Material und Methode: In einer retrospektiven Analyse wurden die Daten von 53 konsekutiven Patienten, 31 Männer und 22 Frauen, mit klinisch oder röntgenologisch präsenten metastatischen epiduralen Spinalkanalkompression ausgewertet. Das mediane Alter war 60 Jahre. Als Primärtumor waren Bronchialkarzinome (13 Patienten), Mammakarzinome (10) und Prostatakarzinome (10) am häufigsten zu finden. Ergebnisse: Die Therapieergebnisse hinsichtlich der Schmerzlinderung waren mit der Literatur vergleichbar (Ansprechrate= 66%). Als wichtigster prognostischer Faktor hinsichtlich der Gehfähigkeit hat sich der prätherapeutische Status erwiesen. Patienten, die Anfang der Therapie gehfähig waren, blieben in 94% der Fälle auch gehfähig, während nur ein Patient seine Gehfähigkeit bis Ende der Therapie wiedergewann (p< 0,001). Im Chi-Quadrat Test war auch der diagnosestellende Arzt prognostisch relevant: Patienten, deren Diagnose durch einen onkologisch tätigen Arzt gestellt wurde, hatten eine höhere Chance gehfähig zu bleiben (p=0,04). Das Gesamtüberleben (8 Monate median, Range 1-27 Monate ) entsprach den Literaturangaben. Nicht ambulante Patienten und Patienten mit Bronchialkarzinom hatten eine signifikant schlechtere Prognose (p / Materials and Methods: therapy charts of 53 consecutive patients, 31 male and 22 female, with metastatic epidural spinal cord compression treated with radiation therapy only have been analyzed. Median age was 60 ys. The most frequent primary tumours were bronchogenic carcinoma (13 patients), breast cancer (10 patients) and prostate cancer (10 patients),respectively.Results: MRI was the most sensitive diagnostic tool in detecting spinal cord compression. Plain X-ray films were not useful.Pain symptoms improved in 66% of the patients. The most important prognostic factor was the pretreatment mobility status. 94% of the ambulatory patients kept their walking ability but only one plegic patient could walk again after radiation therapy. (p=0.001) Patients whose back pain was presented to an oncologist were more likely to keep walking ability by the end of the therapy. (p=0.04) Patients with bronchogenic cancer and plegic patients had a significant worse survival. Conclusion: Patients with a known malignant tumor and progressive or axial back pain should undergo MRI scan to rule out spinal cord compression. For patients without severe neuorologic deficit and MRI proven epidural compression radiation therapy is able to preserve walking ability and reduce pain. General practitioners and patients should be informed about the symptoms and the therapeutic and diagnostic possibilities of spinal cord dompression.

Kolorektale Karzinome weisen eine Rotfluoreszenz auf. Die Art des zugrunde liegenden Fluorophors und sein diagnostisches Potential waren Gegenstand der Arbeit. Protoporphyrin IX (PpIX) wurde als das prädominant vorkommende Fluororphor in Primärtumoren und ihren Metastasen identifiziert. Das Fluorophor wurde in Abwesenheit von Nekrose und in sterilen Lokalisationen nachgewiesen. Affymetrix-GeneChip und quantitative PCR untersuchungen der Enzyme der Häm-Synthese machen eine Minderexpression als Ursache der PpIX Akkumulation wahrscheinlich. In Nicht-vorbehandelten Fällen erlaubt die PpIX-Fluoreszenz eine Diskrimination der metastatisch befallenen Lymphknoten mit einer Sensitivität von 62% bei einer Spezifität von 78% (p / Colorectal cancers exhibit a red fluorescence. The nature of the responsible fluorophore and its eventual diagnostic potential were investigated. Protoporphyrin IX (PpIX) was identified as the predominant fluorophore in primary tumors and their metastases. The fluorophore occurred in the absence of necrosis and in sterile locations. Affymetrix-GeneChip and quantitative PCR investigations of the heme metabolic pathway enzymes suggest a reduced expression of the enzyme ferrochelatase to cause the PpIX accumulation. In untreated cases, PpIX fluorescence discriminates metastatically involved lymph nodes from all other palpable nodes with a sensitivity of 62% at a specificity of 78% (p

La résection hépatique est le seul traitement curatif des tumeurs malignes du foie et l’insuffisance hépatique est la première cause de morbi-mortalité après hépatectomie. L’amélioration du traitement des tumeurs du foie inclut le dévelopement de statégies capables de prévenir ou de traiter cette complication. Sur une série prospective récente de 232 hépatectomies (avec 0,8 % de mortalité à 3 mois) pour métastases hépatiques de cancer colorectal (MHCCR), une insuffisance hépatique était présente dans 7 % des cas d’hépatectomies majeures et était le facteur de plus mauvais pronostic pour la survie à 2 ans. Notre objectif a été d’évaluer de nouvelles approches thérapeutiques pour leur capacité à corriger l’insuffisance hépatique post-opératoire après hépatectomie élargie pour MHCCR. Un moyen mécanique de modulation pneumatique de l’hémodynamique portale et un moyen pharmacologique d’utilisation d’un facteur de survie des hépatocytes, la protéine recombinante HIP/PAP, ont été testés respectivement chez le porc et le rat. Nous montrons qu‘après hépatectomie (PHX) de 70 % sur foie normal, l’injection systémique de protéine HIP/PAP en péri-opératoire stimulait la régénération hépatique et améliorait la fonction hépatique chez le rat. En présence de MHCCR en place depuis 7 jours, la protéine HIP/PAP n’aggravait pas la maladie métastatique, et semblait au contraire diminuer la croissance tumorale après hépatectomie. In vitro, HIP/PAP n’augmentait pas la croissance tumorale de lignées cellulaires transformées dérivées de cancer du colon. Chez le porc, une sténose portale pneumatique pendant et après PHX majeure laissant en place moins de 0,5% du poids corporel entraînait une diminution de la pression portale intra-hépatique sans modifier le débit comparé au groupe sans anneau. Cette modulation de la pression était associée à une diminution significative de la bilirubine sérique et des lésions histologiques du foie restant au 7ème jour après chirurgie. Au total, il serait possible grâce à la protéine HIP/PAP et à l’anneau portal de corriger l’insuffisance hépatique post-hépatectomie en protégeant les cellules du foie de la mort et du stress secondaires aux modifications hémodynamiques et biochimiques. La question de leur association pour diminuer l’incidence de l’insuffisance hépatique reste entière. / Liver resection is the only curative treatment of tumoral liver malignancies and post-operative liver insufficiency is the 1st cause of post-operative mortality. Tumor liver treatment improvements must be associated to innovatives methods to prevent and cure this complication. On a recent prospective study including 232 hepatectomies (with a 3-month post-operative mortality of 0.8 %) for colorectal liver metastases (CRLM), post-operative liver insufficiency was present after 7 % of major hepatectomies and was the worst 2-year survival prognostic factor. To prevent this complication, we have evaluated a perioperative systemic injection of a recombinant anti-oxydant protein (HIP/PAP) before a major hepatectomy for CRLM in rats. In vitro then in model of implanted CLRM since 7 days, we have showed that HIP/PAP did not increased tumoral growth. After 70 % hepatectomy, perioperative systemic HIP/PAP injection improved liver function. After 70 % hepatectomy, HIP/PAP seemed decrease tumoral growth of implanted CRLM. On pig, we have assessed the consequences of a portal vein stenosis with pneumatic ring during and after a major hepatectomy that conserved a liver volume < 0.5 % of body weight. With this method, we have showed that the portal stenosis decreased intra-hepatic portal pressure wihout modify the portal flow by comparison with pigs without ring. This device was associated with a significant diminution of bilirubin plasmatic concentration and liver remnant histological lesions at sacrifice on post-operative day 7. Overall, chemical and physical methods and moreover their combination should allowed to decrease post-operative liver insufficicency.

Neste estudo, foi determinado o dano celular em linfócitos periféricos após exposição ao 153Sm-EDTMP (Samário-153 etilenodiaminotetrametilenofosfonato) por meio da técnica de análise de micronúcleos e coloração diferencial. O 153Sm-EDTMP é um radiofármaco utilizado para alívio da dor em pacientes com metástase óssea. A análise da freqüência de micronúcleos em amostras sangüíneas de pacientes obtidas uma hora após a administração endovenosa do radiofármaco (41 MBq/kg) mostrou que não houve diferença estatística em relação aos valores basais em células binucleadas. Porém, a análise da distribuição do dano em células mononucleadas mostrou que os pacientes sem tratamento radioterápico prévio apresentaram um aumento significativo na freqüência de células com um micronúcleo e aqueles com tratamento radioterápico prévio, nas células com dois ou mais micronúcleos. Os experimentos in vitro realizados com exposição de sangue total a três concentrações radioativas de 153Sm-EDTMP (0,370; 0,555 e 1,110 MBq/mL) por uma hora mostraram um aumento na freqüência de micronúcleos e de células necróticas e apoptóticas com o aumento da dose de radiação. Foram construídas curvas dose-resposta para os indivíduos sadios e para os pacientes com metástases óssea sem prévio tratamento radioterápico. A comparação das curvas mostrou que os pacientes apresentaram uma radiossensibilidade mais alta que os indivíduos sadios tanto quanto a porcentagem de células com micronúcleos como de células mortas (necróticas e apoptóticas). / In this study the cellular damage in peripheral lymphocytes after exposure to 153Sm-EDTMP (Samarium-153 ethylenediaminetetrametylenephosphonate) was determined using the technique of micronuclei analysis and differential coloration. 153Sm- EDTMP is a radiopharmaceutical used for pain relief in patients with bone metastases. The analysis of the frequency of micronuclei in patient blood samples obtained one hour after endovenous administration of radiopharmaceutical (41 MBq/kg) showed no statistical difference in relation to basal values in binucleated cells. However the analysis of damage distribution in mononucleated cells, showed that the patients without previous radiotherapic treatment presented a significant increase in the frequency of cells with one micronucleus and in those who had taken previous radiotherapic treatment, in cells with two or more micronuclei. The in vitro experiments conducted with the exposition of total blood to three radiation concentrations of 153Sm-EDTMP (0.370, 0.555 and 1.110 MBq/mL) during one hour showed an increase in the frequency of micronuclei and necrotic and apoptotic cells with increasing radiation dose. Dose-response curves for healthy donors and patients with bone metastasis without previous radiotherapic treatment were constructed. The comparison of the curves showed that patients presented higher radiosensitivity, either micronuclei or dead cell (necrotic or apoptotic) percentages, than healthy donors.

In etwa 2-10% aller Krebsleiden findet man eine Metastase vor bei unbekanntem Primärtumor, der mit der üblichen Diagnostik nicht bestimmt werden kann. Meist handelt es sich hierbei um ein metastasierendes Adenokarzinom. Als Hilfsmittel bei der immunhistochemischen Differenzierung solcher Metastasen ist ein statistisches Verfahren entwickelt worden. Dabei können Wahrscheinlichkeitsangaben für die mögliche Organlokalisation des Primärtumors auf der Grundlage von immunhistologischen Färbeergebnissen mit 7 verschiedenen Tumormarkern (CEA, CK7, CK20, ER, GCDFP-15, Surfactant A, Vimentin) geliefert werden. Das histologische Untersuchungsmaterial umfaßte 313 Adenokarzinommetastasen mit bekanntem Primärtumor in Mamma, Ovar, Lunge, Niere, Kolon, Magen und Pankreas. Unter der Annahme einer ausreichenden Diagnosesicherheit bei einer Zuordnungswahrscheinlichkeit von >=90% konnten mit Hilfe des Verfahrens 46% der Metastasen ihrem Primärtumor zugeordnet werden. Die Methode erreicht dabei eine Spezifität von 95%. Mamma- und Lungenadenokarzinommetastasen wurden vor allem aufgrund des positiven Färbeergebnisses für ihren spezifischen Marker GCDFP-15 bzw. Surfactant A differenziert. Da die Diagnose hierbei unabhängig von den übrigen Ergebnissen gestellt werden konnte, wird die Anwendung des Verfahrens besonders bedeutsam für Metastasen, die ihren organspezifischen Marker nicht exprimieren, bzw. für Kolon-, Nieren- und Ovarialkarzinommetastasen, die zum Teil charakteristische Markerspektren aufweisen und damit recht gut zu differenzieren waren. Eine Differenzierung von Magen- und Pankreaskarzinommetastasen war dagegen aufgrund der sehr ähnlichen Markerprofile nicht möglich. Das vorgestellte Programm läßt sich nicht nur als Diagnosehilfe für den Immunhistologen nutzen, sondern läßt auch eine bessere Beurteilung der diagnostischen Wertigkeit verwendeter Markerkombinationen zu, so dass evtl. eine effektivere Antikörper-Auswahl getroffen werden kann. / Cancer of unknown primary origin is a common clinical syndrome and accounts for 2-10% of all cancer diagnoses. Most of these cases are related to a metastatic adenocarcinoma. We have developed and tested a statistical method which can serve as a diagnostic tool for the immunhistochemical differentiation of such metastases. Based on the different expression patterns of 7 tumor markers (CEA, CK 7, CK20, GCDFP-15, Vimentin, Surfactant A), the probability for a certain primary cancer site is calculated. To test the method, 313 metastases of adenocarcinoma with primary sites in the breast, the ovary, the kidney, the colon, the stomach, the pancreas and the lung were examined. Taking the diagnosis to be reliable if the method identifies a certain cancer site with a probability of 90 %, we find that we could differentiate 46 % of the metastases with a specificity of 95 %. Metastases of breast and lung carcinoma were identified mainly based on the expression of their specific markers Surfactant A and GCDFP-15. The procedure becomes especially useful, if a specific marker does not exist, or if the staining result is negative. Metastases of carcinoma from the kidney, the colon and the ovary could be differentiated, because they often exhibit specific expression patterns. In contrast, metastases from stomach and pancreas carcinoma have very similar immunhistochemical properties. Here, a differentiation was not possible. The suggested method can help immunhistochemists not only in the diagnosis, but also to estimate the diagnostic value of certain combinations of tumor markers.

There is an ever increasing need of new technologies for identification of molecular markers for early diagnosis of fatal diseases to allow efficient treatment. In addition, there is great value in finding patterns of metabolites, proteins or genes altered in relation to specific disease conditions to gain a deeper understanding of the underlying mechanisms of disease development. If successful, scientific achievements in this field could apart from early diagnosis lead to development of new drugs, treatments or preventions for many serious diseases.  Metabolites are low molecular weight compounds involved in the chemical reactions taking place in the cells of living organisms to uphold life, i.e. metabolism. The research field of metabolomics investigates the relationship between metabolite alterations and biochemical mechanisms, e.g. disease processes. To understand these associations hundreds of metabolites present in a sample are quantified using sensitive bioanalytical techniques. In this way a unique chemical fingerprint is obtained for each sample, providing an instant picture of the current state of the studied system. This fingerprint or picture can then be utilized for the discovery of biomarkers or biomarker patterns of biological and clinical relevance. In this thesis the focus is set on evaluation and application of strategies for studying metabolic alterations in human tissues associated with disease. A chemometric methodology for processing and modeling of gas chromatography-mass spectrometry (GC-MS) based metabolomics data, is designed for developing predictive systems for generation of representative data, validation and result verification, diagnosis and screening of large sample sets. The developed strategies were specifically applied for identification of metabolite markers and metabolic pathways associated with prostate cancer disease progression. The long-term goal was to detect new sensitive diagnostic/prognostic markers, which ultimately could be used to differentiate between indolent and aggressive tumors at diagnosis and thus aid in the development of personalized treatments. Our main finding so far is the detection of high levels of cholesterol in prostate cancer bone metastases. This in combination with previously presented results suggests cholesterol as a potentially interesting therapeutic target for advanced prostate cancer. Furthermore we detected metabolic alterations in plasma associated with metastasis development. These results were further explored in prospective samples attempting to verify some of the identified metabolites as potential prognostic markers.

Ο μυελός των οστών επηρεάζεται από λεμφοϋπερπλαστικές διαταραχές, μεταστατική νόσο, αλλά και από διάφορες θεραπευτικές προσεγγίσεις. Η μαγνητική τομογραφία είναι η πιο κατάλληλη μέθοδος για την ανίχνευση των μεταστάσεων και την παρακολούθηση μετά τη θεραπεία. Τεχνικές ανάλυσης εικόνας χρησιμοποιούνται επιπλέον προκειμένου να αντλήσουμε πρόσθετες διαγνωστικές πληροφορίες. Η παρούσα μελέτη επικεντρώνεται στις πρώιμες αλλαγές που προκαλούνται στον οστικό μυελό μετά από ακτινοβόληση και συγκρίνει καθιερωμένες μεθόδους για την ταυτοποίηση και τον χαρακτηρισμό αυτών των βλαβών με τη χρήση ενός αυτοματοποιημένου συστήματος ταξινόμησης. ΜΕΘΟΔΟΙ: 36 ασθενείς με ιστολογικά επιβεβαιωμένη πρωτοπαθή κακοήθεια και οστικές μεταστάσεις συμπεριλήφθηκαν στη μελέτη. Όλοι οι ασθενείς υποβλήθηκαν σε ακττινοθεραπεία για την αντιμετώπιση οστικών μεταστάσεων στη σπονδυλική στήλη ή τη λεκάνη. Η μαγνητική τομογραφία πραγματοποιήθηκε ακριβώς πριν, 12 έως 18 ημέρες και 3 μήνες μετά την έναρξη της ακτινοθεραπείας. Ελήφθησαν εικόνες εντός, πλησίον και εκτός του πεδίου ακτινοβόλησης. Η ποιοτική αξιολόγηση πραγματοποιήθηκε ανεξάρτητα από δύο έμπειρους ακτινολόγους. Για την ποσοτική αξιολόγηση, συγκεκριμένες μετρήσεις επιλέχθηκαν και αξιολογήθηκαν με τη μέθοδο της περιοχής ενδιαφέροντος. Επιπλέον, χαρακτηριστικά υφής 1ης και 2ης τάξης εξήχθησαν και τοποθετήθηκαν σε ένα πιθανοτικό νευρωνικό δίκτυο, προκειμένου να δημιουργηθεί ένα σύστημα αυτόματης ταξινόμησης των βλαβών. ΑΠΟΤΕΛΕΣΜΑΤΑ: Σύμφωνα με την ποιοτική και ποσοτική αξιολόγηση, εντός του πεδίου ακτινοβολίας 22.22% και 33.33% των ασθενών αντίστοιχα παρουσίασε λιπώδη μεταστροφή του μυελού, 19.44% και 16.67% των ασθενών παρουσίασε αιμορραγία, ενώ 11.11% και 16.67% των ασθενών εμφάνισε οίδημα του οστικού μυελού. Παρακείμενα του πεδίου ακτινοβόλησης 11.11% και 19.44% των ασθενών παρουσίασε λιπώδη μεταστροφή, 8.33% παρουσίασε αιμορραγία, ενώ 2.78% και 8.33% έδειξε οίδημα του μυελού των οστών. Εκτός του πεδίου ακτινοβολίας 5.56% των ασθενών παρουσίασαν αλλαγές συμβατές με λιπώδη μεταστροφή, ενώ το υπόλοιπο 94.44% δεν έδειξε σημαντικές μεταβολές. Δεν υπήρξε στατιστικά σημαντική μεταβολή του δείκτη σκιαγραφικής ενίσχυσης μετά τη χορήγηση γαδολινίου. Με βάση την πολυπαραγοντική ανάλυση, καμία από τις παραμέτρους που μελετήθηκαν δεν φάνηκε να επηρεάζει στατιστικά σημαντικά την εμφάνιση οποιασδήποτε από τις μετακτινικές αλλοιώσεις. Η μέγιστη συνολική ακρίβεια ταξινόμησης του συστήματός μας, ως προς τη διάκριση μεταξύ προ και μετακτινικών εικόνων ήταν 93.02%, με χρήση του συστήματος ταξινόμησης LSFT - PNN και της μεθόδου ECV. Η ακρίβεια του συστήματος στη διάκριση μεταξύ των τριών κυρίων τύπων των μετακτινικών βλαβών ήταν 86.67% . ΣΥΜΠΕΡΑΣΜΑΤΑ: Η παρούσα μελέτη δείχνει ότι σημαντικό ποσοστό των ασθενών που υποβάλλονται σε ακτινοθεραπεία θα εμφανίσει τουλάχιστον μία από τις κοινές μετακτινικές μεταβολές του οστικού μυελού. Η λιπώδης μεταστροφή του μυελού είναι η πιο συχνά εμφανιζόμενη πρώιμη μεταβολή. Η ποιοτική ανάλυση των εικόνων μαγνητικής τομογραφίας υστερεί σε ευαισθησία σε σύγκριση με τις ποσοτικές μετρήσεις. Το βασζόμενο σε νευρικό δίκτυο προτεινόμενο σύστημα ταξινόμησης μπορεί να αποδειχθεί χρήσιμο εργαλείο για το χαρακτηρισμό αυτών των βλαβών. / Bone marrow can be affected by lymphoproliferative disorders and metastatic disease but also by several therapeutic approaches. MRI is the most suitable method for the detection of metastases and post-treatment follow-up. Image analysis techniques are now used to extract additional diagnostic information. This study focuses on the early radiation-induced changes that can be detected by MRI and compares the established methods for the identification and characterization of these lesions with an automated classification system. METHODS: 36 patients with histologically confirmed primary malignancy and associated bone metastases were included in the study. All patients underwent radiation therapy (RT) to treat bone metastases to the spinal column or the pelvis. Magnetic resonance imaging (MRI) was performed just before the start of RT, 12 to 18 days and up to 3 months after the start of RT. Images were obtained within, adjacent and outside the radiation field. Qualitative assessment was performed independently by two experienced radiologists. For quantitative assessment, specific measurements were selected and evaluated by the method of the region of interest (ROI). In addition, textural features of 1st and 2nd class were exported and inserted into a probabilistic neural network classifier, in order to create an automatic classification system for these lesions. RESULTS: Following qualitative and quantitative assessment, within the radiation field, 22.22% and 33.33% of patients respectively showed fatty conversion of the bone marrow, 19.44% and 16.67% of patients showed haemorrhage, while 11.11% and 16.67% of the patients demonstrated bone marrow oedema. Adjacent to the radiation field, 11.11% and 19.44% of patients showed fatty conversion, 8.33% showed haemorrhage, while 2.78% and 8.33% demonstrated bone marrow oedema. Outside of the radiation field, 5.56% of patients showed changes compatible with fatty conversion, while the remaining 94.44% showed no significant change. There was no statistically significant change of the enhancement index after gadolinium administration. In multivariate analysis, none of the studied parameters did not appear to affect significantly the appearance of any of the radiation-induced lesions. The largest overall classification accuracy of the system designed to distinguish between the pre- radiation and radiation-induced images was 93.02% using the LSFT-PNN classification system of multiple sequences and the ECV method. Discrimination accuracy of the classification system designed to distinguish between the three main types of post-radiation lesions was 86.67%. CONCLUSIONS: This study shows that a significant proportion of patients undergoing RT will experience at least one of the common radiation-induced bone marrow changes. Fatty marrow conversion is the most often featured change in the examined period. Qualitative analysis of the MRI images lacks sensitivity comparing to quantitative measurements. The proposed classification system, based on the neural network, can be used as a very helpful tool for the characterization of these lesions.

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