cases were none functioning; one case of them was presented by internal hemorrhage due to tumor rupture. There were 8 males and 4 females. One child has 10 years old. Two cases were extra adrenal. Three patients presented to us with a mass without hypertension and diagnosed post operatively. Preoperative preparation was done using alpha blocker and beta blocker until the hypertension became normalized. lntra operative and post operative control of blood pressure with caring our patients in ICU till the condition became stable. No mortality or significant morbidity had occurred. Post operative normalization of blood pressure had been achieved in all patients

Neuroblastoma Originating from Extra-abdominal Sites: Association with Favorable Clinical and Biological Features

Neuroblastomas originating from different sites might have different clinical and biological characteristics. In the present study, the clinical (age, sex and stage) and biological (N-myc amplification, Shimada pathology and levels of lactate dehydrogenase, ferritin and neuron-specific enolase) characteristics of patients with newly diagnosed neuroblastoma were compared according to the site of tumor origin (extra-abdominal versus abdominal). The event-free survival rate (EFS) was also compared between the two groups. Among 143 neuroblastomas, 115 tumors originated from the abdomen, 26 from extra-abdominal sites and 2 from unknown primary sites. Frequencies of stage 4 tumor and N-myc amplified tumor were lower in the extra-abdominal group than in the abdominal group (34.6% vs. 60.0%, P=0.019 and 4.2% vs. 45.0%, P<0.001, respectively). Levels of lactate dehydrogenase, ferritin and neuron-specific enolase were significantly lower in the extra-abdominal group than in the abdominal group. The probability of 5-yr EFS (+/-95% confidence interval) was higher in the extra-abdominal group than in the abdominal group (94.4+/-10.6% vs. 69.4+/-9.4%, P=0.026). Taken together, neuroblastomas originating from extra-abdominal sites might be associated with more favorable clinical and biological characteristics and a better outcome than neuroblastomas originating from abdomen.

Neuroblastoma Originating from Extra-abdominal Sites: Association with Favorable Clinical and Biological Features

Neuroblastomas originating from different sites might have different clinical and biological characteristics. In the present study, the clinical (age, sex and stage) and biological (N-myc amplification, Shimada pathology and levels of lactate dehydrogenase, ferritin and neuron-specific enolase) characteristics of patients with newly diagnosed neuroblastoma were compared according to the site of tumor origin (extra-abdominal versus abdominal). The event-free survival rate (EFS) was also compared between the two groups. Among 143 neuroblastomas, 115 tumors originated from the abdomen, 26 from extra-abdominal sites and 2 from unknown primary sites. Frequencies of stage 4 tumor and N-myc amplified tumor were lower in the extra-abdominal group than in the abdominal group (34.6% vs. 60.0%, P=0.019 and 4.2% vs. 45.0%, P<0.001, respectively). Levels of lactate dehydrogenase, ferritin and neuron-specific enolase were significantly lower in the extra-abdominal group than in the abdominal group. The probability of 5-yr EFS (+/-95% confidence interval) was higher in the extra-abdominal group than in the abdominal group (94.4+/-10.6% vs. 69.4+/-9.4%, P=0.026). Taken together, neuroblastomas originating from extra-abdominal sites might be associated with more favorable clinical and biological characteristics and a better outcome than neuroblastomas originating from abdomen.

Effect metformin on urinary VMA levels in type II diabetic subjects

The purpose of this study was to observe the effect of metformin on 24-hours urinary VMA levels in newly diagnosed untreated type 2 diabetic subjects. The study consisted of four weeks for each participant with weekly follow up visits. Samples were collected at 0800-0900 hours after over night fast. Study was conducted in the Department of Pharmacology and Therapeutics, BMSI, JPMC, Karachi. Total duration of study was six months. Fifteen newly diagnosed untreated type 2 diabetics, with fasting plasma glucose levels >/= 126 mg/dl on two occasions and/or postprandial glucose levels >/= 200 mg/dl were enrolled in the study. Patients with concurrent illness or diabetic complications were excluded. Metformin was started from 500 mg/day and titrated at weekly intervals according to glycaemic control and the subjects tolerance to the drug. A 24-hour urinary VMA was assessed at day - 0 [before metformin therapy] and day - 28 [4 weeks after metformin therapy] by using VMA reagent kit of Biosystems Spain on Spectronic -21 spectrophotometer USA. Metformin caused highly significant [P < 0.001] reduction in mean fasting plasma glucose from 233.33 +/- 15.62 mg /dl on day-0 to 151.53 +/- 6.02 mg/dl on day - 28, and a significant [P < 0.01] decrease in 24 - hour urinary VMA levels from 5.18 + 0.50 mg / 24 hours on day-0 to 3.32 + 0.28 mg / 24 hours on day-28. Our results indicate that metformin causes highly significant reduction in fasting plasma glucose and a significant decrease in 24 - hour urinary VMA levels in newly diagnosed untreated type 2 diabetic subjects

Metastatic malignant Pheochromocytoma of adrenal gland

Malignant pheochromocytoma is a rare disease with a high mortality. Surgical removal is usually curative while chemotherapy and radiotherapy are palliative treatments. A case of metastatic malignant pheochromocytoma of the right adrenal gland is presented who had fluctuating blood pressure with episodic headache and raised urinary VMA levels. Thoraco-abdominal resection of the tumour resulted in control of blood pressure and patient was asymptomatic at 4 months follow-up

Case report of parathyroid carcinoma with raised urinary catecholamines: a diagnostic dilemma.

Parathyroid carcinoma is often misdiagnosed as thyroid carcinoma clinically and also with fine needle aspiration cytology. Moreover in cases misdiagnosed as thyroid carcinoma pre operatively, raised urinary catecholamines may mislead to a diagnosis of MEN2 A. We report a case of a patient admitted to the surgery department ofour hospital with a swelling in the thyroid region, raised urinary catecholamines and urinary VMA levels, with hypercalciuria and elevated parathyroid hormone levels. It was clinically suspected as thyroid carcinoma with parathyroid adenoma and associated MEN 2A syndrome.