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Department of Surgery – Alfred Hospital

Head:  Professor Jeffrey V. Rosenfeld, MBBS, MD (Monash), MS(Melb), FRACS, FRCS(Ed), FRCS(Glasg)Hon, FACS, FACTM, MRACMA
Contact: 9903 0190
Email: jeffrey.rosenfeld@med.monash.edu.au
Location: Department of Surgery, Alfred Hospital

Chemo-prevention of colorectal cancer

Supervisor: Professor Paul O'Brien
Contact: 9903 0608
Email: paul.obrien@med.monash.edu.au

Non-steroidal anti-inflammatory drugs such as aspirin and sulindac are known to inhibit the development and growth of colorectal tumours in experimental animals and the use of these commonly available agents in prevention of colon cancer in the community is increasingly a question of major importance. We are currently exploring the ways that these drugs work using techniques of molecular biology, immunohistochemistry and quantitative histology. Studies are currently only in animal models but we are planning to commence human studies in the near future.

The microcirculation of liver metastases

Supervisor: Dr Chris Christophi
Contact: 9903 0625
Email: christopher.christophi@med.monash.edu.au

This Department has a strong interest in both animal based research and clinical aspects of liver metastasis. Projects are available in the understanding of tumour biology and underlying mechanisms involved in liver metastasis, as well as clinical projects in the management of this condition. The broad aim of these projects would entail the student to develop an understanding of animal models of liver metastasis as well as expertise in the techniques of tissue culture, angiogenic assays, casting and scanning electron microscopy and immunohistochemistry.

Possible Projects:

  • A study of angiogenesis of liver metastasis and identification of angiogenic inhibitors.
  • An ultrastructural study of human liver tumour specimens.
  • A study of the relationship between adhesion molecule expression and formation of liver metastasis.
  • The effect of hepatotrophic growth factors on liver metastatic growth.
  • The role of laser induced hyperthermia in the treatment of liver metastasis.
  • Both clinical and laboratory based research are available in the above projects.

Measurement of pH in heart muscle using a new miniature electrode

Supervisor: Clinical Associate Professor Frank Rosenfeldt
Contact: 9522 4353
Location: Alfred Hospital

We have been working for several years with the Department of Chemistry and Electrical Engineering at the University of South Australia to perfect tiny electrodes to measure the pH on the human heart during heart surgery and transplantation. We now have a supply of these electrodes and are preparing to use them during heart surgery and transplantation at the Alfred Hospital.

The project is to evaluate these electrodes on the bench and in animals in the research laboratory and then to apply them in the human heart in the Alfred Hospital.

Development of chondrocyte graft treatment for cartilage defects in the knee

Supervisors: J.E. Paddle-Ledinek & Associate Professor John Hart
Contact: 9903 0616
Location: Alfred Hospital

Knee injury with the development of cartilage defects is a common source of persisting pain and disability. Cultured autografts prepared from chondrocytes taken by biopsy and replaced at the site of injury provide an innovative way of repairing these defects and we are one of the leading centres in the world. The aims of the project would include study of optimal processing of biopsies and clinical evaluation of outcomes in the patients

5. Weight loss – study of the changes in physical, psychosocial and medical status

Supervisor: Professor Paul O’Brien & Dr John Dixon
Contact: 9903 0608
Email: paul.obrien@med.monash.edu.au.

We are currently treating people with obesity and generating a weight loss of 30 – 40kg over a period of 18 – 24 months. The changes that occur in the health and well-being of these people is outstanding and in these studies we are seeking to characterise these changes, particularly with respect to co-morbidities and quality of life.

CARDIAC SURGERY RESEARCH UNIT

Contact: A/Prof Franklin Rosenfeldt & Dr. Salvatore Pepe (Tel: 9522 4352)
Location: Alfred Hospital & Baker Medical Research Institute

Bachelor of Medical Science (Hons) Clinical & Basic Science Projects with Cardiac Surgery & Transplant Units, 2000:

Biology of human aging and pathology with relevance to new strategies for improved outcomes in cardiac surgery and heart transplantation. Experience research as part of a team of surgeons, scientists, surgical trainees and MD & PhD scholars. Two examples of basic science areas available are:

Mitochondrial Regulation of Cell Death in Human Myocardium

How is mitochondrial function in the human heart specifically altered in disease states such as cardiac ischemia, heart failure or hypertrophy and with increased age? This project involves the use of physiological, histological, biochemical and electrochemical techniques to study living, freshly isolated cardiac trabeculae, myocytes and mitochondria from clinical cardiac tissue. Specific projects are available in mitochondrial enzyme function, cell death, redox systems, antioxidant and free radical metabolism. Human mitochondrial genetics projects are available in collaboration with Prof. Phillip Nagley, Dept Biochemistry & Molecular Biology, Monash University.

Opioid Peptide-Mediated Protection of Human Heart Against Ischaemic Injury

Opioid proteins, produced by nerve afferents to the heart and by heart muscle itself, specifically alter cardiac excitation-contraction coupling mechanisms and intracellular signaling pathways. Opioids have been shown to afford protection against ischaemia and reperfusion injury via intracellular pathways identical to those that mediate ischaemic preconditioning. Exactly how remains undefined, particularly in human heart. We are presently examining the functional role of Proenkephalin opioid metabolites and synthetic agonists/antagonists in trabeculae and individual myocytes isolated from human hearts. Biochemical studies will characterise in human heart the specific intracellular signalling pathways that are activated after opioid receptor stimulation.

DEPARTMENT OF SURGERY – ALFRED HOSPITAL – PROPOSED PROJECTS.

LIVER METASTASES

Project 1.Mechanism of inhibition of colorectal liver metastases by the macromolecule SMANCS.

Contact Person: Dr. Darsh Kuruppu
Contact Number: 9903-0611/ 9903-0626

Liver metastases account for over 70% of deaths that result from colorectal cancer. At present all treatment options are palliative. Surgical resection can offer hope for a cure in a subgroup of patients. SMANCS is a macromolecule which targets the unique vascular architecture of tumour blood vessels which are highly permeable, hypervascular and lack a lymphatic system. Once injected the compound leaks out of the blood vessels into the tumour interstitium and is retained there to act at the tissue level.

We have shown that SMANCS inhibits liver metastases in a mouse model by altering micorvessel growth. Liver metastases will be induced by injecting colon cancer cells into the spleen during surgery in mice. The possible mechanisms of inhibition of liver metastases by SMANCS will be addressed: (i) tumour cell apoptosis by TUNEL assay, (ii) tumour cell proliferation by BrdU incorporation studies, (iii) angiogenesis by double staining for endothelial cell (EC) proliferation using CD31, (iv) VEGF receptor expression in the tumours and liver parenchyma by immunohistochemistry.

Project 2.The expression of Hepatocyte Growth Factor (HGF), Transforming Growth Factor b (TGFb), and carcinoembryonic antigen (CEA) following laser hyperthermia for colorectal liver metastases.

Contact Person: Dr. Chris Christophi /Dr. Darsh Kuruppu
Contact Number: 9903-0611/ 9903-0626

Liver metastases can be treated by interstitial laser hyperthermia. By inserting a laser fibre into the tumour centre you coagulate the tissue and cause a significant tissue destruction. Tissue necrosis has been shown to occur in a gradient like manner, following laser treatment. However, the effect of growth factors and cytokines in regulating tumour regression and regrowth are unknown. HGF is a cytokine that regulates the migration and motility of tumour cells, and contributes predominantly to the formation of hepatic metastases. TGFb has also been implicated in colon cancer cell migration. CEA is the most widely used tumour marker, for the early detection of liver metastasis, with a sensitivity of approximately 80%.

Liver metastases will be induced by intrasplenic injection of colon cancer cells during surgery in mice. Following induction the following will be considered in the present study: (i) the expression of TGFb, HGF, and CEA in the tumour and liver by immunohistochemistry to determine to level of protein expressed at the tissue level, and (ii) their regulation at the mRNA level will be determined by real time PCR.

Project 3.The mechanism of inhibition of liver metastases by Combretastatin A4 phosphate (CA4P).

Contact Person: Dr. Chris Christophi/ Dr. Darsh Kuruppu
Contact Number: 9903-0611/ 9903-0626

Vascular targeting is a new method of treating tumours. CA4P is an anti-vascular agent that shrinks solid tumours by selectively targeting and destroying tumour specific blood vessels. We have shown CA4P to cause a significant reduction in the growth of liver metastases in a murine model. Large areas of central tumour necrosis and a marked reduction in tumour blood vessels are seen.

The present study will be collectively grouped into two:

3-a. The mechanism of preventing vascular development of liver metastases by CA4P.

CA4P when given as a daily and intermittent administration of 3 doses has significantly reduced the growth of liver metastases by inhibiting blood vessel development. The anti-vascular effect of CA4P on liver metastases will be addressed as follows: (i) the expression of VEGF receptor on endothelial cells of tumours will be studied by double staining for PECAM (CD31) as an endothelial cell marker. (ii) the effect on angiogenesis in vitro by culture of endothelial cells in collagen gels.

3-b. The mechanism of inhibiting liver metastases by CA4P.

Daily and intermittent administration of CA4P results in a significant inhibition in tumour volume. The mechanism of this inhibition will be studied as follows: (i) tumour cell proliferation by Brdu incorporation studies. (ii) tumour cell apoptosis by TUNEL, (iii) the expression of the apoptosis regulatory genes Bcl-2 and Bax by immuno histochemistry,(iv) the expression of cyclooxygenase enzymes (COX 1 and COX 2) by real time-PCR.

Project 4. The effect of Troglitazone on colorectal liver metastases.

Contact Person: Dr. Darsh Kuruppu
Contact Number: 9903-0611/ 9903-0626

Troglitazone belongs to a novel class of compounds containing thiazolidinediones (TZD) which bind and activate the nuclear hormone receptor Peroxisome Proliferator Associated Receptor g (PPARg). PPARg is highly expressed in both poorly and well differentiated adenocarcinomas, in normal colonic mucosa, and in colon cancer cell lines, and have been shown to be involved in tumour progression. The potential therapeutic effect of the anti-diabetic drug Troglitazone on colorectal liver metastases will be tested in an animal model. Following the induction of liver metasatses by surgical procedure, the compound will be injected subcutaneously at the onset of tumour angiogenesis, which is day ten after tumour induction.

Liver metastases will be induced by intrasplenic injection of colon cancer cells during surgery in mice. The effect of the drug on tumour growth will by (i) stereology to assess tumour volume in comparison to the non-diseased liver volume, and (ii) standard H&E to study histopathology of treated tumours. (iii) the effect on the developing blood vessels will be studied by SEM of corrosion casts. (iv) the expression of the cyclooxygenase enzymes COX 1 & COX 2 by real time PCR.