Serial changes in the expression of breast cancer-related proteins in response to neoadjuvant chemotherapy.

BACKGROUND: Tumour expression of cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), erythroblastic leukaemia viral oncogene homologue-2 (ErbB2), Ki-67 and p53 in breast cancer are associated with poorer outcomes. We investigated in vivo changes of these proteins with neoadjuvant chemotherapy. PATIENTS AND METHODS: Four core biopsies were taken from 100 breast cancer patients at baseline, during and upon completion of neoadjuvant chemotherapy. Immunohistochemical expression of these proteins were evaluated and correlated with clinicopathological features, clinical response and progression-free survival (PFS). RESULTS: There was a statistically significant change from positivity to negativity in COX-2 expression with chemotherapy (P = 0.002), predominantly in clinical responders (P = 0.002). COX-2-positive tumours that remained positive had shorter PFS than those that turned negative. Estrogen receptor (ER)+ and COX-2+ tumours at baseline that remained COX-2+ fared worse than those that became COX-2 negative (PFS 27 versus 52 months, P = 0.002). No significant changes in IHC expression were observed for ER, progesterone receptor, ErbB2, EGFR, p53 or Ki67. CONCLUSIONS: Chemotherapy induced change in COX-2 expression from positivity to negativity predominantly among clinical responders and is associated with longer PFS. Interaction between COX-2 and ER was observed, suggesting that some hormone receptor-positive patients may benefit from combining COX-2 inhibition with hormonal therapy.

Pharmacokinetics and pharmacodynamics of docetaxel with or without ketoconazole modulation in chemonaive breast cancer patients.

BACKGROUND: We previously found 70 mg flat-dose docetaxel coadministered with ketoconazole to modulate CYP3A4 to be the maximum tolerated dose that resulted in comparable docetaxel area under the plasma concentration-time curve (AUC) as 75-100 mg/m² docetaxel. PATIENTS AND METHODS: We compared cycle 1 docetaxel pharmacokinetics and pharmacodynamics between ketoconazole-modulated (70 mg flat-dose docetaxel, n = 31) and conventional-dosed docetaxel (75 mg/m², n = 51) in chemonaive breast cancer patients in two sequential phase II studies. RESULTS: Ketoconazole-modulated docetaxel resulted in reduced docetaxel clearance (22.05 ± 8.29 versus 36.52 ± 13.39 l/h, P < 0.001), similar docetaxel AUC (3.93 ± 2.77 versus 3.77 ± 2.70 mg/l·h, P = 0.794) and tumor efficacy (cycle 1 responder 52% versus 55%) and less day 8 neutrophil suppression (1.24 ± 1.02 × 109/l versus 0.47 ± 0.56 × 109/l, P < 0.001), grade 4 neutropenia (32.3% versus 72.0%, P < 0.001) and febrile neutropenia (3.2 versus 23.5%, P = 0.015), compared with conventional-dosed docetaxel. Chinese had the lowest docetaxel clearance, highest AUC and most myelosuppression, followed by Malays and Indians, in response to ketoconazole-modulated docetaxel, while no significant interethnic differences were observed with conventional-dosed docetaxel. CONCLUSIONS: Ketoconazole-modulated docetaxel achieved similar docetaxel AUC and tumor efficacy but reduced neutrophil suppression and febrile neutropenia at ∼40% reduced dose, representing a feasible alternative to conventional-dosed docetaxel. Interethnic differences in CYP3A4 inhibition by ketoconazole exist and are important when evaluating the impact of concomitant medications.

Primary endocrine therapy in locally advanced breast cancers--the Nottingham experience.

INTRODUCTION: There are trials comparing different neoadjuvant chemotherapy regimens for locally advanced primary breast cancer (LAPC). Few studies have evaluated alternative therapeutic approaches towards LAPC. A previous trial from our institute in LAPC patients unselected for oestrogen receptor (ER) status, comparing primary endocrine therapy versus multimodal treatment, showed no difference in breast cancer related deaths or overall survival. We report our experience of primary endocrine therapy in ER+ LAPC. METHODS: Between 1988 and 2007, 195 ER+, non-inflammatory LAPC patients were treated with primary endocrine agents in our institute, due to patient choice, being unfit for chemotherapy, or recruitment into the above mentioned trial. All patients had disease assessable by UICC criteria. RESULTS: Median age was 69 years. The median follow-up was 61 months. 154 patients (79%) received endocrine treatment alone. 185 patients (95%) derived clinical benefit (complete response/ partial response/ stable disease) for > or =6 months from primary endocrine therapy. Overall 5-year survival was 76% and 5-year breast cancer specific survival was 86%. CONCLUSION: In selected group of ER+ LAPC patients, primary endocrine treatment achieves excellent survival outcome and is a viable alternative to other modalities of treatment.

Isolated mesenteric vascular injury following a blunt abdominal trauma--a case report.

Isolated injuries of the small bowel mesentery following blunt abdominal trauma are rare. In this report, one case of such injury with subsequent bowel infarction is described. Bowel resection with end-to-end anastomosis was done and the patient had an uneventful recovery. Other similar case reports are reviewed and compared. The main significance of this injury is the delay and difficulty in diagnosis, especially when there is minimal signs and symptoms to warrant an exploratory laparotomy. Diagnostic peritoneal lavage is a useful tool in such injuries and has produced good results.

Tibial tuberosity fractures in adolescents.

Tibial tuberosity fracture is uncommon. We reviewed five patients with the injury, presenting over a two-year period. All of them were adolescent boys who sustained the injuries during sport. They were treated with open reduction and internal fixation using cancellous screws with additional tension band wiring for comminuted fragments. Results were excellent, with complete union of fracture site, full range of movement by three to five months and no evidence of complication on follow-up for thirty months.