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  • Author: Petra Stieber x
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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.

Abstract

The past decade witnessed an increasing interest in assessing circulating DNA in the plasma and serum of patients with malignant and non-malignant diseases. This might be due to the availability of new and sensitive methods for the determination of qualitative and quantitative changes in circulating DNA. As, previously, tumor-specific mutations or epigenetic modifications have been detected predominantly in tissue specimens, the appealing possibility to use less invasive though specific methods for tumor diagnosis was a noticeable incentive for the exploration of circulating DNA.

A considerable part of the circulating DNA, which is mostly present in serum and plasma as nucleosomal DNA, is released during apoptotic cell death. Because the rate of apoptosis is deregulated in many pathological situations such as degenerative, traumatic, ischemic, inflammatory, and malignant diseases, and because many cytotoxic therapies aim at reducing the cancer cell number by apoptosis, the cell death product “circulating DNA” might serve as an attractive and appropriate biochemical correlative.

In this review, the physiological and pathophysiological background of the arrangement of DNA as nucleosomes and of its release into circulation is shown. Further, the metabolism of circulating DNA in plasma and serum and its role in the pathogenesis of various diseases is discussed. Finally, the diagnostic relevance of qualitative and quantitative changes in circulating DNA for screening, differential diagnosis, prognosis, monitoring of systemic therapies, early prediction of therapy response and detection of recurrence in malignant diseases is reviewed. Concluding, some methodical considerations regarding the measurement of circulating DNA are given.

Abstract

We retrospectively studied the single and combined diagnostic value of carcinoembryonic antigen (CEA), cytokeratin fragment 19 (CYFRA 21-1), neuron specific enolase (NSE) and pro-gastrin-releasing peptide (ProGRP), which were routinely analysed in patients with lung tumours of unknown origin at the time of admission to hospital. Inclusion criteria were the determination of CEA (AxSYM/Abbott), CYFRA 21-1 (ElecSys/Roche) and NSE (Kryptor/Brahms). We examined 1747 patients, where 1325 suffered from lung cancer (LC; small cell lung cancer, SCLC: n=194; non-small cell lung cancer, NSCLC: n=1015; others: n=116), 318 from benign lung diseases and 104 from lung metastases due to another primary malignancy. As ProGRP (ELISA ALSI/IBL) became available only recently, there are less data points of this marker. In total, 99.8% of LC patients released at least one of the four biomarkers (defined as values exceeding the median of healthy controls), and for the discrimination between benign disease (BD) and malignant lung disease each marker reached 100% tumour specificity at high levels (CEA: 20 ng/mL; CYFRA 21–1: 40 ng/mL; NSE: 45 ng/mL; ProGRP: 250 pg/mL). At a specificity of >99%, ProGRP reached the highest diagnostic efficacy for SCLC with 57% true positive results, CEA had the highest capacity (17%) to detect malignant lung tumours in general and adenocarcinomas of the lung with 29%. CYFRA 21-1 was dominant for squamous cell carcinomas (12%). Combining the four markers leads with the prerequisite of high specificity (>99%) to 50% true positives for malignant lung tumours, 44% for NSCLC, 36% for squamous cell carcinomas, 53% for adenocarcinomas, and 78% for SCLC, respectively. In cases of lung tumours of unknown origin, the combined use of CEA, CYFRA 21-1, NSE and ProGRP is useful for the differentiation between benign and primary or secondary malignant disease and suggests the assignment to histological subtypes.

Abstract

Background: The usefulness of S100 as a prognostic marker and aid in follow-up care in patients with malignant melanoma as well as in individuals with various neurological pathologies is well known. The aim of this study was to investigate its release and clinical relevance in benign and malignant disorders beyond these indications to elucidate tumor and organ specificity of S100.

Methods: S100 levels were studied in serum samples of 1856 untreated patients, among them 59 healthy individuals, 358 patients with benign disorders, and 1439 patients with malignant tumors.

Results: Healthy individuals had low S100 levels reaching a median of 0.041 ng/mL and 95th and 100th percentiles of 0.096 ng/mL and 0.144 ng/mL, respectively. The medians of patient groups with benign diseases ranged from 0.030 to 0.057 ng/mL, patients with malignant diseases from 0.020 to 0.059 ng/mL, and thus were comparable to healthy individuals. Only 2% of patients with benign diseases, mainly suffering from infectious, autoimmune, or benign gastrointestinal diseases and 1% of patients with malignant diseases showed slightly higher values than healthy individuals, in most cases up to 0.5 ng/mL.

Conclusions: In contrast to many other oncological biomarkers, S100 is only rarely released in elevated levels from most benign and malignant diseases apart from malignant melanoma and neurological diseases, resulting in superior organ and tumor specificity. As potentially influencing factors, severe infectious diseases have to be considered.