Background: Angiogenesis is the process by which new blood vessels develop from existing vasculature and is a critical step in all tumours to facilitate growth beyond a few millimetres. As this process is largely inactive in physiological circumstances in adults, it represents an attractive therapeutic target in oncology. Drugs that target the angiogenic process are classified as anti-angiogenic agents. The first anti-angiogenic drug to be approved by the FDA was bevacizumab; a recombinant humanized monoclonal antibody against VEGF. Randomised studies in colorectal cancer (and other solid malignancies) have reported prolonged progression free survival and overall survival for bevacizumab. However, standard radiological criteria, Response Evaluation Criteria In Solid Tumours (RECIST), although widely employed to assess response to therapy in clinical trials, are generally insensitive to the predominantly cytostatic effects of anti-angiogenic and other targeted therapies. Alternative methods of predicting or assessing early response to such agents are needed, particularly given the cost and toxicity implications of such treatments. However, biomarkers to aid selection of patients for anti-angiogenic therapies, including bevacizumab, remain elusive. Purpose: To investigate Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI), Diffusion Weighted Imaging (DWI) and circulating angiocytokines, measured using an ELISA multiplex, as prognostic markers in patients with metastatic colorectal cancer treated with bevacizumab and chemotherapy. Results: Seventy patients were treated. DCE-MRI and DWI parameters showed good reproducibility with coefficient of variation between 3.7 to 23% for parameters. The median progression free survival, the primary end point of the trial, was 9.3 months. The overall response rate was 44%. The clinical variables which were significant for progression free survival on univariate analysis were: performance status (p=0.005), CEA (p=0.04) and serum LDH (p=0.005). Biomarkers which were significant for progression free survival on univariate analysis were serum VEGF-A (p=0.02), serum HGF (p=0.005), sVEGFR-2 (p=0.02). In each case, low values of the biomarker were associated with improved outcome. Multivariate analysis identified Ktrans (p=0.015), performance status (p=0.008) and serum HGF (p=0.003) as the most significant predictors of progression free survival. A prolonged progression free survival was associated with a good ECOG performance status, high Ktrans and low serum HGF.Conclusions: Whilst these results are encouraging, future work is required to establish whether HGF and Ktrans are prognostic markers for metastatic colorectal cancer and their precise role in the prediction of patients likely to benefit from treatment with bevacizumab.

Zielsetzung: Die Chronisch-Rekurrierende Multifokale Osteomyelitis/Chronische Nicht-bakterielle Osteitis (CRMO/CNO) ist eine seltene auto-inflammatorische Erkrankung, deren typische Symptome starke Knochenschmerzen und lokale Schwellungen sind. Da die Ursachen muskuloskelettaler Beschwerden bei Kindern und Heranwachsenden vielfältig sein können, ist die differentialdiagnostische Unterscheidung einer CRMO/CNO von anderen Erkrankungen, unspezifischen Schmerzen oder einer malignen Grunderkrankung als Quelle der Symptome schwierig. Neue Techniken wie die diffusionsgewichtete Bildgebung (DWI) in der Magnetresonanztomographie (MRT) erlauben Rückschlüsse auf die Gewebestruktur und können in bestimmten Fällen eine Unterscheidung zwischen entzündlichen und malignen Prozessen vereinfachen. Ziel dieser Studie war es daher, die Sichtbarkeit von CRMO-/CNO-Läsionen mittels der DWI-Ganzkörperbildgebung zu evaluieren und den potentiellen klinischen Wert zu untersuchen. Material und Methoden: Sechzehn Patienten mit bekannter CRMO/CNO wurden bei 3 Tesla untersucht. Das Untersuchungsprotokoll beinhaltete u. a. 2D Short Tau Inversion Recovery (STIR) und diffusionsgewichtete Sequenzen in axialer Schichtführung. Die Sichtbarkeit von Läsionen in der DWI und der STIR wurde von 2 Auswertern im Konsensus evaluiert. Für alle Läsionen und in der korrespondierenden Referenzlokalisation wurden der Apparent Diffusion Coefficient (ADC) ermittelt. Ergebnisse: Insgesamt wurden 33 Läsionen eingeschlossen (durchschnittlich 2 Läsionen pro Patient), die sowohl in der STIR als auch in der DWI sichtbar waren. Diese waren vornehmlich in den langen Röhrenknochen lokalisiert. Der mittlere ADC-Wert in Läsionen betrug 1283 mm2/s und war somit signifikant höher als in der Referenzregion, hier betrug der mittlere ADC 782 mm2/s. Im ADCVerhältnis (Läsion vs. Referenzregion) zeigten 82 % der Läsionen eine relative Signalintensitätssteigerung um mehr als 10 %, und 76 % (25 Läsionen) zeigten eine Intensitätssteigerung von mehr als 15 %. Der mittlere relative Signalintensitätsanstieg betrug 69 %. Schlussfolgerung: Diese Studie zeigt, dass die diffusionsgewichtete Ganzkörperbildgebung bei 3 Tesla zuverlässig bei Kindern durchgeführt werden kann. Die ADC-Werte waren in CRMO-/CNO-Läsionen im Vergleich zur Referenzregion signifikant erhöht. Daher wird die Ganzkörperbildgebung in Kombination mit klinischen Angaben von uns als vielversprechende Methode angesehen, um benigne inflammatorische Prozesse anhand der ADC-Werte von bestimmten Malignitäten zu unterscheiden.

Prostate cancer (PCa) is the most common non-skin malignancy of men in developed countries. In spite of treatment with curative intent up to 30-40% of patients have disease recurrence after treatment, resulting from any combination of lymphatic, hematogenous, or contiguous local spread. The concept of early detection of PCa offer benefits in terms of reduced mortality, but at the cost of over-diagnosis and overtreatment of indolent disease. This is largely due to the random nature of conventional biopsies, with a risk of missing significant cancer and randomly hitting indolent disease. In the present thesis, diagnostic performance of MRI DWI and 11C Acetate PET/CT lymph node staging of intermediate and high risk PCa, was investigated, and additionally, predictive factors of regional lymph node metastases were evaluated. Further, additional value of targeted biopsies to conventional biopsies, for detection of clinically significant PCa, was investigated. In paper one and two, 53 and 40 patients with predominantly high risk PCa underwent 11C Acetate PET/CT and 3T MRI DWI, respectively, for lymph node staging, before extended pelvic lymph node dissection (ePLND). The sensitivity and specificity for PET/CT was 38% and 96% respectively. The sensitivity and specificity for MRI DWI was 55% and 90% respectively. In paper three, 53 patients with newly diagnosed PCa were included. All patients underwent multi-parametric MRI, followed by two cognitive targeted biopsies. Five more clinically significant cancers were detected by adding targeted biopsies to conventional biopsies. In paper four the value of quantitative and qualitative MRI DWI and 11C Acetate PET/CT parameters, alone and in combination, in predicting regional lymph node metastases were examined. ADCmean in lymph nodes and T-stage on MRI were independent predictors of lymph node metastases in multiple logistic regression analysis. In conclusion the specificity of diffusion weighted MRI and 11C Acetate PET/CT for lymph node staging was high, although the sensitivity was low. Predictive factors of regional lymph node metastases could be retrieved from diffusion weighted MRI and 11C Acetate PET/CT. By combining targeted biopsies with conventional biopsies the detection rate of clinically significant PCa could be increased.