Interpretation Of Serial Measurements Research Articles

Reference ranges for clinical electrophysiology of vision

IntroductionEstablishing robust reference intervals for clinical procedures has received much attention from international clinical laboratories, with approved guidelines. Physiological measurement laboratories have given this topic less attention; however, most of the principles are transferable.MethodsHerein, we summarise those principles and expand them to cover bilateral measurements and one-tailed reference intervals, which are common issues for those interpreting clinical visual electrophysiology tests such as electroretinograms (ERGs), visual evoked potentials (VEPs) and electrooculograms (EOGs).ResultsThe gold standard process of establishing and defining reference intervals, which are adequately reliable, entails collecting data from a minimum of 120 suitable reference individuals for each partition (e.g. sex, age) and defining limits with nonparametric methods. Parametric techniques may be used under some conditions. A brief outline of methods for defining reference limits from patient data (indirect sampling) is given. Reference intervals established elsewhere, or with older protocols, can be transferred or verified with as few as 40 and 20 suitable reference individuals, respectively. Consideration is given to small numbers of reference subjects, interpretation of serial measurements using subject-based reference values, multidimensional reference regions and age-dependent reference values. Bilateral measurements, despite their correlation, can be used to improve reference intervals although additional care is required in computing the confidence in the reference interval or the reference interval itself when bilateral measurements are only available from some of subjects.DiscussionGood quality reference limits minimise false-positive and false-negative results, thereby maximising the clinical utility and patient benefit. Quality indicators include using appropriately sized reference datasets with appropriate numerical handling for reporting; using subject-based reference limits where appropriate; and limiting tests for each patient to only those which are clinically indicated, independent and highly discriminating.

Biomarkers along the continuum of care in lung cancer

Blood-based biomarkers are valuable diagnostic tools for the management of lung cancer patients. They support not only differential diagnosis and histological subtyping, but are also applied for estimation of prognosis, stratification for specific therapies, monitoring of therapy response, surveillance monitoring and early detection of residual or progressive disease. Early diagnosis of lung cancer in high risk populations (screening) is a promising future indication but poses high medical and economic challenges to marker performance. The five mostly used classical ‘tumor markers’ show characteristic profiles of sensitivity and specificity for non-small cell lung cancer (NSCLC) like cytokeratin 19-fragments (CYFRA 21-1), carcino-embryonic antigen (CEA) and squamous cancer cell antigen (SCCA) as well as for small cell lung cancer (SCLC) like progastrin-releasing peptide (ProGRP) and neuron-specific enolase (NSE). Combined use and pattern recognition approaches enable highly accurate diagnosis, subtyping and therapy monitoring. For the interpretation of serial measurements on an individual level, marker-specific algorithms have to be developed. So-called companion diagnostics identify druggable molecular changes in signaling pathways of tumor tissue that can be addressed by targeted therapies. New highly sensitive technologies enable the convenient and serial molecular characterization on circulating tumor DNA (ctDNA) in the blood, too. This approach is helpful when biopsies are not available and to overcome tumor molecular heterogeneity and plasticity. As only a portion of patients have such druggable molecular changes, future strategies will imply the combined use of classical and new ctDNA-based biomarkers to optimize the management of lung cancer patients during the course of disease.

Determination of the biological variation of S100β and lactate dehydrogenase in disease-free patients with malignant melanoma

Biological variation is important for determining analytical goals and for establishing the magnitude of change between two consecutive measurements. The aim of this study was to determine the biological variation for S100β and lactate dehydrogenase in patients diagnosed with malignant melanoma but without evidence of disease recurrence. The biological variation of S100β and lactate dehydrogenase was estimated from a mean of four consecutive measurements in 32 patients diagnosed with malignant melanoma but without evidence of disease recurrence, 3 months after tumor resection or 4 months after finishing adjuvant treatment. The mean sampling interval was 3 months. Mean concentrations of S100β and lactate dehydrogenase were 0.0557 μg/L and 6.3 μkat/L, respectively. Between-run analytical variation was 3.5% at 0.181 μg/L for S100β and 3.5% at 2.83 μkat/L for lactate dehydrogenase. Biological variations obtained for S100β and lactate dehydrogenase were 14.2% and 8.2%, respectively. The analytical goals (defined as 50% of biological variation) were 7.1% for S100β and 4.1% for lactate dehydrogenase. The estimation of biological variation allows us to calculate analytical goals and reference change values. These are necessary tools for the correct interpretation of serial measurements in patient follow-up.

Sinnvoller Einsatz von Tumormarkern / Sensible use of tumor markers

Zusammenfassung Als Tumormarker werden heute alle nachweisbaren oder messbaren Substanzen zusammengefasst, die auf einen Tumor hinweisen oder zu seiner Charakterisierung und Messung seiner Ausbreitung und Therapieansprechen beitragen können. Humorale zirkulierende Tumormarkersubstanzen als Vorstufen normaler Antigene, ektopisch gebildete Hormone oder Enzyme, ontogenetisch alte reaktivierte Antigene, hybridom-definierte Muzine und Zytokeratine sind unter den Tumormarkern von besonderem Interesse. Es gibt bis heute keinen tumorspezifischen Biomarker, alle bislang bekannten Tumormarker sind physiologisch beim Menschen im Blut nachweisbar. Ihre diagnostische Bedeutung liegt mehr in der Quantität denn in der Qualität. Die gemessene Tumormarkerkonzentration reflektiert Tumormasse und -ausbreitung und ist primär von der Tumorblutversorgung abhängig. Im Einzelnen stellt sie ein integrales Maß aus der im Tumor vorhandenen Tumormarker-Expression, -Synthese, -Freisetzung, dem im Organismus ablaufenden Tumormarker-Katabolismus und der Tumormarker-Exkretion dar. Tumormarker-Änderungen ohne Korrelation zur Tumormasse können deshalb auch durch Störungen von Katabolismus und der Exkretion (Leber-, Niereninsuffizienz), durch Freisetzung infolge invasiver diagnostischer Maßnahmen (Endoskopie, Biopsie, Katheterisierung) oder durch akute Therapieeinwirkung (Operation, Radio-, Chemotherapie) auftreten. Wegen Standardisierungsproblemen zwischen gleichen Tumormarker-Tests verschiedener Hersteller, muss bei einer punktuellen Diagnostik, z.B. mittels PSA die Interpretation immer auf den assayspezifischen Referenzangaben erfolgen und bei Verlaufsbestimmungen eines Patienten der gleiche Test vom selben Hersteller (evtl. im gleichen Labor bestimmt) herangezogen werden, das Testergebnis ist zusammen mit dem jeweils verwendeten Test und Hersteller anzugeben. Von den potenziellen Indikationen für den Einsatz zirkulierender Tumormarker ist die zur Früherkennung/Screening eines Tumors bis auf die umstrittene von PSA beim Prostatakarzinom unrealistisch, die zur Tumorlokalisation (PSA; HTG) und für die Diagnose begrenzt, die für die Prognose zunehmend von Bedeutung und die für die Therapie-Überwachung und Rezidiverkennung die meist verwandte, im Kontext mit endoskopischen und bildgebenden Verfahren. Unter kritischer Auswahl von Tumormarkern nach Zieltumor, bei Verlaufsbestimmungen unter Verwendung der gleichen Tests und unter Berücksichtigung eines verwertbaren Informationsgehalts leisten Tumormarker einen wichtigen Beitrag zur Diagnostik, Prognosefindung, Beurteilung der Therapieantwort und Rezidiverkennung. Die Qualität des Untersuchers geht besonders auf dem Sektor der onkologischen Labordiagnostik signifikant in die Qualität des erhobenen Befundes ein.