Central obesity and breast cancer risk: a systematic review.

The specific effect of central rather than general obesity on breast cancer risk is not clear. This review examines the relationship between waist and waist-hip ratio (WHR) and risk of breast cancer in pre- and post-menopausal women using all available cohort and case-control data. The databases of the Cochrane Library, Medline, Cancer Lit and Embase were searched until October 2002. Relevant cohort and case-control studies with separate analyses in pre- and/or post-menopausal women were included. Random effects meta-analyses were carried out, subgrouped by pre- or post-menopausal status and cohort or case-control design. Sensitivity analyses were also performed. Five cohort studies with 72,1705 person years of observation (453 pre-menopausal and 2684 post-menopausal cases), and three case-control studies comprising 276 pre-menopausal cases with 758 pre-menopausal controls and 390 post-menopausal cases with 1071 post-menopausal controls were included. Pooled results from cohort studies using the most adjusted data [but without adjustment for weight or body mass index (BMI)] suggest a 39% lower risk of breast cancer in post-menopausal women with the smallest waist (compared with the largest) and a 24% lower risk in women with the smallest WHR. In pre-menopausal women, however, pooled results suggest that measurement of waist or WHR have little effect on risk of breast cancer. Adjustment for BMI abolished the relationship between waist or WHR and risk of post-menopausal breast cancer, but introduced such a relationship amongst pre-menopausal women. The relationship between a smaller measurement of waist or WHR and lower risk of post-menopausal breast cancer appears to result from the associated correlation with BMI. Amongst pre-menopausal women, central (not general) obesity may be specifically associated with an increased risk of breast cancer.

Clinical effects of human macrophage inflammatory protein-1 alpha MIP-1 alpha (LD78) administration to humans: a phase I study in cancer patients and normal healthy volunteers with the genetically engineered variant, BB-10010.

BB-10010 is a genetically engineered variant of human macrophage inflammatory protein-1 alpha (hMIP-1 alpha) with improved pharmaceutical formulation properties. Although initially described as a pro-inflammatory cytokine, it is now recognised that hMIP-1 alpha has additional effects on haemopoietic stem cell cycling and on human immunodeficiency virus uptake by macrophages. In view of the potential clinical utility of the molecule, we have embarked on a clinical trials programme to evaluate the safety, tolerability and haematological effects of BB-10010. We now report the results of two phase I clinical studies in which 49 subjects (9 patients with advanced breast carcinoma and 40 normal healthy volunteers) received escalating doses of BB-10010, from 0.1 to 300 micrograms/kg using the subcutaneous (s.c.) or intravenous route (i.v.) of administration. Treatment was associated with a dose-related increase in monocyte count which peaked at 200% of steady-state levels and was preceded by an acute, short-lived, monocytopenia, 50-100% of baseline. no measurable effects were noted on other leucocyte subsets or on circulating progenitor cell numbers. In all cases, BB-10010 was extremely well tolerated with no significant toxicity observed at any dose level and a maximum tolerated dose was not defined. Pharmacokinetic analysis revealed that serum concentrations of BB-10010 were detectable using doses of > or = 10 micrograms/kg i.v. or > or = 30 micrograms/kg s.c., and that a single s.c. injection resulted in sustained plasma levels over a 24 h period. These preliminary studies have confirmed the safety and tolerability of BB-10010 using a dose range up to 300 micrograms/kg. Further clinical studies are ongoing to determine the biological effects and to investigate the potential myeloprotective properties using a variable dose range and schedule of BB-10010 in combination with cytotoxic chemotherapy.