Elizabeth Salisbury

BACKGROUND: Breast conservative surgery (CS) with radiotherapy (RT) is the most commonly used treatment for early-stage breast carcinoma. However, there is controversy regarding the importance of the pathologic margin status on the risk of ipsilateral breast tumor recurrence (IBTR). The current study evaluated the effect of the pathologic margin status on IBTR rates in a cohort of women with lymph node-negative breast carcinoma treated with CS and RT. METHODS: Between August 1980 and December 1994, 452 women with pathologically lymph node-negative breast carcinoma were treated with CS and RT at Westmead Hospital (Westmead, Australia). Central pathology review was performed for all women. The final margins were negative for 352 women (77.9%), positive (invasive and/or in situ) for 42 women (9.3%), and indeterminate for 58 women (12.8%). Information regarding an extensive intraductal component (EIC), lymphovascular invasion, pathologic tumor size, histologic grade, and nuclear grade was available for most women. After macroscopic total excision of the tumor, all women received whole-breast irradiation (usually 45-50.4 grays [Gy]) and the majority of women also received a local tumor bed boost (range, 8-30 Gy). RESULTS: After a median follow-up of 80 months, 34 women (7.5%) developed an IBTR. The crude 5-year rates of IBTR for women with negative margins, positive margins, and indeterminate margins were 3.1%, 11.9%, and 6.9%, respectively. For women with negative margins, the 5-year and 10-year actuarial rates of freedom from IBTR were 96% and 92%, respectively, compared with 88% and 75%, respectively, for women with positive margins (P = 0.003). Univariate analysis demonstrated that the only factors associated with a significantly higher risk of IBTR were age at diagnosis (P < 0.050) and margin status (P = 0.005). Multivariate analysis showed that both age and margin status were independent predictors of IBTR. None of 24 patients with an EIC and negative margins were found to have developed an IBTR. CONCLUSIONS: The results of the current study were comparable to other published reports and supported the association of higher IBTR rates with positive or indeterminate margins compared with negative, pathologic margins. Furthermore, young age (age < 35 years at diagnosis) was associated with the highest risk of IBTR regardless of margin status.

Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case-control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.

BACKGROUND: There are no clear guidelines on renal transplantation in patients with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. METHODS: We undertook a survey of transplant centres across Europe to assess whether there was consensus about how to manage transplantation in patients with vasculitis. We then identified 107 renal allograft recipients whose primary disease was systemic vasculitis and assessed their outcome post-transplant. RESULTS: All questionnaire respondents felt that vasculitis should be in remission at transplantation, 16% believed that ANCA should be negative pre-transplant and 40% felt that one should wait >12 months after remission before transplanting. Remission was defined by all as an absence of clinical symptoms of vasculitis, but three respondents (13%) also required a negative ANCA test. Overall graft survival was 70% after 10 years (95% C.I. 58-82). A total of 30 (41% of those with known ANCA status) were ANCA-positive peri-transplantation, while 15 (14%) were transplanted <1 year post-remission. Severe vasculopathy occurred more frequently in ANCA-positive recipients (odds ratio 4.4, 95% C.I. 1.1-16.8, P < 0.05), although causation cannot be determined from this study. Vasculopathy significantly reduced 10-year graft survival to 47% (P < 0.05). However, ANCA status per se was not significantly associated with graft failure. The strongest predictor of death was transplantation <1 year post-vasculitis remission on both univariate and multivariate analysis (hazard ratio 2.3, P < 0.05). CONCLUSIONS: In conclusion, circulating ANCA at transplant was associated with the development of vascular lesions in the graft but was not significantly correlated with graft survival. Most grafts were lost due to patient death, which was more likely if transplantation occurred <12 months following induction of remission of ANCA-positive vasculitis.