Volume 37, Issue 1

C-reactive protein (CRP) currently constitutes one of the most widely used parameters for the diagnosis of infections and inflammatory processes, due to simple methods and low costs. However, in recent years, other parameters, such as interleukin 6 (IL-6) and procalcitonin (PCT), have gained in importance. Although these parameters are presently not established everywhere in clinical routine, they provide significant advantages in the diagnosis and monitoring of inflammatory diseases. For instance, in intensive care, the increase in IL-6 levels may indicate inflammatory complications 24 to 48 h prior to the increase in circulating CRP levels. In contrast to CRP, PCT shows a higher specificity for bacterial infections, which facilitates the diagnosis of bacterial infections and sepsis. Therefore, PCT values provide a better evaluation of prognosis and therapeutic success and of a necessary change in therapy. These points raise the question whether CRP levels should at least in part be replaced by PCT and/or IL-6. Thus, this review seeks to examine the value of CRP in relation to PCT and IL-6 in the diagnosis of bacterial infections, in therapeutic monitoring, and regarding prognosis in critical care patients.

C-reactive protein (CRP) currently constitutes one of the most widely used parameters for the diagnosis of infections and inflammatory processes, due to simple methods and low costs. However, in recent years, other parameters, such as interleukin 6 (IL-6) and procalcitonin (PCT), have gained in importance. Although these parameters are presently not established everywhere in clinical routine, they provide significant advantages in the diagnosis and monitoring of inflammatory diseases. For instance, in intensive care, the increase in IL-6 levels may indicate inflammatory complications 24 to 48 h prior to the increase in circulating CRP levels. In contrast to CRP, PCT shows a higher specifity for bacterial infections, which facilitates the diagnosis of bacterial infections and sepsis. PCT measurements further allow assessment of therapeutic success and indicate necessary changes in antibiotic therapy. These points raise the question whether CRP measurements should at least in part be replaced by PCT and/or IL-6. Thus, this review seeks to examine the value of CRP in relation to PCT and IL-6 for the diagnosis of bacterial infections, in therapeutic monitoring, and regarding prognosis in critical care patients.

Background: Hepatic stellate cells are stimulated by insulin-like growth factor 1 (IGF-1) and high IGF-1 levels attenuate fibrogenesis and accelerate liver regeneration. This effect is mainly mediated by upregulation of hepatic growth factor and downregulation of transforming growth factor β1. Thus, decreased IGF-1 levels in patients point to an impaired regeneration potential in chronic liver failure. The objective of this study was to evaluate the relation between liver dysfunction and levels of IGF-1 and IGF-binding protein 3 (IGFBP-3) levels. Methods: One hundred and twenty-seven patients aged 45 to 60 years (36 women, 91 men) with diagnosed liver disease were recruited for the study. From the Study of Health in Pomerania (SHIP), 508 healthy individuals were matched for age and sex as the control group. Associations between laboratory parameters of liver failure and IGF-1 or IGFBP-3 were examined. Serum IGF-1 and serum IGFBP-3 levels were measured by automated two-site chemiluminescence immunoassays. Results: IGF-1 and IGFBP-3 levels were significantly lower in patients with liver diseases. There was no detectable homogeneous relation between liver transaminases and IGF-1 or IGFBP-3 levels in the patient group alone. Patients with a Child Pugh Score of C revealed lower levels of IGF-1 than patients with Child Pugh Scores of B or A. In IGFBP-3, this association was also apparent, but statistically not significant. In pooled analyses of patients and healthy controls, negative associations between aspartate aminotransferase (ASAT) and γ-glutamyltranspeptidase (GGT) activities and IGF-1 and IGFBP-3 levels, as well as between alanine aminotransferase (ALAT) activity and IGF-1 levels were detected. Conclusions: We demonstrated that compared with healthy controls patients with liver disease exhibited lower IGF-1 and IGFBP-3 levels. Zusammenfassung Einleitung: Die stellaren Zellen der Leber werden durch den Insulin like growth factor (IGF-1) stimuliert. Hohe IGF-1-Level vermindern die Fibrogenese und steigern die Regeneration der Leber. Dieser Effekt wird beeinflusst durch Heraufregulierung des hepatischen Wachstumsfaktors und Herunterregulierung des Transforming Growth Factor Beta 1. Niedrige IGF-1-Level verschlechtern somit die Regenerationsfähigkeit bei Patienten mit einer chronischen Leberinsuffizienz. Das Ziel der vorliegenden Studie war es, die Assoziationen zwischen Fehlfunktionen der Leber und IGF-1- und IGFBP-3-Leveln zu untersuchen. Methoden: Einhundertsiebenundzwanzig Patienten im Alter zwischen 45–60 Jahren (36 Frauen, 91 Männer) mit diagnostizierten Lebererkrankungen wurden für die Studie rekrutiert, Als Kontrollgruppe standen 508 gesunde Probanden aus der Study of Health in Pomerania (SHIP) adjustiert nach Alter und Geschlecht zur Verfügung. Assoziationen zwischen Laborparametern die für eine Leberfunktionsstörung sprechen und IGF-1 und IGFBP-3 wurden untersucht. IGF-1 und IGFBP-3-Level im Serum wurden mit automatischen Two-Site-Chemiluminszenz-Immunoassays bestimmt. Ergebnisse: Patienten mit Lebererkrankungen hatten signifikant niedrigere IGF-1- und IGFBP-3-Level. Es konnte keine homogene Relation zwischen den Transaminasen allein und IGF-1- und IGFBP-3-Leveln in der Patientengruppe detektiert werden. Patienten mit einem Child Pugh Score von C wiesen niedrigere IGF-1-Level auf als Patienten mit einem Child Pugh Scores von A und B. Für IGFBP-3 konnten diese Assoziation ebenfalls ermittelt werden, aber nicht statistisch signifikant. In gepoolten Analysen von Patienten und gesunden Kontrollen konnten negative Assoziationen zwischen den Aspartat-Aminotransferase- (ASAT) und γ-Glutamyltranspeptidase-Aktivitäten (GGT) und IGF-1- und IGFBP3-Leveln sowie zwischen der Alanin-Aminotransferase-Aktivität (ALAT) und IGF-1-Leveln gefunden werden. Schlussfolgerung: Wir konnten zeigen, dass im Vergleich zu gesunden Kontrollen Patienten mit Lebererkrankungen niedrigere IGF-1- und IGFBP3-Level aufwiesen.

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. Zusammenfassung Hintergrund: S100 ist als nützlicher Biomarker für die Prognoseaschätzung und die Verlaufsbeobachtung bei Patienten mit malignem Melanom und in Patienten mit verschiedenen neurologischen Erkrankungen anerkannt. Das Ziel dieser Studie war, die Freisetzung und klinische Relevanz von S100 bei anderen benignen and malignen Erkrankungen jenseits dieser Indikationen zu untersuchen, um die Tumor- und Organspezifität von S100 zu bewerten. Methoden: S100-Konzentrationen wurden in Serumproben von 1856 unbehandelten Patienten ermittelt, darunter 59 gesunde Personen, 358 Patienten mit benignen Erkrankungen und 1439 Patienten mit malignen Tumoren. Ergebnisse: Gesunde Personen hatten niedrige S100 Serumwerte, die einen Median von 0.041 ng/mL, eine 95. Perzentile von 0.096 ng/mL und ein Maximum von 0.144 ng/mL erreichten. Die Mediane der Patientengruppen lagen bei benignen Erkrankungen zwischen 0.030 und 0.057 ng/mL, bei Patienten mit malignen Tumoren zwischen 0.020 und 0.059 ng/mL – und waren somit vergleichbar zu gesunden Kontrollpersonen. Lediglich 2% der Patienten mit benignen Erkrankungen, v.a. infektiösen, autoimmunen oder benignen gastrointestinalen Erkrankungen, sowie 1% der Patienten mit malignen Tumoren wiesen im Vergleich zu gesunden Personen leicht erhöhte Werte auf – in den meisten Fällen bis 0.5 ng/mL. Schlussfolgerung : Im Gegensatz zu vielen anderen onkologischen Biomarkern wird S100 nur selten in höheren Konzentrationen von den meisten benignen und malignen Erkrankungen – mit Ausnahme des malignen Melanoms und neurologischer Erkrankungen – freigesetzt, was sich in einer sehr hohen Organ- und Tumorspezifität widerspiegelt. Als möglicher Einflussfaktor sind schwere infektiöse Erkrankungen zu berücksichtigen.

Immunogenic cell death markers are an inhomogeneous group of molecules which are released from apoptotic, necrotic or otherwise dying cells. Once in the extracellular milieu, these danger associated molecular patterns (DAMPs) such as the high mobility group box 1 protein (HMGB1) are able to exert activating and suppressive effects on the immunity system. On the one hand, continuously released HMGB1 – via interaction with its cellular binding partner receptor of advanced glycation end products (RAGE) – can promote tumor growth, whereas, on the other hand, pulsatile release of HMGB1 during cytotoxic therapies may activate the immunity system against tumor cells. Soluble RAGE (sRAGE), however, can act as a decoy receptor, balancing the extracellular effects of HMGB1. Here, we review the structural and functional characteristics of these immunogenic cell death markers and their role in the pathophysiology of diverse benign and malignant diseases. Further, we report on their relevance as serum biomarkers for the diagnosis, estimation of prognosis, as well as the prediction and monitoring of response to cytotoxic therapy in cancer patients. Elevated levels of HMGB1 and lower levels of sRAGE were found to be present in blood of patients suffering from various tumor entities as compared with healthy controls. Furthermore, high HMGB1 and low sRAGE serum levels of cancer patients before or during cytotoxic therapy were associated with poor treatment response and shortened overall survival. These results indicate that immunogenic cell death markers such as HMGB1 and sRAGE are promising new biomarkers for prognosis, patients’ stratification and therapy monitoring in cancer patients.

The laboratory examination of hematologic diseases has made great progress in the last 30 years and is now based on a four-fold strategy: cytomorphology, flow cytometry, cytogenetics, and molecular genetics. Cytomorphology is still the crucial first step, and then it usually followed by flow cytometric immunophenotyping and of relevant cell population. Both investigations require a highly expert laboratory team and, often, an exchange of information among the clinicians. It is a challenge for small specialized laboratories to reach quality standards and economic efficiency nowadays, even with highly specialized personnel. One solution is the collaboration among institutes of laboratory medicine (usually a central laboratory), smaller laboratories specialized in hematology, and usually residents in departments of hematologic diseases, as is the practice in the Interdiscipline Hematologic Competence Center (IHK) of Innsbruck since 2008. Thus, in Innsbruck, this competence center concentrates the whole expertise in the hematology laboratory of the hospital based on cytomorphology and flow cytometry. Besides the clarification of already identified hematologic diseases, the IHK has optimal conditions not only for the specific and prompt first-time diagnosis of hematologic diseases (e.g., additional diagnostic findings) but also for the screening of blood samples, from tertiary care hospitals, that require further diagnostic workup for specific disease clarification based on numeric and morphologic abnormalities. For the further progression of the IHK, the integration of cytogenetic and molecular genetic diagnostics is essential. The interdisciplinary collaboration of specialists in laboratory medicine, hematology, cytogenetics and molecular genetics improves the knowledge tranfer and expertise of all members and enhances the efficiency and quality level of such a collaborating laboratory division. Further advantages can be achieved in important laboratory development processes (e.g., laboratory accreditation, implementation of expensive laboratory equipment, such as ten-color flow cytometers, introduction of modern laboratory information systems, or image-archiving systems), with a high potential of synergetic effects stemming from the collaboration. The establishment of interdisciplinary competence centers for hematologic diagnostics is therefore a milestone in modern laboratory diagnostics.

The laboratory examination of hematologic diseases has made great progress in the last 30 years and is now based on a fourfold strategy: cytomorphology, flow cytometry, cytogenetics, and molecular genetics. Cytomorphology is still the crucial first step, and then it usually followed by flow cytometric immunophenotyping of relevant cell population. Both investigations require a highly expert laboratory team and, often, an exchange of information among the clinicians. It is a challenge for small specialized laboratories to reach quality standards and economic efficiency nowadays, even with highly specialized personnel. One solution is the collaboration among institutes of clinical pathology (usually a central laboratory), smaller laboratories specialized in hematology, and usually residents in departments of hematologic diseases, as is the practice in the Interdiscipline Hematologic Competence Center (IHK) of Innsbruck since 2008. Thus, in Innsbruck, this competence center concentrates the whole expertise in the hematology laboratory of the hospital based on cytomorphology and flow cytometry. Besides the clarification of already identified hematologic diseases, the IHK has optimal conditions not only for the specific and prompt first-time diagnosis of hematologic diseases (e.g., additional diagnostic findings) but also for the screening of blood samples, from tertiary care hospitals, that require further diagnostic workup for specific disease clarification based on numeric and morphologic abnormalities. For the further progression of the IHK, the integration of cytogenetic and molecular genetic diagnostics is essential. The interdisciplinary collaboration of clinical pathologists, hematology clinicians, and cytogenetic and molecular genetics experts improves the knowledge transfer and expertise of all members and enhances the efficiency and quality level of such a collaborating laboratory division. Further advantages can be achieved in important laboratory development processes (e.g., laboratory accreditation, implementation of expensive laboratory equipment, such as ten-color flow cytometers, introduction of modern laboratory information systems, or image-archiving systems), with a high potential of synergetic effects stemming from the collaboration. The establishment of interdisciplinary competence centers for hematologic diagnostics is therefore a milestone in modern laboratory diagnostics.