Limited Diagnostic Utility of Chromogranin A Measurements in Workup of Neuroendocrine Tumors

Background: Plasma chromogranin A (CgA) is related to tumor burden and recommended in the follow-up of patients diagnosed with neuroendocrine tumors (NETs). The use of CgA in the workup of a suspected NET is more questionable. Objective: To assess the positive predictive value (PPV) of CgA plasma concentrations above the upper reference limit (URL) in patients with suspected NET. Method: Patients referred to the NET Centre, Rigshospitalet, Copenhagen from 2015 to 2019 with clinically suspected NET were included if a CgA measurement was performed prior to referral. The utility of CgA was assessed by comparing pre-referral CgA concentrations to the outcome of a thorough workup. In 47 selected cases with continuously unexplained elevated CgA concentrations, a processing-independent analysis (PIA) for CgA was performed. Results: A total of 197 patients were included. NET was ultimately diagnosed in 25 patients. CgA plasma concentrations were above the URL (elevated) in 19/25 patients diagnosed with NET. In total, 167/197 had elevated CgA concentrations at referral. The positive predictive value (PPV) of elevated CgA concentration was 11% (19/167). Proton pump inhibitor (PPI) treatment was identified as the possible cause of CgA elevation in 55/148 patients with falsely elevated CgA. CgA concentration was normal in 28/47 patients when using PIA. Conclusion: Our data do not support using measurement of CgA for screening when NET is suspected since the PPV was rather low. PPI treatment is a common cause of increased CgA concentrations and should always be discontinued before CgA measurement. PIA of CgA could be a way of excluding NET when suspicion is based primarily on elevated CgA.

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Processing-Independent Quantitation of Chromogranin A in Plasma from Patients with Neuroendocrine Tumors and Small-Cell Lung Carcinomas

Clinical Chemistry ◽

10.1373/clinchem.2006.076158 ◽

2007 ◽

Vol 53 (3) ◽

pp. 438-446 ◽

Cited By ~ 23

Author(s):

Tine Børglum ◽

Jens F Rehfeld ◽

Lars B Drivsholm ◽

Linda Hilsted

Keyword(s):

Amino Acid ◽

Neuroendocrine Tumors ◽

Chromogranin A ◽

Plasma Concentrations ◽

Tumor Burden ◽

Small Cell ◽

Size Exclusion ◽

Small Cell Lung ◽

Lung Carcinomas ◽

The Individual

Abstract Background: Most neuroendocrine tumors express chromogranin A (CgA). The posttranslational processing of neuroendocrine proteins such as CgA is often specific for the individual tumor. To cope with this variability and improve tumor diagnosis, we developed a processing-independent analysis (PIA) method to measure the total CgA product. Methods: For PIA, samples underwent trypsin treatment followed by measurement of CgA by the “CgA(340→)” assay, in which the antiserum binds an epitope starting at amino acid 340 of CgA and including amino acid residues located in the C-terminal direction. The diagnostic accuracy of the CgA PIA and 3 sequence-specific assays for CgA were evaluated on plasma samples from patients with neuroendocrine tumors and small-cell lung carcinomas. Furthermore, we investigated whether the CgA plasma concentrations correlated with the tumor burden. Results: Size-exclusion chromatography of plasma showed that CgA immunoreactivity mainly consisted of high–molecular-weight forms, indicating that neuroendocrine tumors may secrete large amounts of poorly processed CgA. Accordingly, trypsination of plasma from 54 patients with neuroendocrine tumors or small-cell lung carcinomas increased the CgA(340→) immunoreactivity up to 500-fold. Both the CgA(340→) assay and the PIA measured significantly higher plasma concentrations in patients with very extensive disease than in patients with less widespread disease. The diagnostic sensitivity was 0.91 when using the CgA(340→) assay and 0.82 using the CgA PIA. Conclusion: The CgA(340→) assay and CgA PIA are both useful for diagnosis of neuroendocrine tumors and small-cell lung carcinomas and both assays correlate with tumor burden.

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Disappearance Rate of Catecholamines, Total Metanephrines, and Neuropeptide Y from the Plasma of Patients after Resection of Pheochromocytoma

Clinical Chemistry ◽

10.1093/clinchem/47.6.1075 ◽

2001 ◽

Vol 47 (6) ◽

pp. 1075-1082 ◽

Cited By ~ 43

Author(s):

Eric Grouzmann ◽

Marc Fathi ◽

Michel Gillet ◽

Antoine de Torrenté ◽

Claudia Cavadas ◽

...

Keyword(s):

Neuropeptide Y ◽

Plasma Concentrations ◽

Amperometric Detection ◽

Reference Interval ◽

Diagnostic Value ◽

Relative Increase ◽

Time Curve ◽

Reference Limit ◽

Upper Reference Limit ◽

Total Sulfate

Abstract Background: Plasma free metanephrines are a more reliable analyte to measure than catecholamines for the biochemical diagnosis of pheochromocytomas. We hypothesized that the long persistence of total (sulfate-conjugated plus free) metanephrines in the blood might have a significant diagnostic value. Methods: We measured plasma concentrations of catecholamines and total metanephrines (sulfate-conjugated plus free forms) by HPLC with amperometric detection, and neuropeptide Y (NPY) by an amplified ELISA in seven patients before and after removal of their pheochromocytomas. The results for catecholamine, total metanephrines, and NPY in each patient were analyzed for up to 120 min, starting from the time of tumor vessel clamping. The persistence of analytes was quantified as the area under the concentration–time curve over 120 min. Results: On the basis of the upper reference limit for each variable, plasma free norepinephrine (NE) and epinephrine (E) concentrations were increased preoperatively in at least one sample in seven and six patients, respectively. Total normetanephrine (NMN) and metanephrine (MN) were increased in all samples in seven and six patients, respectively. NPY was increased 2- to 465-fold. After removal of the tumor, MN and NMN showed a higher average relative increase above the upper limit of the reference interval than NE and E (P = 0.05), whereas NPY was intermediate. The persistence of increased values was significantly shorter for catecholamines than for metanephrines. The half-life estimated by nonlinear regression was 12.3 ± 7.8 min for NPY. Significant correlations were observed among NE, E, NMN, MN, and NPY concentrations, but parent markers (E and MN or NE and NMN) did not appear significantly intercorrelated. Conclusions: A larger increase and a longer persistence of total metanephrines (reflecting predominantly sulfo-conjugated metanephrines) than catecholamines and NPY in plasma may contribute to their greater diagnostic accuracy in pheochromocytoma.

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A pharmacogenetic model predicting low paclitaxel clearance based on the DMET platform.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2597 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2597-2597

Author(s):

Annemieke J.M. Nieuweboer ◽

Anne-Joy M. de Graan ◽

Laure Elens ◽

Marcel Smid ◽

John W. M. Martens ◽

...

Keyword(s):

Positive Predictive Value ◽

Prediction Model ◽

Predictive Value ◽

Plasma Concentrations ◽

Sampling Strategy ◽

High Sensitivity ◽

Cancer Drug ◽

Drug Metabolizing Enzyme ◽

Validation Set ◽

Metabolizing Enzyme

2597 Background: Paclitaxel (PTX) is a commonly used cytotoxic agent. It is metabolized by P450 cytochrome iso-enzymes CYP3A4 and CYP2C8 and has high interindividual variability in pharmacokinetics (PK) and toxicity. Here, we present a genetic prediction model to identify patients with low PTX clearance (CL) using the new Drug-Metabolizing Enzyme and Transporter (DMET; Affymetrix) platform, capable of detecting 1,936 genetic variants (SNPs) in 225 genes. Methods: In a PK study, 270 Caucasian cancer patients were treated with PTX. PK parameters were determined using a limited sampling strategy. HPLC or LC-MS/MS were used to determine PTX plasma concentrations and non-linear mixed effects modelling (NONMEM) was used to estimate individual unbound CL from previously developed PK population models. Subsequently, the cohort of patients was randomly split into a training and validation set. In all patients, the presence of SNPs in metabolic enzymes and transporters was determined using the DMET platform. Selected SNPs were subsequently validated in the validation set. Results: Baseline characteristics were comparable in both sets. The mean CL of the total cohort was 488 ± 149 L/h and the threshold for low CL was set at 339 L/h (1 SD < total mean CL). 14 SNPs were selected to be included in the prediction model and validated in the validation set. For none of these 14 SNPs, evidence for a biological plausible link to taxane metabolism exists. The developed prediction model had a sensitivity of 95% to identify low PTX CL, a positive predictive value of 22% and remained significantly associated with low CL after multivariate analysis correcting for age, gender and Hb levels at start of therapy (P=0.024). Conclusions: This is the first considerably-sized application of the DMET platform to explain PK variability of a widely used anti-cancer drug. Although this validated prediction model for PTX CL had a high sensitivity, its positive predictive value is too low to be of direct clinical use. Likely, genetic variability in DMET genes alone does not sufficiently explain PTX CL, as for example environmental factors may also influence PTX metabolism.

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Rapid determination of serum myoglobin with a routine chemistry analyzer

Clinical Chemistry ◽

10.1093/clinchem/39.4.653 ◽

1993 ◽

Vol 39 (4) ◽

pp. 653-658 ◽

Cited By ~ 6

Author(s):

A J Bakker ◽

D A Boymans ◽

D Dijkstra ◽

J P Gorgels ◽

R Lerk

Keyword(s):

Predictive Value ◽

Rapid Determination ◽

Reference Interval ◽

High Dose ◽

Reference Limit ◽

Hook Effect ◽

Upper Limit ◽

Upper Reference Limit ◽

Serum Myoglobin

Abstract A turbidimetric immunoassay system (Turbitime system, Behringwerke AG) allows rapid determination of myoglobin in serum. We adapted the reagents for this myoglobin assay (Turbiquant myoglobin) for use with a Hitachi 717 analyzer. No high-dose hook effect was observed up to 15,000 micrograms/L. Interassay CVs were 4.6% (mean = 72.0 micrograms/L; n = 9) and 2.5% (mean = 365.6 micrograms/L; n = 11). The calibration curve was stable for at least 1 month. Hemolysis did not interfere, and turbidity from lipemia interfered only when absorbance exceeded 2.0 A. Results of this method (y) correlated well with those by the Turbitime method (y = 1.256x - 44.1 micrograms/L; n = 91; r = 0.991) and by a commercially available radioimmunoassay (Byk-Sangtec; y = 0.739x - 42.2 micrograms/L; n = 94; r = 0.991). The upper limit (95th percentile) of the reference interval for myoglobin was estimated at 57.9 micrograms/L. The positive predictive value for results of myoglobin at admission was 89% with this upper reference limit and 99% with 100 micrograms/L, whereas the negative predictive value was about 60% for both limits.

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Evaluation of plasma N-terminal pro-B-type natriuretic peptide levels in healthy North American Salukis with normal echocardiographic measurements.

10.1101/2021.11.03.467139 ◽

2021 ◽

Author(s):

Tamilselvam Gunasekaran ◽

Christopher Brennan ◽

Robert Sanders

Keyword(s):

Body Weight ◽

Heart Disease ◽

Natriuretic Peptide ◽

Plasma Concentrations ◽

Clinical Use ◽

Reference Limit ◽

Cardiac Health ◽

Percentile Method ◽

Reference Limits ◽

Upper Reference Limit

Measurement of N‐terminal pro‐B‐type natriuretic peptide (NT-proBNP) levels has been shown to have clinical significance for diagnosis and management of heart disease in dogs. Evaluation of current reference limits for specific breeds is necessary to ensure the test can accurately distinguish between healthy and diseased animals. The objective of this study is to evaluate the adequacy of currently established NT-proBNP reference limits for clinical use in healthy Salukis. Cardiac health of 33 clinically healthy Salukis was evaluated via echocardiography using available breed standards. Plasma concentrations of NT-proBNP were measured using a commercially available assay. A one-sided 97.5% upper reference limit for the NT-proBNP concentrations was calculated using non-parametric percentile method. The 97.5% upper reference limit was 769 pmol/L (90% CI, 547-1214 pmol/L) for the study dogs. This upper reference limit was within the currently established non-breed specific NT-proBNP upper reference limit of 900 pmol/L. No relationship between sex, age, or body weight on plasma levels of NT-proBNP was noted. Results of this study supports the use of currently available non-breed specific NT-proBNP cut-off values for clinical evaluation of healthy Salukis.

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Standard Pre- and Postoperative Determination of Chromogranin A in Resectable Non-Functioning Pancreatic Neuroendocrine Tumors - Diagnostic Accuracy: NF-pNET and Low Tumor Burden

Digestive Surgery ◽

10.1159/000370007 ◽

2014 ◽

Vol 31 (6) ◽

pp. 407-414 ◽

Cited By ~ 11

Author(s):

Anneke P.J. Jilesen ◽

Olivier R.C. Busch ◽

Thomas M. van Gulik ◽

Dirk J. Gouma ◽

Els J.M. Nieveen van Dijkum

Keyword(s):

Diagnostic Accuracy ◽

Neuroendocrine Tumors ◽

Chromogranin A ◽

Tumor Burden ◽

Pancreatic Neuroendocrine Tumors

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Correlation between Lipid-Associated Sialic Acid and Tumor Burden in Melanoma

The International Journal of Biological Markers ◽

10.1177/172460089400900408 ◽

1994 ◽

Vol 9 (4) ◽

pp. 247-250 ◽

Cited By ~ 9

Author(s):

A.C. Buzaid ◽

A.B. Sandler ◽

C.L. Hayden ◽

J. Scinto ◽

W.-J. Poo ◽

...

Keyword(s):

Sialic Acid ◽

Positive Predictive Value ◽

Tumor Marker ◽

Metastatic Disease ◽

Predictive Value ◽

Clinical Evidence ◽

Tumor Burden ◽

High Tumor Burden ◽

Significant Difference ◽

The Relationship

Recent studies have suggested that lipid-associated sialic acid (LSA) may be a useful tumor marker for monitoring patients with melanoma, but the relationship between LSA and tumor burden has not been previously studied. We therefore examined LSA levels in 240 patients of whom 169 had no clinical evidence of disease (NED) and 71 had metastatic disease. There was a statistically significant difference in LSA levels in patients with NED compared with metastatic disease as well as those with high tumor burden compared with low or intermediate tumor burden. There was no difference between the groups with low and intermediate tumor burden. An LSA level of 25 mg/dl provided a positive predictive value of 70% and a negative value of approximately 80%. Our data show that LSA levels correlate with tumor burden in patients with melanoma.

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