Preoperative AUS-FNAC avoided unnecessary SNB in 28.5 per cent of node-positive patients and in 7.8 per cent of patients overall.

Background: Non-palpable breast cancers require localization-guided surgery and axillary staging using sentinel lymph node biopsy (SLNB). This study investigated the novel technique of magnetic-guided lesion localization and concurrent SLNB, which avoids the need for wire-guided localization and radioisotopes.Methods: An ultrasound-guided intratumoral injection of magnetic tracer (0⋅5 ml) was performed in a protocol-driven predefined minimum of ten patients with palpable breast cancer to assess the ability of the magnetic tracer safely to localize the tumour at the site of injection and concurrently drain to the lymphatics. Once successful lesion localization had been confirmed (peak magnetometer count retained at the centre of the tumour), the technique was undertaken in a further 20 patients with non-palpable breast cancers awaiting wide local excision and SLNB. All patients underwent SLNB with both the magnetic and standard dual (radioisotope and Patent Blue V dye) techniques.Results: Thirty-two patients were recruited, of whom 12 (1 with bilateral disease) presented with palpable and 20 with non-palpable breast cancer. Peak magnetometer counts were retained at the tumour centre in all palpable (13) and non-palpable (20) breast cancers. Re-excisions for involved margins were necessary in two patients with non-palpable breast cancers. The sentinel lymph node identification rates were 28 of 33 procedures for the magnetic technique alone, 32 of 33 for the magnetic technique combined with blue dye, and 32 of 33 for the standard dual technique.Conclusion: Magnetic lesion localization is feasible, with intratumoral magnetic tracer injection combined with a periareolar injection of blue dye for subsequent SNLB. * Other members of the MagSNOLL Trialists Group are co-authors of this study and can be found under the heading Collaborators

Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer.Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrineresistant and endocrine-na€ ve breast tumors.Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo. In primary culture, TRAIL significantly depleted CSCs in 85% endocrineresistant, compared with 8% endocrine-na€ ve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP.Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential.

Assessment of immune responses in lymph nodes (LNs) is routine in animals, but rarely done in humans. We have applied minimally invasive ultrasound-guided fine-needle aspiration of the LN to a before-and-after study of the immune response to intradermally delivered Ag in healthy volunteers (n = 25). By comparison with PBMCs from the same individual, LN cells (LNCs) were characterized by reduced numbers of effector memory cells, especially CD8+ TEMRA cells (3.37 ± 1.93 in LNCs versus 22.53 ± 7.65 in PBMCs; p = 0.01) and a marked increased in CD69 expression (27.67 ± 7.49 versus 3.49 ± 2.62%, LNCs and PBMCs, respectively; p < 0.0001). At baseline, there was a striking absence of IFN-γ ELISPOT responses to recall Ags (purified protein derivative, Tetanus toxoid, or flu/EBV/CMV viral mix) in LN, despite strong responses in the peripheral blood. However, 48 h after tuberculin purified protein derivative administration in the ipsilateral forearm resulting in a positive skin reaction, a clear increase in IFN-γ ELISPOT counts was seen in the draining LN but not in PBMCs. This response was lost by 5 d. These data suggest that the low levels of effector memory cells in the LN may explain the low background of baseline ELISPOT responses in LNs as compared with PBMCs, and the appearance of a response after 48 h is likely to represent migration of effector memory cells from the skin to the LN. Hence, it appears that the combination of intradermal Ag administration and draining LN sampling can be used as a sensitive method to probe the effector memory T cell repertoire in the skin.

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