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MMed (Neurological Surgery), Faculty of Health Sciences, University of the Witwatersrand / The purpose of this retrospective study was to review the patient records with regard to demographics, clinical presentation, laboratory tests, histology, management and outcome of patients presenting at Chris Hani Baragwanath and Charlotte Maxeke Johannesburg Academic Hospitals with pituitary adenomas over a ten year period from 1999 to 2008. Methods: The patient records accessed included discharge summaries, admission files, laboratory results, imaging films, ophthalmology records and histology results. The information gathered was analyzed in terms of the above mentioned parameters. Results: There was a slight female preponderance at 55% vs 45% males, with a mean age of 46 years. 89% of the study population was of a Black race, reflecting the actual demographic pattern of the hospital population rather than the tumour prevalence in Blacks. Visual disturbance (94%) and headaches (75%) were very common and reflected the late presentation of our patients. Features of hypopituitarism and hyperprolactinaemia were the commonest of hormone imbalances at 33% and 39% respectively. 80% of the total study population was treated by transphenoidal surgery. The remainder was mainly prolactinomas treated with oral dopamine agonists and those who refused surgery. 2% required transcranial approach while 13% received further radiation therapy. Outcome was good with regard to improvement or resolution of headaches at 65%, while improvement in visual acuity and field defects were less satisfactory, with 51% showing improvement, and 44% remaining the same post operatively. This underlies the concern regarding late presentation of our patients with irreversible visual impairment. v 100% of prolactinomas showed improvement or normalization of the prolactin levels with bromocriptine or carbegoline, however, of those who presented with hypopituitarism 43% required post operative hormone replacement in the form of cortisol acetate or prednisone and thyroxin. Conclusion: Our patient demographics are similar to those published elsewhere, however, of great concern is the late presentation with irreversible visual impairment and hormonal imbalance. Government and community education, in a multidisciplinary approach is required to improve our situation.

Chemotherapy is often administered once every three weeks to allow repopulation of essential normal tissues such as the bone marrow. Repopulation of surviving tumour cells can also occur between courses of chemotherapy and can decrease the efficacy of anticancer treatment. This thesis aims to characterize repopulation, to study the effect of targeted cytostatic agents to inhibit repopulation, and to determine the optimal scheduling of chemotherapy and molecular targeted treatment. The distribution of proliferating and apoptotic cells in human squamous cell carcinoma (A431) xenografts was studied following chemotherapy using fluorescence immunohistochemistry. There was an initial decrease in cell proliferation and in the total functional blood vessels, and an increase in apoptosis observed following treatment with paclitaxel chemotherapy. A rebound in cell proliferation occurred approximately 12 days following treatment, which corresponded with a rebound in vascular perfusion. The effect of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, to inhibit repopulation between courses of chemotherapy was determined using EGFR-overexpressing A431 cells and xenografts. Furthermore, concurrent and sequential schedules of combined chemotherapy and molecular targeted treatment were compared. Gefitinib inhibited the repopulation of A431 cells in culture when administered sequentially between chemotherapy; sequential treatment was more efficacious than concurrent treatment probably because concomitant scheduling rendered quiescent cells less responsive to chemotherapy. However, in vivo studies using chemotherapy in combination with gefitinib or temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, showed that concurrent scheduling of combined treatment was more effective at delaying regrowth of xenografts than sequential treatment; this was likely due to dominant effects on the tumour microenvironment. The work completed in this thesis has shown that repopulation occurs in A431 xenografts following paclitaxel treatment, and these changes are associated with changes in the tumour vasculature. Repopulation of A431 cells was inhibited by gefitinib administered sequentially with paclitaxel. However, studies in mice showed better inhibitory effects when chemotherapy was given concomitantly with cytostatic agents such as gefitinib or temsirolimus. Our in vivo data highlight the importance of characterizing changes in the tumour microenvironment when determining optimal scheduling of chemotherapy and molecular targeted treatment.

Chemotherapy is often administered once every three weeks to allow repopulation of essential normal tissues such as the bone marrow. Repopulation of surviving tumour cells can also occur between courses of chemotherapy and can decrease the efficacy of anticancer treatment. This thesis aims to characterize repopulation, to study the effect of targeted cytostatic agents to inhibit repopulation, and to determine the optimal scheduling of chemotherapy and molecular targeted treatment. The distribution of proliferating and apoptotic cells in human squamous cell carcinoma (A431) xenografts was studied following chemotherapy using fluorescence immunohistochemistry. There was an initial decrease in cell proliferation and in the total functional blood vessels, and an increase in apoptosis observed following treatment with paclitaxel chemotherapy. A rebound in cell proliferation occurred approximately 12 days following treatment, which corresponded with a rebound in vascular perfusion. The effect of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, to inhibit repopulation between courses of chemotherapy was determined using EGFR-overexpressing A431 cells and xenografts. Furthermore, concurrent and sequential schedules of combined chemotherapy and molecular targeted treatment were compared. Gefitinib inhibited the repopulation of A431 cells in culture when administered sequentially between chemotherapy; sequential treatment was more efficacious than concurrent treatment probably because concomitant scheduling rendered quiescent cells less responsive to chemotherapy. However, in vivo studies using chemotherapy in combination with gefitinib or temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, showed that concurrent scheduling of combined treatment was more effective at delaying regrowth of xenografts than sequential treatment; this was likely due to dominant effects on the tumour microenvironment. The work completed in this thesis has shown that repopulation occurs in A431 xenografts following paclitaxel treatment, and these changes are associated with changes in the tumour vasculature. Repopulation of A431 cells was inhibited by gefitinib administered sequentially with paclitaxel. However, studies in mice showed better inhibitory effects when chemotherapy was given concomitantly with cytostatic agents such as gefitinib or temsirolimus. Our in vivo data highlight the importance of characterizing changes in the tumour microenvironment when determining optimal scheduling of chemotherapy and molecular targeted treatment.