Functional polymorphisms in the BRCA1 promoter influence transcription and are associated with decreased risk for breast cancer in Chinese women.

BACKGROUND: The BRCA1 gene is an important breast-cancer susceptibility gene. Promoter polymorphisms can alter the binding affinity of transcription factors, changing transcriptional activity and may affect susceptibility to disease. METHODS AND RESULTS: Using direct sequencing of the BRCA1 promoter region, we identified four polymorphisms c.-2804T-->C (rs799908:T-->C), c.-2265C-->T (rs11655505:C-->T), c.-2004A-->G (rs799906:A-->G) and c.-1896(ACA)(1)-->(ACA)(2) (rs8176071:(ACA)(1)-->(ACA)(2)) present in Hong Kong Chinese. Each polymorphism was studied independently and in combination by functional assays. Although all four variants significantly altered promoter activity, the c.-2265T allele had stronger binding than the C allele, and the most common mutant haplotype, which contains the c.-2265T allele, increased promoter activity by 70%. Risk association first tested in Hong Kong Chinese women with breast cancer and age-matched controls and replicated in a large population-based study of Shanghai Chinese, together totalling >3000 participants, showed that carriers of the c.-2265T allele had a reduced risk for breast cancer (combined odd ratio (OR) = 0.80, 95% CI 0.69 to 0.93; p = 0.003) which was more evident among women aged >or=45 years at first diagnosis of breast cancer and without a family history of breast cancer (combined OR = 0.75, 95% CI 0.61 to 0.91; p = 0.004). The most common haplotype containing the c.-2265T allele also showed significant risk association for women aged >or=45 years without a family history of breast cancer (OR = 0.64, 95% CI 0.46 to 0.89; p = 0.008). CONCLUSION: This comprehensive study of BRCA1 promoter polymorphisms found four variants that altered promoter activity and with the most significant contribution from c.-2265C-->T, which could affect susceptibility to breast cancer in the Chinese population. Its significance in other populations remains to be investigated.

Efficacy of combination chemotherapy with irinotecan (CPT-11) plus capecitabine in patients with metastatic or advanced colorectal carcinoma--a dual-centre phase II study: the MAC-6.

AIMS: A phase II trial was initiated to evaluate the efficacy and toxicity of combination chemotherapy with irinotecan (CPT-11) plus capecitabine in patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients received a combination of CPT-11 plus capecitabine. CPT-11 was infused intravenously on day 1 every 2 weeks and oral capecitabine was taken twice daily for 5 days every 7 days. Efficacy and toxicities were assessed. RESULTS: Between 2004 and 2005, 43 patients were enrolled. The overall response rate was 51.35%. With a median follow-up of 13 months, the median time to progression was 10 months (95% confidence interval 7.6-12.3 months); the median survival was 15 months (95% confidence interval 13.9-16.9 months). The most common grade 3 haematological and non-haematological toxicities were neutropenia (5.4%), diarrhoea (8.1%) and hand-foot syndrome (2.7%). CONCLUSIONS: CPT-11 plus capecitabine with a 14 day cycle showed a comparable response with international phase II data with a 3 weekly regimen and was well tolerated as a first-line palliative chemotherapy in patients with metastatic colorectal cancer. The data should be interpreted with caution due to the limited sample size and should be further confirmed by a phase III randomised trial.

Radiation dose measurements for personnel performing 90Y-ibritumomab tiuxetan administration: a comparison between two injection methods for dose reduction.

The purpose of this study was to directly measure, using thermoluminescent dosimeters, the radiation doses received by radiation team members performing (90)Y-ibritumomab tiuxetan administration. The occupational doses associated with two injection methods for patient administration - an automatic syringe driver and an injection box - were compared. The associated risks, namely cancer induction and hereditary effect, were also estimated from the results and compared with risk factors recommended by the International Commission on Radiological Protection publication 103. The results showed that the doses received by the index and thumb of the right hand and the index finger of the left hand of the radiation oncologist were significantly reduced by using the injection box method. The difference in the dose received by the medical physicist using the two methods was not statistically significant. It was observed that three pairs of latex gloves could further reduce the dose to the hands. The radiological risks of cancer induction and hereditary effect were negligible: of the order of 10(-6) and 10(-7) per (90)Y-ibritumomab tiuxetan administration, respectively, for both methods. However, the results of our study also showed that it would be possible in a busy centre for pregnant women to receive a dose of (90)Y-ibritumomab tiuxetan that exceeds the recommended annual dose limit for the surface of the abdomen.

Hypersensitivity reactions to oxaliplatin: experience in a single institute.

BACKGROUND: A rising incidence of hypersensitivity reactions to oxaliplatin has been observed as a result of increasing clinical use. Epidemiological and clinical features of these reactions are reviewed. PATIENTS AND METHODS: Records of patients treated with a modified FOLFOX regimen from March 1999 to March 2004 were reviewed. RESULTS: One hundred and eighty patients were identified. Twenty-seven patients (15%) have been labelled as allergic to oxaliplatin, the proportion being higher among those receiving oxaliplatin in palliative second-line or above settings (19.6%) than in adjuvant or palliative first-line settings (10.2%). Some 2.2% of them developed grade 3-4 reactions. The reactions occurred after a mean (+/-SD) of 8.5 (+/-4.2) cycles (range 1-18). Among the 14 patients re-exposed to oxaliplatin, four (28.6%) developed hypersensitivity reaction, in two of whom (14.3%) reactions were grade 3-4 in severity. CONCLUSIONS: The risk of developing hypersensitivity reactions in patients receiving oxaliplatin should not be underestimated. The risk of developing potentially life-threatening hypersensitivity reactions should be explained to patients in the context of the potential benefits of such therapy. Patients receiving oxaliplatin infusion should be closely monitored. Once a patient develops hypersensitivity reaction to oxaliplatin, re-exposure should only be considered if the reaction is mild and there has been documented clinical benefit from previous doses of this agent.