Volume 36, Issue 2

Disorders of sex development or “DSD” describe a heterogeneous group of abnormalities of sexual determination and differentiation. This may be caused by chromosomal as well as monogenic aberrations, which may lead either primarily or through endocrine mechanisms to abnormal sexual development. Laboratory investigations play an important role in the diagnostic process. However, special analytical methods have to be taken into account and the usual reference intervals do not apply. Therefore, laboratory results should be interpreted in a specialized center in context with clinical and imaging findings. Furthermore, molecular genetic analysis can be performed for several entities. In a majority of cases, however, a definitive diagnosis is not possible even today. Therefore, management by a highly specialized multidisciplinary team is necessary for stringent diagnosis, prognosis and overall therapeutic decision making. The team must include physicians from different subspecialties as well as psychosocial experts to counsel patients and their families appropriately.

Disorders of sex development or “DSD” describe a heterogeneous group of abnormalities of sexual determination and differentiation. This may be caused by chromosomal as well as monogenic aberrations, which may lead either primarily or through endocrine mechanisms to abnormal sexual development. Laboratory investigations play an important role in the diagnostic process. However, special analytical methods have to be taken into account and the usual reference intervals do not apply. Therefore, laboratory results should be interpreted in a specialized center in context with clinical and imaging findings. Furthermore, molecular genetic analysis can be performed for several entities. In a majority of cases, however, a definitive diagnosis is not possible even today. Therefore, management by a highly specialized multidisciplinary team is necessary for stringent diagnosis, prognosis and overall therapeutic decision-making. The team must include physicians from different subspecialties as well as psychosocial experts to counsel patients and their families appropriately.

D-dimer concentrations are elevated in a variety of clinical situations with hypercoagulability, such as venous thromboembolism (VTE), disseminated intravascular coagulation (DIC), ischemic cardiopathy, stroke, acute aortic dissection, malignomas, pregnancy, after surgery, traumas, and burns. D-dimer testing has become an essential tool for the diagnosis of VTE and pulmonary embolism because of its high negative predictive value, especially when used in conjunction with a clinical pretest score. D-dimer testing can be used for the diagnosis of DIC and other thrombotic diseases. It is also helpful for risk stratification in coronary artery disease, in first and recurrent thrombotic events, and for the timing of the duration of oral anticoagulation after a first episode of VTE. The use of D-dimer testing is limited in certain clinical conditions in which elevated D-dimer concentrations render the test unsuitable for the detection of acute thrombotic events.

D-dimer concentrations are elevated in a variety of clinical situations with hypercoagulability, such as venous thromboembolism (VTE), disseminated intravascular coagulation (DIC), ischemic cardiopathy, stroke, acute aortic dissection, malignomas, pregnancy, after surgery, traumas, and burns. D-dimer testing has become an essential tool for the diagnosis of VTE and pulmonary embolism because of its high negative predictive value, especially when used in conjunction with a clinical pretest score. D-dimer testing can be used for the diagnosis of DIC and other thrombotic diseases. It is also helpful for risk stratification in coronary artery disease, in first and recurrent thrombotic events, and for the timing of the duration of oral anticoagulation after a first episode of VTE. The use of D-dimer testing is limited in certain clinical conditions in which elevated D-dimer concentrations render the test unsuitable for the detection of acute thrombotic events.

In addition to the monographs which have been published in the past 7 years by the working group “Drug Monitoring” of the Swiss Society of Clinical Chemistry (SSCC) [1–6], new monographs have been written. The data presented in these monographs provide an overview of the information which is important for the request and interpretation of the results. Therefore, laboratory health professionals and the receivers of the reports are the targeted readers. In this series, antiretroviral drugs are presented for which drug concentrations are regularly determined (protease inhibitors, non-nucleoside reverse transcriptase inhibitors). To date, no clear evidence has been established that therapeutic drug monitoring of these drugs increases the success of the antiretroviral therapy. Nevertheless, many cases have demonstrated that the therapy can be guided with much more confidence and with good success if the drug concentrations are determined, especially if the patient has a combination therapy with many pharmacokinetically interfering compounds. First, information is given about pharmacology and pharmacokinetics of these drugs, such as protein binding, metabolic pathways with specific enzymes involved, elimination half-life time, elimination route(s) of the parent drug, as well as therapeutic and toxic concentrations. Moreover, indications for therapeutic drug monitoring are listed with important preanalytical information (time point of blood sampling and time to steady state since beginning or after change of posology). Furthermore, the stability of the drug and its metabolite(s) after blood sampling are described. For readers with a specific interest, references to important publications are given. The number of monographs will be further enlarged. The updated files are presented on the homepage of the SSCC (www.sscc.ch). We hope that these monographs are helpful for the better handling of therapeutic drug monitoring and we are looking forward to receiving comments from the readers. Zusammenfassung Ergänzend zu den in den letzten 7 Jahren publizierten Arzneimittelmonographien der Arbeitsgruppe Medikamente der Schweizerischen Gesellschaft für Klinische Chemie (SGKC) [1–6], sind weitere Monographien erstellt worden. Wiederum sollen diese Monographien dem Labormediziner bzw. dem Empfänger der Befunde eine Übersicht über die wichtigsten Informationen geben, die für die Veranlassung einer Analyse bzw. für die Interpretation der Resultate hilfreich sind. In dieser Serie werden diejenigen antiretroviralen Medikamente (Proteaseinhibitoren, nicht nukleotide Inhibitoren der reversen Transkriptase) beschrieben, bei denen regelmässig Messungen der Konzentrationen durchgeführt werden. Obwohl bis heute keine klare Evidenz vorhanden ist, dass ein Therapeutic Drug Monitoring den Therapieerfolg verbessert, zeigt sich doch in vielen Einzelfällen, dass vor allem bei Kombinationstherapien, auch mit Medikamenten aus anderen Arzneimittelklassen, die Therapie durch das Messen der Medikamentenkonzentrationen und die anschliessende Dosisanpassung sicherer und mit gutem therapeutischem Erfolg gestaltet werden kann. Die einzelnen Monographien beinhalten einerseits Angaben zu klinisch-pharmakologischen Daten wie zum Beispiel den Proteinbindungen, Metabolisierungswegen und den daran beteiligten Enzymen, Halbwertszeiten und Eliminationswege der Muttersubstanz, sowie Informationen zu therapeutischen bzw. toxischen Bereichen. Andererseits werden bei jeder Substanz die Indikationen für das Therapeutic Drug Monitoring aufgelistet und wichtige Angaben zur Präanalytik gemacht (Zeitpunkt der Blutentnahme und Zeitpunkt des Erreichens einer steady-state-Situation nach einer Dosisänderung). Ausserdem werden Angaben über die Stabilität der Medikamente bzw. ihrer Metaboliten nach der Blutentnahme gemacht. Für die interessierten Leser sind die verwendeten Referenzen als Zitate aufgeführt. Die Zahl der Monographien wird weiterhin ergänzt. Die aktuellsten Versionen der Monographien sind auf der Homepage der SGKC abrufbar (www.sscc.ch). Wir hoffen, dass diese Monographien im Umgang mit dem Therapeutic Drug Monitoring hilfreich sein werden und freuen uns über Kommentare und Bemerkungen.

The so-called systematic toxicological analysis (STA) aiming at simultaneous analysis of as many toxicologically relevant compounds in biosamples as possible is an important part of routine analysis in clinical and forensic toxicology. Gas chromatography-mass spectrometry and liquid chromatography with diode array detection have been the most widely used techniques for this purpose. However, in recent years STA methods based on liquid chromatography coupled to mass spectrometry (LC-MS) or tandem mass spectrometry (LC-MS/MS) have become increasingly important, although their widespread use is still hampered by the lack of a universal reference library of mass spectra that can be used on all major instrument platforms. In this review, LC-MS(/MS) methods for STA in urine and/or blood published in the past 6 years will be compared and discussed with regard to sample preparation, separation, instrument types used for mass spectrometric detection, and method validation. In addition, different approaches to achieving the goal of a universal reference library will be summarized. Zusammenfassung Die so genannte Systematisch-toxikologische Analyse (STA), sprich die simultane Analyse möglichst vieler toxikologisch relevanter Substanzen in biologischen Flüssigkeiten, ist ein wichtiger Bestandteil der Routineanalytik in der Klinischen und Forensischen Toxikologie. Bisher waren Gaschromatographie-Massenspektrometrie und Flüssigchromatographie mit Diodenarraydetektion die am weitesten verbreiteten Techniken für diesen Zweck. In den letzten Jahren haben jedoch Methoden an Bedeutung gewonnen, die auf der Kopplung von Flüssigchromatographie und Massenspektrometrie (LC-MS) oder Tandemmassenspektrometrie LC-MS/MS basieren, auch wenn ihre weitere Verbreitung durch das Fehlen einer universellen Massenspektren-bibliothek für unterschiedliche Geräteplattformen behindert wird. In der vorliegenden Übersichtsarbeit werden in den letzten sechs Jahren publizierte LC-MS(/MS)-basierte Methoden für die STA in Urin und/oder Blut verglichen und im Hinblick auf Probenvorbereitung, Trennung, verwendete Art von Massenspektrometern und Methodenvalidierung diskutiert. Darüber hinaus werden unterschiedliche Herangehensweisen bei der Entwicklung einer universellen Spektrenbibliothek zusammengefasst.

New antifungal compounds, advanced diagnostic tools, early initiation of antifungal therapy, and the option of combination therapy have improved the treatment of fungal diseases. Despite these progresses invasive yeast and mould infections are still associated with a high incidence of mortality, especially for patients with severe immunosuppression. Therapeutic drug monitoring can help to avoid toxic effects and to improve efficacy of antifungal agents. For flucytosine and some azoles, this method is already recommended in current guidelines. The body of evidence and available information, as well as options and indications for the determination of drug concentrations are different for each compound. Intra- and interindividual variability of concentrations and their association with outcome and adverse events are the most important factors and determine whether therapeutic drug monitoring may provide an option to improve therapy, which is the case for some, but not for all, antifungal agents.

New antifungal compounds, advanced diagnostic tools, early initiation of antifungal therapy, and the option of combination therapy have improved the treatment of fungal diseases. Despite this progress, invasive yeast and mould infections are still associated with a high rate of mortality, especially for patients with severe immunosuppression. Therapeutic drug monitoring (TDM) can both help to avoid toxic effects and improve the efficacy of antifungal agents. For flucytosine and some azoles, a TDM guided therapy is already recommended in current guidelines. Actual knowledge about different antifungal agents varies, and the options and indications for the determination of drug concentrations are likewise different for each compound. Intra- and interindividual variability of concentrations and their association with outcome and adverse events are the most important factors. They determine whether therapeutic drug monitoring may provide an option to improve therapy, which is the case for some, but not all, antifungal agents.

The validation of analytical procedures in laboratory medicine has been discussed by many authors and several recommendations have been elaborated by working groups and standardization bodies. However, some problems have not sufficiently been solved, for example, permissible limits for the comparability between methods (permissible equivalence), what is the best statistical procedure for estimating the function of the fitting line in scatter plots, and permissible limits for the spread around the fitting line. The present article attempts to summarize the present state-of-the-art and to provide answers to some of the open problems. Zusammenfassung Die Validierung von Analysenverfahren in der Laboratoriumsmedizin wurde bereits von vielen Autoren diskutiert und verschiedene Empfehlungen von Arbeitsgruppen und Standardisierungsstellen ausgearbeitet. Jedoch sind einige Probleme noch nicht ausreichend gelöst, wie z.B. zulässige Grenzen der Vergleichbarkeit zwischen Methoden (zulässige Äquivalenz), das beste statistische Verfahren zur Schätzung der Funktion und der Streuung um die Ausgleichsgerade von Streudiagrammen beim Methodenvergleich. Der Übersichtsartikel versucht den derzeitigen state-of-the-art zusammenzufassen und Antworten auf einige noch offene Fragen zu geben.