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Soft tissue sarcomas account for about 1% of all malignancies. The increase in incidence of soft tissue sarcomas during the recent decades may predominantly be attributed to AIDS-related Kaposi’s sarcoma; when this tumor is excluded, conclusive evidence for an age-adjusted increase is lacking. Beside the well investigated role of the human immunodeficiency virus 1 (HIV-1) and the human herpesvirus 8 (HHV-8) in the tumorigenesis of AIDS-related Kaposi’s sarcoma and several inherited disorders, considerable evidence support a relationship between occupational chemicals as vinyl chloride, phenoxyacetic acid herbicides, chlorphenols, dioxin, medicinal measures as Thorotrast exposure and therapeutic irradiation, and the development of soft tissue sarcoma. Hormones and chronic repair processes are further probably sarcoma-promoting factors. Considering the rarity of soft tissue sarcomas despite the vast portion that soft tissues comprise in the human body, additional knowledge on the tumorigenesis of soft tissue sarcomas might considerably contribute to the understanding of the etiologic pathways of malignant tumors in humans. / Weichteilsarkome stellen etwa 1% aller bösartigen Neubildungen. Der in den vergangenen Jahrzehnten beobachtete Inzidenzanstieg geht fast ausschließlich auf die rasante Zunahme an AIDS-assoziierten Kaposi-Sarkomen zurück. Bei Außerachtlassung dieses Tumors gibt es bisher keinen schlüssigen Beweis für eine wirkliche alterskorrigierte Häufigkeitszunahme der Weichteilsarkome. Neben der gut untersuchten Rolle des HIV-1-Virus und des humanen Herpes-Virus 8 bei der Entstehung des AIDS-assoziierten Kaposi-Sarkoms und einigen prädisponierenden genetischen Erkrankungen existieren starke Hinweise für einen Zusammenhang zwischen Industriegiften wie Vinylchlorid, Phenoxyessigsäure-Herbiziden, Chlorphenolen, Dioxinen, medizinischen Maßnahmen wie therapeutischer Bestrahlung oder dem Einsatz von Thorotrast, und der Entwicklung von Weichteilsarkomen. Hormone und chronische Reparaturprozesse sind weitere wahrscheinlich fördernde Einflüsse auf die Entstehung von Weichteilsarkomen. Die Tatsache, daß trotz des großen Anteils, den die Binde- und Stützgewebe an der Körpermasse stellen, nur selten maligne Tumoren von diesen Strukturen ausgehen, läßt hoffen, daß ein besseres Verständnis der an der Kanzerogenese von Weichteilsarkomen beteiligten Mechanismen in der Zukunft wichtige Erkenntnisse über die Entstehung menschlicher Tumoren liefern kann. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Despite improvements in the clinical management of soft tissue sarcomas (STS), 50% of patients will die of metastatic disease that is largely unresponsive to conventional chemotherapeutic agents. The aims of this study were to identify genes and pathways that are dysregulated in progressive and metastatic STS. In addition to this, cell lines from fresh tumours were initiated and established, thus increasing the repository of cell lines available for functional studies. Recent advances in the understanding of the molecular biology of STS have thus far not resulted in the use of molecular markers for clinical prognostication. Identifying novel genes and pathways will lead to molecular diagnostic methods to better stratify prognostic groups and could identify cellular targets for more efficacious treatments. Gene expression profiling of sarcoma cell lines of increasing metastatic potential revealed over-expression of genes involved in the epidermal growth factor (EGF) and transforming growth factor beta (TGFb) pathways. Factors involved in invasion and metastasis such as integrins and MMPs were over-expressed in the cell lines with higher metastatic potential. The developmental Notch pathway and cell cycle regulators were also dysregulated. NDRG1 was significantly over-expressed in the high grade sarcoma cell line, a novel finding in sarcomas. The expression of EGFR, NDRG1 and other genes from the above pathways was validated using quantitative RT-PCR in real time (qRT-PCR). A tissue microarray (TMA) comprising STS of varying tumour grades was constructed for high throughput assessment of target proteins. EGFR, its activated form and its signal transducers were investigated using immunohistochemistry (IHC). Activated EGFR (HR 2.228, p < 0.001) and phosphorylated Akt (HR 2.032, p = 0.003) were found to be independent predictors of overall survival and both correlated with tumour grade. Of the several STS cultures initiated and maintained, two of these cell lines were fully characterised in terms of cytogenetics, telomerase and alternate lengthening of 5 telomeres (ALT) status, KIT and TP53 mutation and the expression of certain biomarkers using both qRT-PCR and IHC. In summary, transcript profiling identified several potential biomarkers of tumour progression and metastasis in STS. Crucially, activated EGFR and pAkt were found in a cohort of STS samples to correlate with clinical outcome, identifying them as potential diagnostic and therapeutic targets in the treatment of STS. Activated EGFR can be used as a diagnostic marker for patient selection, as well as for target effect monitoring. Furthermore, the cell lines established in this project will serve as valuable tools in future preclinical studies.

This thesis presents research that was conducted to develop anatomically realistic finite element models of breast deformation under a variety of gravity loading conditions to assist clinicians in tracking suspicious tissues across multiple imaging modalities. Firstly, the accuracy of the modelling framework in predicting deformations of a homogeneous body was measured using custom designed silicon gel phantoms. The model predicted surface deformations with an average RMS error of 1.5 mm +/- 0.2 mm and tracked internal marker locations with an average RMS error of 1.4 mm +/- 0.7 mm. A novel method was then developed to determine the reference configuration of a body, when given its mechanical properties, boundary conditions and a deformed configuration. The theoretical validity of the technique was confirmed with an analytic solution. The accuracy of the method was also measured using silicon gel experiments, predicting the reference configuration surface with an average RMS error of 1.3 mm +/- 0.1 mm, and tracking internal marker locations with an average error of 1.5 mm +/- 0.8 mm. Silicon gel composites were then created to measure the accuracy of standard techniques to model heterogeneity. The models did not match the experimentally recorded deformations. This highlighted the need for further validation exercises on modelling heterogeneity before modelling them in the breast. A semi-automated algorithm was developed to fit finite element models to the skin and muscle surfaces of each individual, which were segmented from breast MR images. The code represented the skin with an average RMS error of 1.46 mm +/- 0.32 mm and the muscle with an average RMS error of 1.52 mm +/- 0.3 mm. The framework was then tested using images of the breast obtained under different gravity loading conditions and neutral buoyancy. A homogeneous model was first developed using the neutral buoyancy images as a representation of the reference configuration. The model did not accurately capture the regional deformations of the breast under gravity loading. However, the gross shape of the breast was reproduced, indicating that a biomechanical model of the breast could be useful to reliably track tissues across multiple images for cancer diagnosis. / This research was sponsored by the Top Achiever Doctoral Scholarship and the University of Auckland Doctoral Scholarship. Extra funding for travel was provided by the Graduate Research Fund and the John Logan Campbell Trust Fund.

This thesis presents research that was conducted to develop anatomically realistic finite element models of breast deformation under a variety of gravity loading conditions to assist clinicians in tracking suspicious tissues across multiple imaging modalities. Firstly, the accuracy of the modelling framework in predicting deformations of a homogeneous body was measured using custom designed silicon gel phantoms. The model predicted surface deformations with an average RMS error of 1.5 mm +/- 0.2 mm and tracked internal marker locations with an average RMS error of 1.4 mm +/- 0.7 mm. A novel method was then developed to determine the reference configuration of a body, when given its mechanical properties, boundary conditions and a deformed configuration. The theoretical validity of the technique was confirmed with an analytic solution. The accuracy of the method was also measured using silicon gel experiments, predicting the reference configuration surface with an average RMS error of 1.3 mm +/- 0.1 mm, and tracking internal marker locations with an average error of 1.5 mm +/- 0.8 mm. Silicon gel composites were then created to measure the accuracy of standard techniques to model heterogeneity. The models did not match the experimentally recorded deformations. This highlighted the need for further validation exercises on modelling heterogeneity before modelling them in the breast. A semi-automated algorithm was developed to fit finite element models to the skin and muscle surfaces of each individual, which were segmented from breast MR images. The code represented the skin with an average RMS error of 1.46 mm +/- 0.32 mm and the muscle with an average RMS error of 1.52 mm +/- 0.3 mm. The framework was then tested using images of the breast obtained under different gravity loading conditions and neutral buoyancy. A homogeneous model was first developed using the neutral buoyancy images as a representation of the reference configuration. The model did not accurately capture the regional deformations of the breast under gravity loading. However, the gross shape of the breast was reproduced, indicating that a biomechanical model of the breast could be useful to reliably track tissues across multiple images for cancer diagnosis. / This research was sponsored by the Top Achiever Doctoral Scholarship and the University of Auckland Doctoral Scholarship. Extra funding for travel was provided by the Graduate Research Fund and the John Logan Campbell Trust Fund.

This thesis presents research that was conducted to develop anatomically realistic finite element models of breast deformation under a variety of gravity loading conditions to assist clinicians in tracking suspicious tissues across multiple imaging modalities. Firstly, the accuracy of the modelling framework in predicting deformations of a homogeneous body was measured using custom designed silicon gel phantoms. The model predicted surface deformations with an average RMS error of 1.5 mm +/- 0.2 mm and tracked internal marker locations with an average RMS error of 1.4 mm +/- 0.7 mm. A novel method was then developed to determine the reference configuration of a body, when given its mechanical properties, boundary conditions and a deformed configuration. The theoretical validity of the technique was confirmed with an analytic solution. The accuracy of the method was also measured using silicon gel experiments, predicting the reference configuration surface with an average RMS error of 1.3 mm +/- 0.1 mm, and tracking internal marker locations with an average error of 1.5 mm +/- 0.8 mm. Silicon gel composites were then created to measure the accuracy of standard techniques to model heterogeneity. The models did not match the experimentally recorded deformations. This highlighted the need for further validation exercises on modelling heterogeneity before modelling them in the breast. A semi-automated algorithm was developed to fit finite element models to the skin and muscle surfaces of each individual, which were segmented from breast MR images. The code represented the skin with an average RMS error of 1.46 mm +/- 0.32 mm and the muscle with an average RMS error of 1.52 mm +/- 0.3 mm. The framework was then tested using images of the breast obtained under different gravity loading conditions and neutral buoyancy. A homogeneous model was first developed using the neutral buoyancy images as a representation of the reference configuration. The model did not accurately capture the regional deformations of the breast under gravity loading. However, the gross shape of the breast was reproduced, indicating that a biomechanical model of the breast could be useful to reliably track tissues across multiple images for cancer diagnosis. / This research was sponsored by the Top Achiever Doctoral Scholarship and the University of Auckland Doctoral Scholarship. Extra funding for travel was provided by the Graduate Research Fund and the John Logan Campbell Trust Fund.

Ankle sprains are one of the most common musculoskeletal injuries. Physiotherapy treatment and advice to rest, use ice, use compression, and elevate the ankle (RICE advice) is believed to speed up the functional recovery and enhance healing associated with acute ankle sprains. However, there is limited evidence to support the efficacy of RICE treatment. This study investigated whether physiotherapy (including RICE advice) was as effective as RICE advice alone in improving the time to recovery in a clinical situation.The evidence for RICE advice was reviewed along with the different treatment modalities currently used by physiotherapists in New Zealand for acute ankle sprain. This review highlighted the low number and poor quality of studies investigating RICE and early intervention physiotherapy management for ankle sprains. RICE principals appear to be relatively inexpensive and somewhat effective for pain relief and may reduce further tissue damage in the acute stage of Grade I and II ankle sprains. Evidence extrapolated from studies investigating the use of post surgical ice appears to support the use of ice in the acute stage of an ankle sprain to minimise bleeding and oedema. The intermittent application of ice is more effective for pain relief in the acute phase than sustained icing. Physiotherapy interventions such as TENS for pain relief and bracing for the support of Grade II - III ankle sprains have been shown to be beneficial for pain relief in the acute phase. A need for further high quality, randomised controlled trials (RCT's) was identified.Subsequently a RCT was conducted with 28 participants to investigate the difference between (a) early intervention physiotherapy management combined with RICE advice, and (b) self management RICE advice without physiotherapy.Twenty eight individuals (males n = 22, females n = 6), between the ages of 16 and 40 with acute ankle sprains, who met the inclusion criteria, were approached by physiotherapists working on this project and invited to participate. Dependant variables were pain, function, swelling, compliance and medication use up to Day 11 post injury. Swelling, pain and function were measured over three assessments on Days 1, 3 and 11, using volumetric analysis, a visual analogue scale (VAS) and a functional question derived from a validated functional questionnaire respectively. Medication use and compliance were elicited from information gathered in a participant home diary. Both groups were similar on Day 1 in respect to their initial pain, swelling, the number of participants who were referred for X-rays, and the time taken to present to the physiotherapist. However the RICE group had significantly higher function scores (p = 0.042). The RICE group also had a significantly higher use of medication on Day 1 (p = 0.035) and Day 11 (p = 0.048). For both groups there was a statistically significant decrease in swelling (p = 0.003), pain scores (p = 0.000), and an increase in function scores (p = 0.000) in relation to time over the eleven days of assessment. The physiotherapy group had significantly improved function scores (p = 0.042) from Day 1 to Day 11 compared to the RICE group. There were no significant differences between groups for swelling, pain scores, and their first day of documented non-compliance. The within day range of error in the volumetric measurements was within 189.9 ml and 1.2 ml. Three trials were conducted per person within a Day session. The first volumetric analysis was significantly less than the subsequent two measurements (p = 0.040).It was concluded that, in the early stage of an ankle injury both physiotherapy and RICE, and RICE advice alone, resulted in significant improvements in swelling, pain and function. Early intervention physiotherapy was significantly better at improving the functional ability of participants by Day 11. Early intervention physiotherapy may also identify complications associated with ankle sprains.Despite its limitations this research could potentially lead to changes in the standard treatment protocols for soft tissue ankle injuries. Implementation of self management RICE by patients in the acute stage would initially reduce the cost of physiotherapy treatments, and may lead to equal improvements in pain and swelling outcomes. However, it appears that physiotherapy may lead to better functional outcomes which would reduce the costs associated with time off work, and rehabilitation. It is important to note that these findings are based on a small sample size and on Grade I or II ankle ligament sprains, and that treatment for more severe ankle injuries may be better with physiotherapy, or surgery, rather than self management RICE by patients. Findings contribute to the growing body of 'best practice' evidence for health practitioners. Keywords: Acute soft tissue injuries, ankle, sprain, early intervention, physiotherapy, RICE, volumetric measurement.

Despite improvements in the clinical management of soft tissue sarcomas (STS), 50% of patients will die of metastatic disease that is largely unresponsive to conventional chemotherapeutic agents. The aims of this study were to identify genes and pathways that are dysregulated in progressive and metastatic STS. In addition to this, cell lines from fresh tumours were initiated and established, thus increasing the repository of cell lines available for functional studies. Recent advances in the understanding of the molecular biology of STS have thus far not resulted in the use of molecular markers for clinical prognostication. Identifying novel genes and pathways will lead to molecular diagnostic methods to better stratify prognostic groups and could identify cellular targets for more efficacious treatments. Gene expression profiling of sarcoma cell lines of increasing metastatic potential revealed over-expression of genes involved in the epidermal growth factor (EGF) and transforming growth factor beta (TGFb) pathways. Factors involved in invasion and metastasis such as integrins and MMPs were over-expressed in the cell lines with higher metastatic potential. The developmental Notch pathway and cell cycle regulators were also dysregulated. NDRG1 was significantly over-expressed in the high grade sarcoma cell line, a novel finding in sarcomas. The expression of EGFR, NDRG1 and other genes from the above pathways was validated using quantitative RT-PCR in real time (qRT-PCR). A tissue microarray (TMA) comprising STS of varying tumour grades was constructed for high throughput assessment of target proteins. EGFR, its activated form and its signal transducers were investigated using immunohistochemistry (IHC). Activated EGFR (HR 2.228, p < 0.001) and phosphorylated Akt (HR 2.032, p = 0.003) were found to be independent predictors of overall survival and both correlated with tumour grade. Of the several STS cultures initiated and maintained, two of these cell lines were fully characterised in terms of cytogenetics, telomerase and alternate lengthening of 5 telomeres (ALT) status, KIT and TP53 mutation and the expression of certain biomarkers using both qRT-PCR and IHC. In summary, transcript profiling identified several potential biomarkers of tumour progression and metastasis in STS. Crucially, activated EGFR and pAkt were found in a cohort of STS samples to correlate with clinical outcome, identifying them as potential diagnostic and therapeutic targets in the treatment of STS. Activated EGFR can be used as a diagnostic marker for patient selection, as well as for target effect monitoring. Furthermore, the cell lines established in this project will serve as valuable tools in future preclinical studies.

Despite improvements in the clinical management of soft tissue sarcomas (STS), 50% of patients will die of metastatic disease that is largely unresponsive to conventional chemotherapeutic agents. The aims of this study were to identify genes and pathways that are dysregulated in progressive and metastatic STS. In addition to this, cell lines from fresh tumours were initiated and established, thus increasing the repository of cell lines available for functional studies. Recent advances in the understanding of the molecular biology of STS have thus far not resulted in the use of molecular markers for clinical prognostication. Identifying novel genes and pathways will lead to molecular diagnostic methods to better stratify prognostic groups and could identify cellular targets for more efficacious treatments. Gene expression profiling of sarcoma cell lines of increasing metastatic potential revealed over-expression of genes involved in the epidermal growth factor (EGF) and transforming growth factor beta (TGFb) pathways. Factors involved in invasion and metastasis such as integrins and MMPs were over-expressed in the cell lines with higher metastatic potential. The developmental Notch pathway and cell cycle regulators were also dysregulated. NDRG1 was significantly over-expressed in the high grade sarcoma cell line, a novel finding in sarcomas. The expression of EGFR, NDRG1 and other genes from the above pathways was validated using quantitative RT-PCR in real time (qRT-PCR). A tissue microarray (TMA) comprising STS of varying tumour grades was constructed for high throughput assessment of target proteins. EGFR, its activated form and its signal transducers were investigated using immunohistochemistry (IHC). Activated EGFR (HR 2.228, p < 0.001) and phosphorylated Akt (HR 2.032, p = 0.003) were found to be independent predictors of overall survival and both correlated with tumour grade. Of the several STS cultures initiated and maintained, two of these cell lines were fully characterised in terms of cytogenetics, telomerase and alternate lengthening of 5 telomeres (ALT) status, KIT and TP53 mutation and the expression of certain biomarkers using both qRT-PCR and IHC. In summary, transcript profiling identified several potential biomarkers of tumour progression and metastasis in STS. Crucially, activated EGFR and pAkt were found in a cohort of STS samples to correlate with clinical outcome, identifying them as potential diagnostic and therapeutic targets in the treatment of STS. Activated EGFR can be used as a diagnostic marker for patient selection, as well as for target effect monitoring. Furthermore, the cell lines established in this project will serve as valuable tools in future preclinical studies.

This thesis presents research that was conducted to develop anatomically realistic finite element models of breast deformation under a variety of gravity loading conditions to assist clinicians in tracking suspicious tissues across multiple imaging modalities. Firstly, the accuracy of the modelling framework in predicting deformations of a homogeneous body was measured using custom designed silicon gel phantoms. The model predicted surface deformations with an average RMS error of 1.5 mm +/- 0.2 mm and tracked internal marker locations with an average RMS error of 1.4 mm +/- 0.7 mm. A novel method was then developed to determine the reference configuration of a body, when given its mechanical properties, boundary conditions and a deformed configuration. The theoretical validity of the technique was confirmed with an analytic solution. The accuracy of the method was also measured using silicon gel experiments, predicting the reference configuration surface with an average RMS error of 1.3 mm +/- 0.1 mm, and tracking internal marker locations with an average error of 1.5 mm +/- 0.8 mm. Silicon gel composites were then created to measure the accuracy of standard techniques to model heterogeneity. The models did not match the experimentally recorded deformations. This highlighted the need for further validation exercises on modelling heterogeneity before modelling them in the breast. A semi-automated algorithm was developed to fit finite element models to the skin and muscle surfaces of each individual, which were segmented from breast MR images. The code represented the skin with an average RMS error of 1.46 mm +/- 0.32 mm and the muscle with an average RMS error of 1.52 mm +/- 0.3 mm. The framework was then tested using images of the breast obtained under different gravity loading conditions and neutral buoyancy. A homogeneous model was first developed using the neutral buoyancy images as a representation of the reference configuration. The model did not accurately capture the regional deformations of the breast under gravity loading. However, the gross shape of the breast was reproduced, indicating that a biomechanical model of the breast could be useful to reliably track tissues across multiple images for cancer diagnosis. / This research was sponsored by the Top Achiever Doctoral Scholarship and the University of Auckland Doctoral Scholarship. Extra funding for travel was provided by the Graduate Research Fund and the John Logan Campbell Trust Fund.