The significance of BRAF V600E mutation status discordance between primary cutaneous melanoma and brain metastases: The implications for BRAF inhibitor therapy.

To compare BRAF V600E status of primary melanoma and brain metastases to assess for discordance by cross-sectional study, and to evaluate clinical implications on BRAF inhibitor therapy.Brain metastases are common in patients with advanced melanoma. Between 40% and 60% of melanomas demonstrate BRAF mutations, BRAF V600E being most common. Selective BRAF inhibitor therapy has shown improvement in outcome in patients with melanoma. It has been demonstrated that not all metastatic lesions carry the same BRAF mutation status as the primary, but the frequency in which discordance occurs remains unclear. Establishing this may have implications in the use of BRAF inhibitors in patients with melanoma brain metastases.Patients who underwent metastectomy for melanoma brain metastases were identified using our local histopathology database. A review of histology of the primary lesion and the metastasis was performed for each patient, assessing for BRAF mutation status discordance.Fourty-two patients who underwent a brain metastectomy following excision of a melanoma primary were identified over a 7-year period. Median survival was 9 months. The median Breslow thickness for the primary lesion was 3.4 mm. Six patients (14%) had discrepancy between the BRAF status of a melanoma primary and metastatic lesion. Of these 6 patients, 3 had a BRAF mutation positive primary with a BRAF mutation negative metastatic lesion, while the other 3 had a BRAF mutation negative primary with BRAF mutation positive metastasis.There is an important discordance rate in the BRAF mutation status of melanoma primaries versus brain metastases.

A comparison of intra-operative margin management techniques in breast-conserving surgery: a standardised approach reduces the likelihood of residual disease without increasing operative time.

INTRODUCTION: Breast-conserving surgery (BCS) is established as a standard treatment option for women with early-stage invasive breast cancers. Margin status predicts local disease recurrence. Up to 59 % of patients may undergo re-excision of their tumour cavity to establish clear margins. Intra-operative margin assessment may decrease re-excision rates. It is unclear if this procedure increases operative time. We compared intra-operative macroscopic assessment of margins, routine cavity shave margins and no formal intra-operative margin assessment to assess their impact on re-excision rates, residual disease burden and operative time. METHODS: Over a 42 month period, 188 patients from our retrospective breast cancer database were reviewed in our study. Of these, 68 had macroscopic margin assessment, 70 had cavity shave margins and 50 had no formal intra-operative assessment. Statistical analysis was performed as appropriate. RESULTS: Formal intra-operative margin assessment had a re-excision rate of 25 %, compared with 34 % for those without formal assessment. Formal assessment had a significantly reduced likelihood of having residual disease following the primary procedure (p = 0.02). Close margins (<2 mm) also predicted the presence of residual disease (p = 0.01). There was no difference in operative duration between the groups. CONCLUSION: Directed intra-operative margin assessment reduces residual disease burden in BCS without increasing operative duration.

Management of unusual histological types of breast cancer.

There is increased understanding of the heterogeneity of breast tumors, with greater emphasis now being placed on histological and molecular profiles and, in particular, their implications for prognosis and therapy. This review addresses breast cancers of unusual histological subtype with an approximate incidence ≤1%. Given the rarity of these tumors, the literature contains primarily case reports, small series, and population-based studies. Data are heterogeneous and almost entirely retrospective, frequently gathered over long time periods, in the context of changing pathological techniques and reporting. In addition, our understanding of the disease biology and therapeutic context has also evolved significantly over this time. There is often limited information about the specific therapies used and the rationale for choosing such an approach. Meaningful comparisons of treatment modalities are not feasible and it is not possible to define management guidelines. Instead, this review correlates the available information to give an impression of how each subgroup behaves-of the favored surgical technique, responses to therapy, and prognosis-as well as the emerging molecular data, highlighting new research areas for potential target in clinical trials. Each tumor subtype described represents a small but real cohort of patients with breast cancer, and although inferences may be made from this review, we are mindful of the paucity of data. The management of each patient must be considered in the context of their unique clinical presentation and correlated with the evidence-based principles that apply to more common breast cancer histologies.

Bacterial lipoprotein delays apoptosis in human neutrophils through inhibition of caspase-3 activity: regulatory roles for CD14 and TLR-2.

The human sepsis syndrome resulting from bacterial infection continues to account for a significant proportion of hospital mortality. Neutralizing strategies aimed at individual bacterial wall products (such as LPS) have enjoyed limited success in this arena. Bacterial lipoprotein (BLP) is a major constituent of the wall of diverse bacterial forms and profoundly influences cellular function in vivo and in vitro, and has been implicated in the etiology of human sepsis. Delayed polymorphonuclear cell (PMN) apoptosis is a characteristic feature of human sepsis arising from Gram-negative or Gram-positive bacterial infection. Bacterial wall product ligation and subsequent receptor-mediated events upstream of caspase inhibition in neutrophils remain incompletely understood. BLP has been shown to exert its cellular effects primarily through TLR-2, and it is now widely accepted that lateral associations with the TLRs represent the means by which CD14 communicates intracellular messages. In this study, we demonstrate that BLP inhibits neutrophil mitochondrial membrane depolarization with a subsequent reduction in caspase-3 processing, ultimately leading to a significant delay in PMN apoptosis. Pretreatment of PMNs with an anti-TLR-2 mAb or anti-CD14 mAb prevented BLP from delaying PMN apoptosis to such a marked degree. Combination blockade using both mAbs completely prevented the effects of BLP (in 1 and 10 ng/ml concentrations) on PMN apoptosis. At higher concentrations of BLP, the antiapoptotic effects were observed, but were not as pronounced. Our findings therefore provide the first evidence of a crucial role for both CD14 and TLR-2 in delayed PMN apoptosis arising from bacterial infection.