Diagnostic Superiority Research Articles

High-Throughput, Automated, and Accurate Biochemical Screening for Pheochromocytoma: Are We There Yet?

Biochemical testing for pheochromocytoma is a diagnostic challenge due both to the highly variable nature of this rare catecholamine-producing tumor and the technical demands required for accurate and reliable laboratory tests of catecholamine excess. In this issue of Clinical Chemistry , de Jong et al. (1) describe a high-throughput automated liquid–chromatography-tandem mass spectrometry (LC-MS/MS) method enabling simultaneous extraction, concentration, separation, and mass-selective detection of plasma free normetanephrine and metanephrine, the respective O-methylated metabolites of norepinephrine, and epinephrine. This method for measurements of plasma free metanephrines (Note: the term “metanephrines” refers to both normetanephrine and metanephrine) also allows quantification of methoxytyramine, the O-methylated derivative of dopamine and a metabolite normally present in plasma at lower concentrations (<0.1 nmol/L) than free normetanephrine (<0.6 nmol/L) or metanephrine (<0.3 nmol/L). Recognition that catecholamines are metabolized to free metanephrines within pheochromocytoma tumor cells, and that this process is independent of catecholamine release, provides a rationale for use of these metabolites in the diagnosis of pheochromocytoma (2). The diagnostic superiority of metanephrines over catecholamines has led to the recommendation that initial testing for pheochromocytoma should always include measurements of metanephrines in plasma or urine or both (3). Metanephrines in urine are usually measured after an acid hydrolysis step that converts the high concentrations of sulfate-conjugated metabolites into free metanephrines. In part because of this step, concentrations of metanephrines in urine are 2–3 orders of magnitude higher than those for the free metanephrines in plasma. These higher concentrations, along with the simpler matrix, make urinary metanephrines easier to measure than plasma free metanephrines. However, the enzyme responsible for sulfate conjugation is present mainly in gastrointestinal tissues (2). Thus, the free metanephrines produced within tumor cells should provide …

M14-01: Mediastinal staging of NSCLC and 18FDG PET

M14-01: Mediastinal staging of NSCLC and 18FDG PET

Effect of hemodialysis on serum complexed prostate-specific antigen levels

The measurement of prostate-specific antigen (PSA) is a useful tool in the screening and follow-up of prostate cancer, but its diagnostic validity is uncertain in hemodialysis patients. The aim of this study was to evaluate the effects of hemodialysis on serum complexed PSA (cPSA) levels. A total of 36 men (mean age 62.54+/-8.20 years) with end-stage renal disease were enrolled in a prospective study. Serum total PSA (tPSA), free PSA (fPSA) and cPSA, and hematocrit levels were measured before and immediately after dialysis using low-flux membranes in the serum and in the dialysis ultrafiltrate. After hemodialysis, cPSA, fPSA and the fPSA:tPSA ratio increased significantly (p<0.05). However, there was no significant increase in tPSA. fPSA, cPSA and tPSA were not detected in ultrafiltrate. Hematocrit levels increased significantly (p<0.0001) due to hemoconcentration. Of patients with initial serum tPSA and cPSA values and fPSA:tPSA ratios below the cut-off values, none had a post-hemodialysis value greater than the cut-off point. There were weak correlation between the difference in values after and before hemodialysis of hematocrit and cPSA (p=0.035), and between the percentage change in levels before and after hemodialysis of hematocrit and cPSA (p=0.041). Hemodialysis induced elevations in all forms of PSA, but tPSA was the least affected form. cPSA did not show any diagnostic superiority over other forms of PSA. Thus, serum tPSA remains a reliable parameter for follow-up of prostate cancer in uremic patients receiving long-term dialysis. However, further research is needed to explain the pathophysiology of alterations in the concentrations of different forms of PSA.

Placenta Praevia - Comparison of Four Sonographic Modalities

The aim of this study was the evaluation of four ultrasound modalities (transabdominal, perineal, transvaginal and transrectal) to examine placenta praevia or low lying placenta. We prospectively investigated 24 patients after 25 weeks of their pregnancy with suspected placenta praevia or low lying placenta. We analysed picture quality and compared the results of all four scanning modalities with the actual diagnosis made at delivery. The abdominal and perineal approach provided significantly poorer scanning quality (good or moderate in 79/38 %) as compared to the transvaginal and transrectal approach (good or moderate in 83/97 %). We can state similar results concerning accuracy of the diagnosis (abdominal/perineal 42/21 %, transvaginal/transrectal 67/86 %). Our study supports the diagnostic superiority of transvaginal ultrasound in the diagnosis of placenta praevia in comparison to the abdominal/perineal view. We also show that transrectal scanning is at least equivalent in quality and safety without the imminent risks of transvaginal manipulation and infection. The evaluation of the transrectal approach proved equivalent to the standard transvaginal approach in depiction quality and diagnostic safety. Thus, with less potential trauma to the pregnancy, it is a reasonable alternative.

Erythrocyte adhesiveness/aggregation: A novel biomarker for the detection of low-grade internal inflammation in individuals with atherothrombotic risk factors and proven vascular disease

We have introduced a concept of using the erythrocyte as a sensor for the detection of enhanced inflammation-sensitive protein concentrations. We presently evaluated the capability of this new biomarker to detect the presence of inflammation in individuals with a history of a vascular disease as opposed to individuals with atherothrombotic risk factors but no clinically evident vascular disease. The degree of erythrocyte adhesiveness/aggregation was determined in the peripheral venous blood by using a simple blood test. Blood was drawn into a syringe containing sodium citrate and trickled onto a slide at an angle of 30 degrees. The slides were than scanned by a blinded technician by using an image analyzer to determine the area that is covered by the erythrocytes. One hundred fifty-six subjects (61 women and 95 men) of 2586 (1238 women and 1348 men) met the criteria of a definite vascular disease (history of stroke, myocardial infarction, coronary artery bypass grafting, or peripheral vascular disease). The degree of erythrocyte aggregation was significantly (P = .008) higher in men, but not in women, with vascular disease as opposed to these without a vascular disease. The results of receiver operating characteristic curve analysis confirmed the diagnostic superiority of the erythrocyte aggregation biomarker over other commonly used markers of the acute phase in men. Similar results were obtained by using discriminant analysis. Finally, a significant correlation was found between the degree of erythrocyte aggregation and other markers of the acute phase suggesting its relevance for the detection and quantitation of low-grade inflammation in individuals with atherothrombosis. Erythrocyte adhesiveness/aggregation may be a useful biomarker to detect internal inflammation in individuals with atherothrombosis.

Pro-kinetic medications as aids in imaging the small bowel by video-capsule

The m2a wireless video-capsule (Given Imaging Ltd., Israel) is a miniature ingestible camera utilized for the color imaging of the small intestine walls. Despite its diagnostic yield superiority over all other diagnostic modalities, a substantial part of the pathologies are not spotted. Considering the transmitted pictures high quality a resolution problem is ruled out, but rather it is assumed that parts of the intestinal wall surface are missed in the imaging process. Another important problem is the difficulty encountered by the capsule in crossing the antro-duodenal junction, probably due to pyloric hypomotility. Pro-kinetic drugs are capable of increasing the small intestine peristaltic wave velocity and contractile amplitude, thus assisting the video-capsule movements and widening the camera photo arc. The arc width is directly proportional to the surface imaging capacity. A specific dose range (cisapride 25-30 mg, metoclopramide 30 mg approximately) is calculated and an analysis is made of the use of these pro-kinetic drugs to increase the device diagnostic yield. It should be emphasized that: (1) despite a potential risk for complications, such as bleeding from small intestine lesions, radiological studies underline the high safety profile of metoclopramide; (2) increased capsule speed of progress is not expected to cause a loss of imaged area; (3) an oral dose below 15 mg (metoclopramide or cisapride) may not suffice to accelerate the capsule transit through the antro-duodenal junction. The concept is patent protected.

Free or Total Metanephrines for Diagnosis of Pheochromocytoma: What Is the Difference?

Pheochromocytomas, although a rare cause of hypertension, are dangerous tumors that require consideration in large numbers of patients. The resulting low prevalence of these tumors among the tested population and the inadequate sensitivity and specificity of commonly used biochemical tests make diagnosis of pheochromocytoma difficult and time-consuming. As outlined in two articles in this issue of the Journal (1)(2), measurements of plasma concentrations of metanephrines provide a promising, new, highly sensitive test for diagnosis of pheochromocytoma. A negative test result for plasma metanephrines means that a pheochromocytoma is highly unlikely so that no other tests are necessary (3)(4). Thus, measurements of plasma metanephrines provide a particularly good initial diagnostic test for exclusion of pheochromocytoma. The diagnostic superiority of plasma metanephrines over plasma or urinary catecholamines and urinary vanillylmandelic acid is clear (3)(4)(5)(6). What remains unclear, as illustrated in the two articles in this issue of the Journal (1)(2), is whether measurements of plasma free (unconjugated) metanephrines or total metanephrines provide the better diagnostic test, and how these tests differ. Also unclear is how these tests differ from measurements of urinary metanephrines. Part of the confusion about tests of urinary total or fractionated metanephrines and plasma free, unconjugated, or total metanephrines stems from the unfortunate and confusing terminology used to distinguish these analytes. The term “metanephrines” describes two catecholamine metabolites: …

Clinical Situations in which Musculoskeletal Ultrasound is Helpful

Musculoskeletal ultrasound (MSUS) has newly evolved by the mechanical improvement of the machine over past several years, becoming a part of imaging techniques for the evaluation of variable diseases in the musculoskeletal system. MSUS has proven diagnostic superiority in pathologies including rotator cuff disease of the shoulder, lateral epicondylitis of the elbow, diseases of the peripheral nerve, detection of intra-articular loose bodies and soft tissue foreign bodies, and in evaluating small superficial soft tissue tumors such as ganglion, epidermoid cyst, and glomus tumor. Besides, MSUS is very useful for obtaining tissue or fluid via percutaneous fine needle aspiration and/or biopsy for the histopathologic diagnosis. Combining MSUS with MR would play a great role in the field of the diagnostic imaging of the musculoskeletal system. The MSUS examiner should have the knowledge of cross-sectional anatomy, and of the mechanical and physical properties of ultrasound in order to interpret the ultrasound findings accurately and properly, and to avoid diagnostic errors due to variable artifacts subsequently. The goal of this article is to introduce the capabilities of MSUS in certain kinds of clinical situation and to familiarize the reader with MSUS. For the purpose, author intends to describe this article according not to the disease-, or organ-based, but to the clinical problem-based format.

IS EVERYTHING ALL RIGHT IF NOTHING SEEMS WRONG? A SIMPLE METHOD OF ASSESSING THE DIAGNOSTIC VALUE OF ENDOSCOPIC PROCEDURES WHEN A GOLD STANDARD IS ABSENT

Purpose We demonstrate a simple yet comprehensive method to evaluate the sensitivity of endoscopic procedures when no gold standard is available. Materials and Methods In 208 consecutive patients with superficial bladder cancer 328 endoscopies were performed to compare the sensitivity of white light and 5-aminolevulinic acid induced fluorescence endoscopy. Both procedures were performed during the same session. Results The maximum interval of observable sensitivity for 5-aminolevulinic acid induced fluorescence endoscopy ranged between 78 and 97.5%, and the best estimate for sensitivity based on realistic assumptions was 93.4% (95% confidence intervals 90 to 97.3). The best sensitivity estimate for white light endoscopy was 46.7% (95% confidence intervals 39.4 to 54.3, maximum range 47.2 to 53%). Conclusions This method to determine the maximum possible range of sensitivity estimates for endoscopic procedures without a gold standard is easily applied. Depending on the assumptions a range of reasonable scenarios can be constructed and the corresponding sensitivities can be reported. This approach gives fast and valid results, and could further indicate the diagnostic superiority of 5-aminolevulinic acid induced fluorescence compared to white light endoscopy.

Computed Tomography of Diffuse Infiltrative Lung Diseases: Value and Limitations

In the last 10 years there has been an increasing amount of literature on the application of high-resolution computed tomography (HRCT) to the evaluation of patients with diffuse infiltrative lung disease. Although the diagnostic superiority of HRCT over chest radiography in most instances is not in doubt, the clinical indications for HRCT and the selection criteria for patients who will benefit from HRCT continue to evolve. The limitations as well as the advantages of HRCT need to be understood. In addition to the clinical applications of HRCT, the ability of HRCT to quantify various disease patterns has lent insights into the biologic and functional behaviour of several diffuse lung diseases.

Intravenous Albunex during transesophageal echocardiography: Quantitative assessment by videodensitometry and integrated backscatter analysis from unprocessed radiofrequency signals

This study investigates the comparative sensitivity of video and radiofrequency imaging to detect changes of the myocardial acoustic properties after intravenous Albunex. Thirty-six patients received Albunex, 0.08 and 0.22 ml/kg intravenously, during transesophageal imaging of the ventricular short axis. Analysis of video images was performed in all patients and of radiofrequency data in 20 patients. Although myocardial videointensity remained unchanged, 57% of the myocardial backscatter plots demonstrated significant contrast enhancement. The study demonstrates that intravenous Albunex is capable of myocardial contrast enhancement and proves the diagnostic superiority of radiofrequency compared with video imaging. Ultrasonic radiofrequency imaging may provide a technical basis for future noninvasive assessment of myocardial perfusion.

COMPARATIVE EFFICACY OF DIAGNOSTIC PROCEDURES IN PNEUMONIA IN CHILDREN

Various investigative methods used in diagnosis, in 200 children with pneumonia, were analyzed to establish the diagnostic superiority. Lung juice aspirate culture yielded 52.4% positivity and laryngeal swab culture 52%. Gastric aspirate culture was positive in 36% cases and blood culture positivity was in 10% cases only. Thus laryngeal swab culture is as effective as lung-juice aspiration culture in the isolation of the organisms causing lower respiratory tract infections. Gastric aspirate smear examination for polymorphonuclear leucocyte count is helpful in screening bacterial pneumonias.

Magnetic resonance imaging of the spine: An initial experience.

Retrospective analysis was carried out for 477 magnetic resonance imaging (MRI) studies of the spine. The overall mean age ± SD of the entire series was 38.7 ± 12.9 years. Degenerative spinal lesions and prolapsed intervertebral disks were detected in 62% and 73% of all the studies and of those which showed spinal abnormalities respectively. Postoperative granulation tissue was the third most common abnormality detected (12%). MRI was superior to computed tomography (CT) and CT myelograms in the diagnosis of disk prolapse (97% versus 66%), degenerative disease of the spine (94% versus 48%), and postsurgical granulation tissue (100% versus 6%). Comparing the numbers of CT and CT myelograms requested in the year prior to the installation of the MRI to the numbers requested during the year where the MRI was functioning did not show any change in the frequency of ordering CT studies. We conclude that our hospital-based series has shown an interesting pattern for spinal disorders. The first year experience of the utilization of MRI in various spinal diseases has been satisfactory with prevailing diagnostic superiority for that modality.

Acetaldehyde adducts of proteins: Diagnostic and pathogenic implications in diseases caused by excessive alcohol consumption

Alcohol abuse and alcoholism continue to be a major threat to human health. Given their increasing incidence and the detrimental impact on society, it is actually surprising that no objective, specific indicators for the early detection of alcohol-related health problems are available. A diagnostic test for a disease involving excessive alcohol consumption should be extremely specific in order to achieve positive predictive power, and: ideally it should also be very sensitive in order to identify problem drinkers in broad screening programs. The present research indicates that such a test for alcohol abuse may be provided by measurements of covalent chemical addition products (adducts) of acetaldehyde with biologically stable macromolecules. It was recently demonstrated that proteins modified with acetaldehyde are formed in vivo and can induce an antibody response as a result of alcohol consumption. Monoclonal and polyclonal antibodies raised by immunizations against acetaldehyde-modified proteins recognize acetaldehyde adducts irrespective of the nature of the carrier protein. Use of such antibodies in sensitive two-site immunoenzymatic or immunofluorometric assays has indicated that high acetaldehyde adduct concentrations exist in the erythrocytes of alcohol abusers, in healthy volunteers after a bout of drinking, and also in alcohol consuming mothers who subsequently give birth to children with foetal alcohol effects. We have developed the first immunohistochemical techniques for the detection of acetaldehyde adducts in human tissues. The centrilobular region of the liver of alcohol abusers with an early stage of histological tissue damage was found to contain acetaldehyde-modified epitopes, whereas the adducts were more widespread in advanced liver disease. The diagnostic superiority of acetaldehyde adducts as markers of ethanol consumption is due to the fact that they represent true metabolites of ethanol and allow estimations of past alcohol consumption after the ethanol has been eliminated from the body. Investigations into the formation of acetaldehyde adducts in alcohol consumers do not only have diagnostic applications but also help to explain the pathogenesis of alcohol-induced organ damage. Many types of hypersensitivity and immune responses are brought about by acetaldehyde-modified proteins. In addition, such metabolites of ethanol also aggravate liver disease through disturbed protein function and stimulation of fibrogenesis.

Peptide hormone processing in tumours: biogenetic and diagnostic implications.

Insight into the biogenesis of peptide hormones has grown explosively by elucidation of gene, mRNA and prohormone structures. In addition, information about prohormone processing enzymes is rapidly accumulating. Prohormones vary in size and organization from poly- to monoprotein structures. According to their structural organization and sequence homology, hormones are grouped in families. Prohormones are processed to bioactive peptides by multiple modifications during the transport from the endoplasmic reticulum to secretory granules. The modifications comprise different proteolytic cleavages and amino acid derivatizations. By constitutive secretion, the processing is less pronounced. The same prohormone may be expressed in several cell types that process the precursor in different ways. Awareness of cell-specific processing patterns is important for understanding the tumour synthesis of peptides and for appropriate diagnosis of peptide-producing tumours. These tumours comprise not only well-known neuroendocrine neoplasias. An increasing number of common carcinomas also expresses peptide hormone genes. However, the translation and post-translational processing in tumours are generally attenuated. Consequently, the expression is often functionally and clinically silent. A new diagnostic tool, processing-independent analysis (PIA), seems promising in quantitation of hormone gene expression at peptide level irrespective of the degree of processing. Studies of progastrin expression and processing in tumours illustrate the diagnostic superiority of PIA.

Sandwich Immunoassay for Intact Human Osteocalcin

To overcome the problems of limited-region specificity associated with conventional radioimmunoassay (RIA), we developed a sandwich enzyme immunoassay (EIA) for intact human osteocalcin (hOC). For this EIA we used antibodies to the N- and C-terminal regions of hOC that were raised against an N-terminal 20-residue peptide and a C-terminal 7-residue peptide, both synthetic. Immunoassay profiles of tryptic digests of hOC and serum from patients with renal failure, fractionated by reversed-phase HPLC, facilitated direct demonstration of the region specificity of this method. A preliminary study of serum osteocalcin concentrations in patients with renal failure further confirmed this specificity, showing lower positive rates obtained by this method than by conventional RIA. The cross-reactivity data of hOC with bovine and rat osteocalcins by the sandwich method indicated its species specificity. These studies demonstrate the superior specificity of this sandwich EIA compared with conventional RIA and thus confirm its potential diagnostic superiority.

Computed tomography in the evaluation of the portal venous system.

Computed tomography has widespread clinical application in the evaluation of the portal venous system, even though quantitative methods are impractical due to the inability to measure portal flow discrete from hepatic arterial flow, morbidity associated with the use of large volumes of iodinated contrast, and technical limitations. This represents a major disadvantage compared to Doppler ultrasound and magnetic resonance angiography. Qualitative applications include evaluation of portal vein patency, diagnosis of portal vein thrombosis, underlying inflammatory or neoplastic conditions, and evaluation of surgically created portosystemic shunts and collateral flow. Diagnostic criteria for portal venous thrombosis include nonopacification of the central portion of the portal vein, peripheral enhancement of the vein, and irregular periportal hepatic parenchymal enhancement. However, misdiagnosis is common, occurring in 16% of cases analyzed in one limited series, and periportal vein enhancement is now recognized as a nonspecific finding associated with underlying endothelial injury. Cavernous transformation of the portal vein and neoplastic invasion of the portal system are more reliably recognized. Computed tomography arterial portography demonstrates collateral pathways and arteriovenous shunts. Computed tomography has a sensitivity of 85% in detection of esophageal varices compared to endoscopy, but has the advantage of demonstrating splenorenal, gastrorenal, peripancreatic, pericholecystic, retroperitoneal and omental collateral vessels, and spontaneous large portosystemic shunts, with greater sensitivity than angiography. Computed tomography combined with Doppler ultrasound angiography remains popular, despite a lack of large-scale prospective efficacy studies demonstrating diagnostic superiority over other imaging techniques, largely because of its accessibility, and its detailed axial anatomic images providing an overview of multiple organ systems, and patency of major vessels.

Processing-Independent Analysis (Pia) -A New Diagnostic Tool

Posttranslational processing is an important phase of the expression of most eucaryotic genes in terms of functional proteins. Among these, secretory proteins and peptides are of particular interest for clinical chemists, since diagnostic measurements of circulating proteins and peptides constitute a major discipline in clinical chemistry. The posttranslational covalent maturation of secretory proteins and peptides involves multiple enzymatic modifications of the corresponding proproteins along the intracellular secretory pathway. During the eighties, an increasing amount of evidence has indicated that sick secretory cells fail to process their secretory products normally. The diseased cells therefore fail to process their secretory products normally. The diseased cells therefore release also incompletely processed precursors and processing-intermediates. In order to measure the degree of disease, assays that measure proteins and peptides independent of the degree of processing are therefore desirable. We have now designed a new analytical principle, according to which secretory proteins, peptides and their precursors can be accurately quantitated irrespective of the degree of processing. This principle, named processing-independent analysis (PIA), is generally applicable to all cellular synthesized substances. The principle has been applied to and developed first for a well-defined secretory peptide system, progastrin and its products. Using this model, the results obtained so far confirm the diagnostic superiority of processing-independent analysis in comparison with conventional assays for bioactive peptides.

The Diagnosis of Pulmonary Embolism-Reply

In Reply.— As reported in our discussion of study methods, the PIOPED ventilation scans included left and right posterior oblique views in addition to the posterior views. The PIOPED investigators considered the use of aerosol and of xenon 127 for ventilation scans during the planning phase for PIOPED. In comparison to xenon 133, aerosol has not been shown to be a superior diagnostic agent. 1 Because of aerosol's greater cost, the limitations Dr Boxen describes, and the lack of evidence of diagnostic superiority, aerosol was not used. Although xenon 127 has some desirable characteristics, at the time of the PIOPED planning phase it was much more expensive than xenon 133 and was distributed by only one commercial supplier, which made it impractical for use in PIOPED. We do not know of any large series conducted to establish whether xenon 127 is indeed superior as a diagnostic agent. The PIOPED investigators took

Laboratory comparison of diagnostic specificity of intact hormone and region‐specific immunoassays of parathyroid hormone

A 2-site immunochemiluminometric assay (ICMA) for intact parathyroid hormone (PTH) has been developed to overcome the problems of limited sensitivity and specificity associated with conventional PTH immunoassays. The present investigation assesses the relative merits of the 2-site intact PTH (ICMA) and a midmolecule PTH radioimmunoassay (RIA). Immunoassay profiles of dispersed hyperparathyroid cell supernatants and hyperparathyroid sera obtained during parathyroidectomy and from renal failure patients, fractionated by gel filtration chromatography, facilitated a direct comparison of the specificity of PTH immunoassays. Using gel filtration matrices which permitted the separation of intact hormone, large C-terminal fragment(s), and a small midmolecule fragment in adenomatous cell supernatant and peripheral sera, the intact PTH (ICMA) assay consistently yielded a single peak of immunoreactivity. In contrast, the midmolecule RIA yielded 2 and 3 broad peaks of immunoreactivity after fractionation of serum and adenomatous cell supernatant, respectively. There was no evidence for the secretion of a small midregion fragment in vitro or its peripheral derivation in vivo. These studies demonstrate the superior specificity of the 2-site intact PTH assay compared with a midmolecule RIA and, thus, confirm the potential diagnostic superiority of the ICMA.